1
|
Diebold M, Gauthier PT, Mayer KA, Mackova M, Hinze C, Chang J, Patel UD, Schütz E, Jilma B, Schrezenmeier E, Budde K, Böhmig GA, Halloran PF. Effect of felzartamab on the molecular phenotype of antibody-mediated rejection in kidney transplant biopsies. Nat Med 2025; 31:1668-1676. [PMID: 40301559 DOI: 10.1038/s41591-025-03653-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 03/10/2025] [Indexed: 05/01/2025]
Abstract
A recent randomized controlled trial demonstrated that treatment with anti-CD38 monoclonal antibody felzartamab suppressed antibody-mediated rejection (ABMR) in kidney transplant patients but with recurrence after treatment in some patients. Here we examined the molecular effects of 6 months of felzartamab treatment on biopsies from the trial using genome-wide microarray analysis, comparing pretreatment, end-of-treatment (week 24) and posttreatment (week 52) biopsies from ten patients treated with felzartamab and ten patients in the placebo group. Felzartamab reduced molecular ABMR activity scores in all nine patients with baseline ABMR activity, selectively suppressing interferon gamma-inducible and natural killer cell transcripts, with minimal effect on ABMR stage-related endothelial transcripts. Suppression was often incomplete when ABMR activity was intense, and molecular recurrence was nearly universal by week 52. However, we also found that felzartamab had parenchymal benefits at week 52, slowing the trajectories of molecular injury scores beyond the treatment period, suggesting that suppression of ABMR activity could potentially slow future progression to kidney failure. These data provide preliminary molecular insights into the effects of CD38-directed treatment for ABMR, which have the potential to inform future therapeutic strategies.
Collapse
Affiliation(s)
- Matthias Diebold
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Patrick T Gauthier
- Alberta Transplant Applied Genomics Centre, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Katharina A Mayer
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Martina Mackova
- Alberta Transplant Applied Genomics Centre, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Christian Hinze
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Jessica Chang
- Alberta Transplant Applied Genomics Centre, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Uptal D Patel
- Human Immunology Biosciences, South San Francisco, CA, USA
| | | | - Bernd Jilma
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Eva Schrezenmeier
- Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Klemens Budde
- Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Georg A Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
| | - Philip F Halloran
- Alberta Transplant Applied Genomics Centre, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
| |
Collapse
|
2
|
Hillenbrand CA, Akbari Bani D, Follonier O, Kaur A, Weissbach FH, Wernli M, Wilhelm M, Leuzinger K, Binet I, Bochud PY, Golshayan D, Hirzel C, Manuel O, Mueller NJ, Schaub S, Schachtner T, Van Delden C, Hirsch HH. BK polyomavirus serotype-specific antibody responses in blood donors and kidney transplant recipients with and without new-onset BK polyomavirus-DNAemia: A Swiss Transplant Cohort Study. Am J Transplant 2025; 25:985-1001. [PMID: 39580075 DOI: 10.1016/j.ajt.2024.11.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 11/03/2024] [Accepted: 11/17/2024] [Indexed: 11/25/2024]
Abstract
BK polyomavirus (BKPyV) causes premature renal failure in 10% to 30% of kidney transplant recipients (KTRs). Current guidelines recommend screening for new-onset BKPyV-DNAemia/nephropathy and reducing immunosuppression to regain BKPyV-specific immune control. Because BKPyV encompasses 4 major genotype (gt)-encoded serotypes (st1,-2,-3,-4), st-specific antibodies may inform the risk and course of BKPyV-DNAemia/nephropathy. Using BKPyV st-virus-like particle (VLP) enzyme-linked immunosorbent assay, we analyzed plasma from 399 blood donors (BDs) and 428 KTRs (134 KTR-cases with BKPyV-DNAemia, 294 KTR-controls). BDs were anti-BKPyV-VLP immunoglobulin G-seropositive in 85% compared to 93% of KTRs at the timepoint at transplantation (T0) (P < .001). Anti-st1 was predominant in both groups followed by anti-st4, anti-st2, and anti-st3. Antibody levels and quadruple sero-reactivity at T0 were higher in KTR-controls than in KTR-cases (P = .026) or in BDs (P < .001). In KTR-cases, anti-st increased posttransplant (P < .0001) and independently of ongoing or cleared BKPyV-DNAemia. However, anti-st levels were significantly higher at T0 in KTR-cases able to clear at timepoint 6-month posttransplant or timepoint 12-month posttransplant. In 34 KTR-cases with deep genome sequencing, BKPyV-gtI was predominant, and anti-st1 and st1-neutralizing antibodies were significantly lower at T0 than in KTR-controls. Thus, BKPyV st-specific antibody levels at transplantation might reflect gt/st-BKPyV-specific immunity clearing or preventing BKPyV-DNAemia in KTR-cases or KTR-controls, respectively. Accordingly, active or passive immunization may be most efficient pretransplant or early posttransplant.
Collapse
Affiliation(s)
- Caroline A Hillenbrand
- Transplantation & Clinical Virology, Department of Biomedicine, Medical Faculty, University of Basel, Basel, Switzerland
| | - Dorssa Akbari Bani
- Transplantation & Clinical Virology, Department of Biomedicine, Medical Faculty, University of Basel, Basel, Switzerland
| | - Océane Follonier
- Transplantation & Clinical Virology, Department of Biomedicine, Medical Faculty, University of Basel, Basel, Switzerland; Biozentrum, University of Basel, Basel, Switzerland; SIB Swiss Institute of Bioinformatics, Basel, Switzerland
| | - Amandeep Kaur
- Transplantation & Clinical Virology, Department of Biomedicine, Medical Faculty, University of Basel, Basel, Switzerland
| | - Fabian H Weissbach
- Transplantation & Clinical Virology, Department of Biomedicine, Medical Faculty, University of Basel, Basel, Switzerland
| | - Marion Wernli
- Transplantation & Clinical Virology, Department of Biomedicine, Medical Faculty, University of Basel, Basel, Switzerland
| | - Maud Wilhelm
- Transplantation & Clinical Virology, Department of Biomedicine, Medical Faculty, University of Basel, Basel, Switzerland
| | | | - Isabelle Binet
- Nephrology & Transplantation Medicine, Kantonsspital St Gallen, St Gallen, Switzerland
| | - Pierre-Yves Bochud
- Transplantation Center, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Dela Golshayan
- Transplantation Center, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Cédric Hirzel
- Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Oriol Manuel
- Infectious Diseases Service, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Nicolas J Mueller
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland
| | - Stefan Schaub
- Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Thomas Schachtner
- Department of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Christian Van Delden
- Transplant Infectious Diseases Unit, University Hospitals Geneva, Geneva, Switzerland
| | - Hans H Hirsch
- Transplantation & Clinical Virology, Department of Biomedicine, Medical Faculty, University of Basel, Basel, Switzerland.
| |
Collapse
|
3
|
Parisudha RD, Ghinorawa T, Hardjo IS. The neutrophil-to-lymphocyte ratio for acute allograft rejection and delayed graft function prediction in kidney transplant recipients: a meta-analysis. CLINICAL TRANSPLANTATION AND RESEARCH 2025; 39:36-45. [PMID: 39905720 PMCID: PMC11959434 DOI: 10.4285/ctr.24.0041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 10/27/2024] [Accepted: 11/20/2024] [Indexed: 02/06/2025]
Abstract
Background The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been the focus of several observational studies investigating their roles in acute allograft rejection (AR) and delayed graft function (DGF) among kidney transplant (KT) recipients. This meta-analysis evaluated the impact of the NLR and PLR on the incidence of AR and DGF in KT recipients. Methods We searched PubMed, MEDLINE and Science Direct from their inception through October 2023. Random effects models were used. To investigate potential sources of heterogeneity, we performed subgroup and meta-regression analyses. The Comprehensive Meta-Analysis ver. 3 software package was used. Results Seven studies (247 KT recipients with AR or DGF and 475 controls) were analyzed. Our pooled analysis showed a significantly higher NLR in KT recipients with AR (weighted mean difference [WMD], 2.292; 95% confidence interval [CI], 1.449-3.135; P<0.001) than in controls. The preoperative NLR was insignificantly higher in patients with DGF (WMD, 0.871; 95% CI, -0.103 to 1.846; P=0.08). The PLR was insignificantly higher in KT recipients with AR than in controls (WMD, 32.125; 95% CI, -19.978 to 84.228; P=0.227). The PLR was not significantly different between KT recipients with DGF and controls. Region, publication year, sample size, donor type, biopsy type, AR type and Newcastle-Ottawa Scale score did not affect the outcomes of the meta-analysis. Meta-regression showed that publication year and donor type might be sources of heterogeneity. Conclusions This study revealed a significantly higher NLR in patients with AR. This suggests that NLR may be utilized as a noninvasive marker for AR in KT recipients.
Collapse
Affiliation(s)
- Ryuu Damara Parisudha
- Division of Urology, Department of Surgery, Dr. Sardjito General Hospital, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Tanaya Ghinorawa
- Division of Urology, Department of Surgery, Dr. Sardjito General Hospital, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Indrawarman Soero Hardjo
- Division of Urology, Department of Surgery, Dr. Sardjito General Hospital, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
| |
Collapse
|
4
|
Li MH, Zhou GX, Lan P, Li YX, Zhang X, Kuang PD, Zhang Y, Wang Y, Zhang MY, Ding XM, Xue WJ, Zheng J. Characteristics of mismatched eplets affecting de novo donor-specific antibody production and antibody-mediated rejection after kidney transplantation. BMC Nephrol 2025; 26:73. [PMID: 39939899 PMCID: PMC11823255 DOI: 10.1186/s12882-025-04016-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 02/07/2025] [Indexed: 02/14/2025] Open
Abstract
De novo donor-specific antibody (dnDSA) generation is the most important marker of antibody-mediated rejection (AMR). However, not all dnDSAs induce AMR. The effects of mismatched eplets on dnDSA production and the occurrence AMR remain controversial. We analyzed 64 cases of dnDSA positive kidney transplantation that occurred between 2017 and 2021 at our center to reveal the relationships between mismatched eplet and dnDSA generation and the characteristics of antibody-specific and AMR associated mismatched eplets. Among the 64 dnDSA positive cases, 114 dnDSA were produced. Both the average production time and medium fluorescence index (MFI) value of human leukocyte antigen (HLA) II dnDSA were higher than those of HLA I (time, p = 0.024; MFI, p = 0.032). More HLA II dnDSAs were generated in the AMR group (p < 0.001). The frequency of HLA II dnDSAs was higher in cases of longer antibody generation time, higher MFI, and AMR( p < 0.05). The differences in the numbers of mismatched HLA I and II eplets were statistically significant between the rejection and no rejection groups (p = 0.030). dnDSA-specific and AMR associated mismatched eplets were strongly correlated (p < 0.0001). The dominant mismatched eplets included 41 T, 163R, 25Q, 78 V, 47QL and 55PP. dnDSA-specific eplets accounted for majority of the total mismatched eplets of donors and recipients. The amino acids with increased proportions of dnDSA-specific eplets were mainly non-polarity amino acids (p < 0.0001). AMR-associated mismatched eplets accounted for majority of the dnDSA-specific mismatched eplets. Arginine, histidine, glutamine, glutamate, lysine and asparagine levels increased significantly in the rejection group compared with the no rejection group (p < 0.001). The amino acids with increased proportions of AMR-associated mismatched eplets were all polar (p < 0.0001) and mainly positively charged (p < 0.0001). The polarity and charge of amino acids in mismatched eplets may be the key factors affecting the occurrence of AMR after kidney transplantation.
Collapse
Affiliation(s)
- Mei-He Li
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, China
| | - Gu-Xiang Zhou
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, China
| | - Ping Lan
- Department of Nephrology, Hospital of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, China
| | - Yi-Xuan Li
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, China
| | - Xuan Zhang
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, China
| | - Pei-Dan Kuang
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, China
| | - Ying Zhang
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, China
| | - Ying Wang
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, China
| | - Min-Yue Zhang
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, China
| | - Xiao-Ming Ding
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, China
| | - Wu-Jun Xue
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, China.
| | - Jin Zheng
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, China.
| |
Collapse
|
5
|
Lim Z, Taverniti A, Downing J, Le C, Lopez P, Larkins N, Chan D, Chakera A, D'Orsogna L, Krishnan A, Chau M, Ooi E, Boroumand F, Teixeira-Pinto A, Gately R, Sharma A, Wong G, Lim WH. Clinical Applicability of 2-Field High-Resolution and Extended HLA-Allele Typing in Deceased Donor Kidney Allocation. HLA 2024; 104:e15784. [PMID: 39637319 DOI: 10.1111/tan.15784] [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: 08/26/2024] [Revised: 11/07/2024] [Accepted: 11/18/2024] [Indexed: 12/07/2024]
Abstract
HLA-compatibility remains an important triage test for deceased donor kidney allocation. Low-intermediate resolution donor HLA-typing is typically available at allocation, but its accuracy in assigning pre-transplant donor-specific anti-HLA antibody (DSA) and HLA mismatches compared to 2-field high-resolution typing is poorly characterised. Consecutive deceased donor/recipient pairs from a single centre between 2016 and 2020 were included. Majority of donor typing at HLA-ABDRB1 loci were performed at low-intermediate resolution, with 2-field high-resolution NGS typing across extended loci performed by NGS-technique post-transplantation. We compared the two typing methods for (1) accuracy of pre-transplant DSA assignment; (2) misassignment of HLA-antigen/allele mismatches and performance of each model for acute rejection and (3) proportion of recipients who developed de novo DSA (dnDSA) when matched at antigen but mismatched at allele level. Of 179 deceased donor/recipient pairs, 157 donors had low-intermediate resolution typing and 22 with high-resolution ONT typing. Sixty-two recipients (35%) had potential pre-transplant DSAs, with incorrect assignment of allele-specific Class I and II actual DSAs in 31% and 53% of cases, respectively. NGS typing identified 59 (33%) additional HLA-DRB1 allele mismatches. ONT typing accurately assigned pre-transplant DSAs and allele mismatches in all cases. Seven (4%) recipients with antigen/allele level discordance developed dnDSAs, majority HLA-DQ antibodies. Two-field high-resolution donor HLA typing may provide a more accurate transplant immunological risk assessment and identify those at risk of developing dnDSA to matched HLA antigen.
Collapse
Affiliation(s)
- Zhan Lim
- Department of Renal Medicine and Transplantation, Sir Charles Gairdner Hospital, Perth, Australia
| | - Anne Taverniti
- Centre for Kidney Research, The Children's Hospital at Westmead, Sydney, Australia
| | - Jonathan Downing
- PathWest Laboratory Medicine, Fiona Stanley Hospital, Perth, Australia
| | - Cindy Le
- PathWest Laboratory Medicine, Fiona Stanley Hospital, Perth, Australia
| | - Pedro Lopez
- Grupo de Pesquisa em Exercício para Populações Clínicas (GPCLIN), Universidade de Caxias do Sul, Caxias do Sul, Rio Grande do Sul, Brazil
- Programa de Pós-Graduação em Ciências da Saúde, Universidade de Caxias do Sul, Caxias do Sul, Rio Grande do Sul, Brazil
- Pleural Medicine Unit, Institute for Respiratory Health, Perth, Western Australia, Australia
| | - Nicholas Larkins
- Medical School, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Australia
- Department of Nephrology, Perth Children's Hospital, Perth, Australia
| | - Doris Chan
- Department of Renal Medicine and Transplantation, Sir Charles Gairdner Hospital, Perth, Australia
| | - Aron Chakera
- Department of Renal Medicine and Transplantation, Sir Charles Gairdner Hospital, Perth, Australia
- Medical School, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Australia
- Harry Perkins Institute of Medical Research, Perth, Australia
| | - Lloyd D'Orsogna
- PathWest Laboratory Medicine, Fiona Stanley Hospital, Perth, Australia
- Medical School, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Australia
| | - Anoushka Krishnan
- Department of Renal Medicine and Transplantation, Royal Perth Hospital, Perth, Australia
| | - Matthew Chau
- Department of Renal Medicine and Transplantation, Sir Charles Gairdner Hospital, Perth, Australia
| | - Esther Ooi
- Medical School, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Australia
| | - Farzaneh Boroumand
- Sydney School of Public Health, University of Sydney, Sydney, Australia
- School of Mathematical and Physical Sciences, Macquarie University, Australia
| | - Armando Teixeira-Pinto
- Centre for Kidney Research, The Children's Hospital at Westmead, Sydney, Australia
- Sydney School of Public Health, University of Sydney, Sydney, Australia
| | - Ryan Gately
- Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, Australia
| | - Ankit Sharma
- Department of Renal Medicine and Transplantation, Westmead Hospital, Sydney, Australia
| | - Germaine Wong
- Centre for Kidney Research, The Children's Hospital at Westmead, Sydney, Australia
- Sydney School of Public Health, University of Sydney, Sydney, Australia
- Department of Renal Medicine and Transplantation, Westmead Hospital, Sydney, Australia
| | - Wai H Lim
- Department of Renal Medicine and Transplantation, Sir Charles Gairdner Hospital, Perth, Australia
- Medical School, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Australia
- School of Medical and Health Sciences, Edith Cowan University, Perth, Australia
| |
Collapse
|
6
|
Tharmaraj D, Mulley WR, Dendle C. Current and emerging tools for simultaneous assessment of infection and rejection risk in transplantation. Front Immunol 2024; 15:1490472. [PMID: 39660122 PMCID: PMC11628869 DOI: 10.3389/fimmu.2024.1490472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 10/14/2024] [Indexed: 12/12/2024] Open
Abstract
Infection and rejection are major complications that impact transplant longevity and recipient survival. Balancing their risks is a significant challenge for clinicians. Current strategies aimed at interrogating the degree of immune deficiency or activation and their attendant risks of infection and rejection are imprecise. These include immune (cell counts, function and subsets, immunoglobulin levels) and non-immune (drug levels, viral loads) markers. The shared risk factors between infection and rejection and the bidirectional and intricate relationship between both entities further complicate transplant recipient care and decision-making. Understanding the dynamic changes in the underlying net state of immunity and the overall risk of both complications in parallel is key to optimizing outcomes. The allograft biopsy is the current gold standard for the diagnosis of rejection but is associated with inherent risks that warrant careful consideration. Several biomarkers, in particular, donor derived cell-free-DNA and urinary chemokines (CXCL9 and CXCL10), show significant promise in improving subclinical and clinical rejection risk prediction, which may reduce the need for allograft biopsies in some situations. Integrating conventional and emerging risk assessment tools can help stratify the individual's short- and longer-term infection and rejection risks in parallel. Individuals identified as having a low risk of rejection may tolerate immunosuppression wean to reduce medication-related toxicity. Serial monitoring following immunosuppression reduction or escalation with minimally invasive tools can help mitigate infection and rejection risks and allow for timely diagnosis and treatment of these complications, ultimately improving allograft and patient outcomes.
Collapse
Affiliation(s)
- Dhakshayini Tharmaraj
- Department of Nephrology, Monash Health, Clayton, VIC, Australia
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, VIC, Australia
| | - William R. Mulley
- Department of Nephrology, Monash Health, Clayton, VIC, Australia
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, VIC, Australia
| | - Claire Dendle
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, VIC, Australia
- Monash Infectious Diseases, Monash Health, Clayton, VIC, Australia
| |
Collapse
|
7
|
Kotsifa E, Mavroeidis VK. Present and Future Applications of Artificial Intelligence in Kidney Transplantation. J Clin Med 2024; 13:5939. [PMID: 39407999 PMCID: PMC11478249 DOI: 10.3390/jcm13195939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 09/27/2024] [Accepted: 10/02/2024] [Indexed: 10/15/2024] Open
Abstract
Artificial intelligence (AI) has a wide and increasing range of applications across various sectors. In medicine, AI has already made an impact in numerous fields, rapidly transforming healthcare delivery through its growing applications in diagnosis, treatment and overall patient care. Equally, AI is swiftly and essentially transforming the landscape of kidney transplantation (KT), offering innovative solutions for longstanding problems that have eluded resolution through traditional approaches outside its spectrum. The purpose of this review is to explore the present and future applications of artificial intelligence in KT, with a focus on pre-transplant evaluation, surgical assistance, outcomes and post-transplant care. We discuss its great potential and the inevitable limitations that accompany these technologies. We conclude that by fostering collaboration between AI technologies and medical practitioners, we can pave the way for a future where advanced, personalised care becomes the standard in KT and beyond.
Collapse
Affiliation(s)
- Evgenia Kotsifa
- Second Propaedeutic Department of Surgery, National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, Agiou Thoma 17, 157 72 Athens, Greece
| | - Vasileios K. Mavroeidis
- Department of Transplant Surgery, North Bristol NHS Trust, Southmead Hospital, Bristol BS10 5NB, UK
| |
Collapse
|
8
|
Baert L, Mahmudul HM, Stegall M, Joo H, Oh S. B Cell-mediated Immune Regulation and the Quest for Transplantation Tolerance. Transplantation 2024; 108:2021-2033. [PMID: 38389135 DOI: 10.1097/tp.0000000000004948] [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: 02/24/2024]
Abstract
Pathophysiologic function of B cells in graft rejection has been well recognized in transplantation. B cells promote alloantigen-specific T-cell response and secrete antibodies that can cause antibody-mediated graft failures and rejections. Therefore, strategies targeting B cells, for example, B-cell depletion, have been used for the prevention of both acute and chronic rejections. Interestingly, however, recent mounting evidence indicates that subsets of B cells yet to be further identified can display potent immune regulatory functions, and they contribute to transplantation tolerance and operational tolerance in both experimental and clinical settings, respectively. In this review, we integrate currently available information on B-cell subsets, including T-cell Ig domain and mucin domain 1-positive transitional and T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domain-positive memory B cells, displaying immune regulatory functions, with a focus on transplantation tolerance, by analyzing their mechanisms of action. In addition, we will discuss potential T-cell Ig domain and mucin domain 1-positive and T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domain-positive B cell-based strategies for the enhancement of operational tolerance in transplantation patients.
Collapse
Affiliation(s)
- Laurie Baert
- Department of Immunology, Mayo Clinic, Scottsdale, AZ
| | | | - Mark Stegall
- Department of Surgery, William J. von Liebig Transplant Center, Mayo Clinic, Rochester, MN
| | - HyeMee Joo
- Department of Immunology, Mayo Clinic, Scottsdale, AZ
| | - SangKon Oh
- Department of Immunology, Mayo Clinic, Scottsdale, AZ
| |
Collapse
|
9
|
Bromberg JS, Bunnapradist S, Samaniego-Picota M, Anand S, Stites E, Gauthier P, Demko Z, Prewett A, Armer-Cabral M, Marshall K, Kaur N, Bloom MS, Tabriziani H, Bhorade S, Cooper M. Elevation of Donor-derived Cell-free DNA Before Biopsy-proven Rejection in Kidney Transplant. Transplantation 2024; 108:1994-2004. [PMID: 38595232 PMCID: PMC11335081 DOI: 10.1097/tp.0000000000005007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 02/02/2024] [Accepted: 02/11/2024] [Indexed: 04/11/2024]
Abstract
BACKGROUND Standard-of-care biomarkers for renal allograft rejection are lagging indicators, signaling existing organ injury. This precludes early intervention, when immunological cascades leading to rejection are most susceptible. Donor-derived cell-free DNA (dd-cfDNA) shows promise as an early indicator of rejection, allowing earlier and possibly more effective treatment. This analysis was designed to assess this promise using real-world dd-cfDNA testing evidence. METHODS This retrospective analysis of the prospective, observational ProActive registry study (NCT04091984) assessed dd-cfDNA and serum creatinine levels before biopsy in 424 patients with ≥1 dd-cfDNA test (n = 1013) in the 6 mo before biopsy. RESULTS Of 4667 enrolled patients, 1631 patients had ≥18 mo of follow-up data, of which 424 had a biopsy and were included in this analysis. Twenty-six biopsies showed antibody-mediated rejection (ABMR), 62 showed T cell-mediated rejection, and 336 showed nonrejection; each from a unique patient. dd-cfDNA fractions were significantly elevated 5 mo before ABMR biopsies, and 2 mo before T cell-mediated rejection biopsies, compared with nonrejection biopsies. In contrast, serum creatinine did not discriminate between rejection and nonrejection in advance, or concurrent with biopsy. Among patients with nonrejection biopsies, estimated glomerular filtration rate was significantly lower in cases with ≥2 increased dd-cfDNA results (≥1%), compared with those with 0 or 1 increased dd-cfDNA result. CONCLUSIONS These data indicate that dd-cfDNA is an early indicator of biopsy-proven rejection, especially ABMR, suggesting a greater role for dd-cfDNA in surveillance to identify patients at high risk of ongoing or future rejection, thus requiring closer monitoring, biopsy, or other management changes.
Collapse
Affiliation(s)
- Jonathan S. Bromberg
- Department of Surgery, University of Maryland, School of Medicine, Baltimore, MD
| | | | | | | | - Erik Stites
- School of Medicine, University of Colorado Anschutz Medical Campus, Denver, CO
| | | | | | | | | | | | | | | | | | | | - Matthew Cooper
- Department of Surgery, Medical College of Wisconsin, Milwaukee, WI
| |
Collapse
|
10
|
Giarraputo A, Goutaudier V, Robin B, Angelini A, Sablik M, Aubert O, Rosales IA, Smith RN, Roufosse C, Adam B, Haas M, Colvin RB, Lefaucheur C, Mengel M, Zielinski D, Loupy A. Relevance of the Banff Human Organ Transplant Consensus Gene Panel for Detecting Antibody and T-Cell-Mediated Rejection of Kidney Allografts. Kidney Int Rep 2024; 9:2290-2294. [PMID: 39081730 PMCID: PMC11284421 DOI: 10.1016/j.ekir.2024.04.054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 04/23/2024] [Accepted: 04/25/2024] [Indexed: 08/02/2024] Open
Affiliation(s)
- Alessia Giarraputo
- Université de Paris Cité, INSERM U970, PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France
- Cardiovascular Pathology, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Padua, Italy
| | - Valentin Goutaudier
- Université de Paris Cité, INSERM U970, PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France
- Kidney Transplant Department, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Blaise Robin
- Université de Paris Cité, INSERM U970, PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France
| | - Annalisa Angelini
- Cardiovascular Pathology, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Padua, Italy
| | - Marta Sablik
- Université de Paris Cité, INSERM U970, PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France
| | - Olivier Aubert
- Université de Paris Cité, INSERM U970, PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France
- Kidney Transplant Department, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Ivy A. Rosales
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Rex N. Smith
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Candice Roufosse
- Department of Immunology and Inflammation, Imperial College, Center for Inflammatory Disease, London, UK
| | - Benjamin Adam
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
| | - Mark Haas
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Robert B. Colvin
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Carmen Lefaucheur
- Université de Paris Cité, INSERM U970, PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France
- Kidney Transplant Department, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Michael Mengel
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
| | - Dina Zielinski
- Université de Paris Cité, INSERM U970, PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France
| | - Alexandre Loupy
- Université de Paris Cité, INSERM U970, PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France
- Kidney Transplant Department, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| |
Collapse
|
11
|
Madill-Thomsen K, Halloran P. Precision diagnostics in transplanted organs using microarray-assessed gene expression: concepts and technical methods of the Molecular Microscope® Diagnostic System (MMDx). Clin Sci (Lond) 2024; 138:663-685. [PMID: 38819301 PMCID: PMC11147747 DOI: 10.1042/cs20220530] [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: 02/22/2024] [Revised: 04/26/2024] [Accepted: 05/02/2024] [Indexed: 06/01/2024]
Abstract
There is a major unmet need for improved accuracy and precision in the assessment of transplant rejection and tissue injury. Diagnoses relying on histologic and visual assessments demonstrate significant variation between expert observers (as represented by low kappa values) and have limited ability to assess many biological processes that produce little histologic changes, for example, acute injury. Consensus rules and guidelines for histologic diagnosis are useful but may have errors. Risks of over- or under-treatment can be serious: many therapies for transplant rejection or primary diseases are expensive and carry risk for significant adverse effects. Improved diagnostic methods could alleviate healthcare costs by reducing treatment errors, increase treatment efficacy, and serve as useful endpoints for clinical trials of new agents that can improve outcomes. Molecular diagnostic assessments using microarrays combined with machine learning algorithms for interpretation have shown promise for increasing diagnostic precision via probabilistic assessments, recalibrating standard of care diagnostic methods, clarifying ambiguous cases, and identifying potentially missed cases of rejection. This review describes the development and application of the Molecular Microscope® Diagnostic System (MMDx), and discusses the history and reasoning behind many common methods, statistical practices, and computational decisions employed to ensure that MMDx scores are as accurate and precise as possible. MMDx provides insights on disease processes and highly reproducible results from a comparatively small amount of tissue and constitutes a general approach that is useful in many areas of medicine, including kidney, heart, lung, and liver transplants, with the possibility of extrapolating lessons for understanding native organ disease states.
Collapse
Affiliation(s)
- Katelynn S. Madill-Thomsen
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
- Alberta Transplant Applied Genomics Center, University of Alberta, Edmonton, AB, Canada
| | - Philip F. Halloran
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
- Alberta Transplant Applied Genomics Center, University of Alberta, Edmonton, AB, Canada
| |
Collapse
|
12
|
Zhang D, Zhang H, Lu J, Hu X. Multiomics Data Reveal the Important Role of ANXA2R in T Cell-mediated Rejection After Renal Transplantation. Transplantation 2024; 108:430-444. [PMID: 37677931 PMCID: PMC10798590 DOI: 10.1097/tp.0000000000004754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 06/14/2023] [Accepted: 06/29/2023] [Indexed: 09/09/2023]
Abstract
BACKGROUND T cell-mediated rejection (TCMR) is a severe issue after renal transplantation, but research on its T cell-receptor (TCR) repertoire is lacking. This study intended to elucidate the TCR repertoire landscape in TCMR and hence identify novel potential targets. METHODS A total of 12 multiomics data sets were collected. The TRUST4 algorithm was used to construct and analyze the TCR repertoire in renal allografts with TCMR and stable renal function. Then, novel TCR-related key genes were identified through various criteria and literature research. In bulk transcriptome, cell line, single-cell transcriptome data sets, multiple immune cell infiltration algorithms, and gene set enrichment analysis were used to analyze potential mechanisms of the identified key gene. Twenty-three pathological sections were collected for immunofluorescence staining in the clinical cohort. Finally, the diagnostic and prognostic values of ANXA2R were evaluated in multiple renal transplant data sets. RESULTS Allografts with TCMR showed significantly increased clonotype and specific clonal expansion. ANXA2R was found to be a novel key gene for TCMR and showed strong positive connections with the TCR complex and lymphocyte cells, especially CD8 + T cells. Immunofluorescence staining confirmed the existence of ANXA2R + CD8 + T cells, with their percentage significantly elevated in TCMR compared with stable renal function. Finally, both mRNA and protein levels of ANXA2R showed promising diagnostic and prognostic value for renal transplant recipients. CONCLUSIONS ANXA2R , identified as a novel TCR-related gene, had critical roles in clinicopathology, diagnosis, and prognosis in renal transplantation, which offered promising potential therapeutic targets.
Collapse
Affiliation(s)
- Di Zhang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
- Institute of Urology, Capital Medical University, Beijing, China
| | - He Zhang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
- Institute of Urology, Capital Medical University, Beijing, China
| | - Jun Lu
- Department of Pathology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Xiaopeng Hu
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
- Institute of Urology, Capital Medical University, Beijing, China
| |
Collapse
|
13
|
Gao S, Gong H, Li M, Lan P, Zhang M, Kuang P, Zhang Y, Hu X, Ding C, Li Y, Ding X, Xue W, Zheng J. HLA B eplet mismatches in the context of delayed graft function and low tacrolimus trough levels are risk factors influencing the generation of de novo donor-specific antibodies and acute rejection in the early stage after kidney transplantation. Transpl Immunol 2023; 81:101955. [PMID: 37931666 DOI: 10.1016/j.trim.2023.101955] [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: 05/05/2023] [Revised: 10/30/2023] [Accepted: 11/01/2023] [Indexed: 11/08/2023]
Abstract
BACKGROUND De novo donor-specific antibody (dnDSA) generation and acute rejection (AR) are the main factors affecting long-term graft survival. This study aims to investigate human leukocyte antigen (HLA) eplet mismatching (MM), delayed graft function (DGF), and tacrolimus (TAC) trough levels on the occurrence of dnDSA and AR in the early stages after kidney transplantation (KT). METHODS This retrospective study included 526 cases of deceased donation KT. The effects of DGF, HLA eplet MM, and TAC trough levels on dnDSA and AR occurrence were analyzed with logistic regression analysis. RESULTS Multivariate logistic regression analysis showed the independent risk factor of dnDSA generation was HLA B eplet MM (OR: 1.201, 95% CI: 1.007-1.431, P = 0.041). The independent risk factors of AR occurrence include DGF (OR: 4.045, 95% CI: 1.047-15.626, P = 0.043), HLA B eplet MM (OR: 1.090, 95% CI: 1.000-1.187, P = 0.050), and TAC trough levels at 12 months (OR: 0.750, 95% CI: 565-0.997, P = 0.048). HLA B eplet MM combined with DGF and TAC trough levels at 12 months increased the predictive value of dnDSA (AUC 0.735) and AR (AUC 0.730) occurrence. HLA B eplet MM > 9 and TAC trough levels below 5.95 ng/mL at 12 months could increase the risk of early AR occurrence. CONCLUSIONS HLA B eplet MM, DGF, and TAC trough levels at 12 months after KT could affect the occurrence of dnDSA and AR in the early stage of KT.
Collapse
Affiliation(s)
- Shan Gao
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China
| | - Huilin Gong
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China
| | - Meihe Li
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China
| | - Ping Lan
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China
| | - Minyue Zhang
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China
| | - Peidan Kuang
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China
| | - Ying Zhang
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China
| | - Xiaojun Hu
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China
| | - Chenguang Ding
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China
| | - Yang Li
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China
| | - Xiaoming Ding
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China
| | - Wujun Xue
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China.
| | - Jin Zheng
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China.
| |
Collapse
|
14
|
Bansal S, Arjuna A, Franz B, Guerrero-Alba A, Canez J, Fleming T, Rahman M, Hachem R, Mohanakumar T. Extracellular vesicles: a potential new player in antibody-mediated rejection in lung allograft recipients. FRONTIERS IN TRANSPLANTATION 2023; 2:1248987. [PMID: 38993876 PMCID: PMC11235353 DOI: 10.3389/frtra.2023.1248987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 08/22/2023] [Indexed: 07/13/2024]
Abstract
Identification of recipients with pre-existing antibodies and cross-matching of recipient sera with donor lymphocytes have reduced the incidence of antibody-mediated rejection (AMR) after human lung transplantation. However, AMR is still common and requires not only immediate intervention but also has long-term consequences including an increased risk of chronic lung allograft dysfunction (CLAD). The mechanisms resulting in AMR remain largely unknown due to the variation in clinical and histopathological features among lung transplant recipients; however, several reports have demonstrated a strong association between the development of antibodies against mismatched donor human leucocyte antigens [donor-specific antibodies (DSAs)] and AMR. In addition, the development of antibodies against lung self-antigens (K alpha1 tubulin and collagen V) also plays a vital role in AMR pathogenesis, either alone or in combination with DSAs. In the current article, we will review the existing literature regarding the association of DSAs with AMR, along with clinical diagnostic features and current treatment options for AMR. We will also discuss the role of extracellular vesicles (EVs) in the immune-related pathogenesis of AMR, which can lead to CLAD.
Collapse
Affiliation(s)
- Sandhya Bansal
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
| | - Ashwini Arjuna
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
| | - Brian Franz
- HLA Laboratory, Vitalant, Phoenix, AZ, United States
| | - Alexa Guerrero-Alba
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
| | - Jesse Canez
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
| | - Timothy Fleming
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
| | - Mohammad Rahman
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
| | - Ramsey Hachem
- Department of Surgery, Washington University, St. Louis, MO, United States
| | - T. Mohanakumar
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
| |
Collapse
|
15
|
Schnider TW, Nieuwenhuijs-Moeke GJ, Beck-Schimmer B, Hemmerling TM. Pro-Con Debate: Should All General Anesthesia Be Done Using Target-Controlled Propofol Infusion Guided by Objective Monitoring of Depth of Anesthesia? Anesth Analg 2023; 137:565-575. [PMID: 37590801 DOI: 10.1213/ane.0000000000006293] [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: 08/19/2023]
Abstract
In this Pro-Con commentary article, we discuss whether all general anesthesia should be done using target-controlled propofol anesthesia guided by monitoring of depth of anesthesia. This is an ongoing debate since more than 25 years, representing a scientific, cultural as well as geographical divide in the anesthesia community. The Pro side argues that total intravenous anesthesia causes less postoperative nausea and higher patient satisfaction than anesthesia using volatile anesthetics. Target-controlled infusion (TCI) of anesthetic agents allows for better titration of intravenous anesthesia using pharmacokinetic models. Processed EEG monitors, such as bispectral index monitoring, allows for better assessing the effect of TCI anesthesia than solely assessment of clinical parameters, such as ECG or blood pressure. The combination of TCI propofol and objective depth of anesthesia monitoring allows creating a pharmacokinetic-pharmacodynamic profile for each patient. Finally, anesthesia using volatile anesthetics poses health risks for healthcare professionals and contributes to greenhouse effect. The Con side argues that for procedures accompanied with ischemia and reperfusion injury of an organ or tissue and for patients suffering from a severe inflammation' the use of volatile anesthetics might well have its advantages above propofol. In times of sudden shortage of drugs, volatile anesthetics can overcome the restriction in the operating theater or even on the intensive care unit, which is another advantage. Volatile anesthetics can be used for induction of anesthesia when IV access is impossible, end-tidal measurements of volatile anesthetic concentration allows confirmation that patients receive anesthetics. Taking environmental considerations into account, both propofol and volatile anesthetics bear certain harm to the environment, be it as waste product or as greenhouse gases. The authors therefore suggest to carefully considering advantages and disadvantages for each patient in its according environment. A well-balanced choice based on the available literature is recommended. The authors recommend careful consideration of advantages and disadvantages of each technique when tailoring an anesthetic to meet patient needs. Where appropriate, anesthesia providers are encouraged to account for unique features of anesthetic drug behavior, patient-reported and observed postoperative outcomes, and economic and environmental considerations when choosing any of the 2 described techniques.
Collapse
Affiliation(s)
- Thomas W Schnider
- From the Department for Anesthesiology, Intensive, Rescue and Pain medicine, Kantonsspital St Gallen, St Gallen, Switzerland
| | - Gertrude J Nieuwenhuijs-Moeke
- Department of Anesthesiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
| | | | | |
Collapse
|
16
|
Yoshida M, Yamanaga S, Hiraki M, Nishiyama H, Fukuoka S, Uchida A, Yoshimaru K, Hidaka Y, Yamasaki T, Yoshimura H, Toyoda M, Ito T. A Case of Chronic Active Antibody-Mediated Rejection Caused by a Pre-Existing Anti-DQ Donor-Specific Antibody in a Systemic Lupus Erythematosus Recipient Without History of Sensitization: A Case Report. Transplant Proc 2023:S0041-1345(23)00139-2. [PMID: 37055294 DOI: 10.1016/j.transproceed.2023.03.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 03/13/2023] [Indexed: 04/15/2023]
Abstract
BACKGROUND Systemic lupus erythematosus (SLE) is reported to produce anti-HLA antibodies. We report a case of chronic active antibody-mediated rejection caused by pre-existing donor-specific antibody (DSA) in a patient with SLE without a history of sensitization. CASE REPORT The case was a 29-year-old man with end-stage renal disease due to lupus nephritis. Cross-match with the mother was negative, but low titer anti-DQ DSA was detected, although he had no prior history of sensitization. After desensitization with rituximab and mycophenolate mofetil, a living donor kidney transplant was undergone, and his early postoperative period was uneventful. However, his renal function started to decline at 2 years post-transplant. Although there was no rejection on the biopsy at 2.5 years post-transplant, his renal function continued to decline after that. At 7 years, he had failed his graft due to chronic active antibody-mediated rejection. Retrospective analysis of human leukocyte antigen antibody tests revealed that anti-DQ DSA had disappeared at 1 year post-transplant, but high titer DSA was detected again with complement-binding capacity at 2 years and after that. CONCLUSION Careful monitoring might be warranted in an SLE patient with pre-existing DSA, even though the titer was low and without any prior histories of sensitization events.
Collapse
Affiliation(s)
- Masaya Yoshida
- Department of Clinical Laboratory, Japanese Red Cross Kumamoto Hospital, Kumamoto, Kumamoto, Japan.
| | - Shigeyoshi Yamanaga
- Department of Surgery, Japanese Red Cross Kumamoto Hospital, Kumamoto, Kumamoto, Japan
| | - Mikihisa Hiraki
- Department of Clinical Laboratory, Japanese Red Cross Kumamoto Hospital, Kumamoto, Kumamoto, Japan
| | - Hinoka Nishiyama
- Department of Clinical Laboratory, Japanese Red Cross Kumamoto Hospital, Kumamoto, Kumamoto, Japan
| | - Seiya Fukuoka
- Department of Clinical Laboratory, Japanese Red Cross Kumamoto Hospital, Kumamoto, Kumamoto, Japan
| | - Arisa Uchida
- Department of Clinical Laboratory, Japanese Red Cross Kumamoto Hospital, Kumamoto, Kumamoto, Japan
| | - Kiho Yoshimaru
- Department of Clinical Laboratory, Japanese Red Cross Kumamoto Hospital, Kumamoto, Kumamoto, Japan
| | - Yuji Hidaka
- Department of Surgery, Japanese Red Cross Kumamoto Hospital, Kumamoto, Kumamoto, Japan
| | - Takashi Yamasaki
- Department of Clinical Laboratory, Japanese Red Cross Kumamoto Hospital, Kumamoto, Kumamoto, Japan
| | - Hiromi Yoshimura
- Department of Clinical Laboratory, Japanese Red Cross Kumamoto Hospital, Kumamoto, Kumamoto, Japan
| | - Mariko Toyoda
- Department of Nephrology, Japanese Red Cross Kumamoto Hospital, Kumamoto, Kumamoto, Japan
| | - Teruhiko Ito
- Department of Clinical Laboratory, Japanese Red Cross Kumamoto Hospital, Kumamoto, Kumamoto, Japan
| |
Collapse
|
17
|
Hurdogan O, Karakus F, Dirim AB, Aksu B, Saygili S, Turkmen A, Yilmaz A, Canpolat N, Solakoglu S, Kilicaslan I, Ozluk Y. Spatial Distribution of Macrophage Subtypes Among Rejection Subtypes in Renal Transplant Biopsies by Dual Immunohistochemistry. Appl Immunohistochem Mol Morphol 2023; 31:224-231. [PMID: 36812388 DOI: 10.1097/pai.0000000000001109] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 01/19/2023] [Indexed: 02/24/2023]
Abstract
We performed dual immunohistochemistry for CD163/CD34 and CD68/CD34 in 108 renal transplant indication biopsies to investigate the presence and distribution of macrophages in various renal compartments. All Banff scores and diagnoses were revised according to the Banff 2019 classification. CD163 and CD68 positive cell counts (CD163pos and CD68pos) were evaluated in the interstitium, glomerular mesangium, and, within glomerular and peritubular capillaries. The diagnosis was antibody-mediated rejection (ABMR) in 38 (35.2%), T-cell mediated rejection (TCMR) in 24 (22.2%), mixed rejection in 30 (27.8%), and no rejection in 16 (14.8%). Banff lesion scores t , i , and ti were correlated with both CD163 and CD68 interstitial inflammation scores ( r > 0.30; P < 0.05). Glomerular total CD163pos was correlated to Banff lesion scores g and cg ( r > 0.30; P < 0.05). Glomerular total, mesangial, and intracapillary CD68pos were correlated with g ( r > 0.30; P < 0.05). Both glomerular total and peritubular capillary CD68pos were correlated with peritubular capillaritis ( r > 0.30; P < 0.05). Glomerular CD163pos were significantly higher in ABMR compared with no rejection, in mixed rejection compared with no rejection and TCMR. CD163pos in peritubular capillaries was significantly higher in mixed rejection compared with no rejection. Glomerular CD68pos was significantly higher in ABMR compared with no rejection. CD68pos per peritubular capillary was higher in mixed rejection, ABMR, and TCMR compared with no rejection. In conclusion, compared with CD68 positive macrophages, localization of CD163 positive macrophages in various renal compartments seems to be different among rejection subtypes and their glomerular infiltration seems to be more specific for the presence of ABMR component.
Collapse
Affiliation(s)
| | | | | | - Bagdagul Aksu
- Department of Pediatrics, Subdivision of Pediatric Nephrology, Istanbul University
| | - Seha Saygili
- Department of Pediatrics, Subdivision of Pediatric Nephrology, Istanbul University Cerrahpasa, Istanbul, Turkey
| | - Aydin Turkmen
- Department of Internal Medicine, Subdivision of Nephrology
| | - Alev Yilmaz
- Department of Pediatrics, Subdivision of Pediatric Nephrology, Istanbul University
| | - Nur Canpolat
- Department of Pediatrics, Subdivision of Pediatric Nephrology, Istanbul University Cerrahpasa, Istanbul, Turkey
| | | | | | | |
Collapse
|
18
|
Johnson AC, Silva JAF, Kim SC, Larsen CP. Progress in kidney transplantation: The role for systems immunology. Front Med (Lausanne) 2022; 9:1070385. [PMID: 36590970 PMCID: PMC9800623 DOI: 10.3389/fmed.2022.1070385] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 11/16/2022] [Indexed: 12/23/2022] Open
Abstract
The development of systems biology represents an immense breakthrough in our ability to perform translational research and deliver personalized and precision medicine. A multidisciplinary approach in combination with use of novel techniques allows for the extraction and analysis of vast quantities of data even from the volume and source limited samples that can be obtained from human subjects. Continued advances in microfluidics, scalability and affordability of sequencing technologies, and development of data analysis tools have made the application of a multi-omics, or systems, approach more accessible for use outside of specialized centers. The study of alloimmune and protective immune responses after solid organ transplant offers innumerable opportunities for a multi-omics approach, however, transplant immunology labs are only just beginning to adopt the systems methodology. In this review, we focus on advances in biological techniques and how they are improving our understanding of the immune system and its interactions, highlighting potential applications in transplant immunology. First, we describe the techniques that are available, with emphasis on major advances that allow for increased scalability. Then, we review initial applications in the field of transplantation with a focus on topics that are nearing clinical integration. Finally, we examine major barriers to adapting these methods and discuss potential future developments.
Collapse
|
19
|
Varnell CD, Rich KL, Modi AC, Hooper DK, Eckman MH. A Cost-effectiveness Analysis of Adherence Promotion Strategies to Improve Rejection Rates in Adolescent Kidney Transplant Recipients. Am J Kidney Dis 2022; 80:330-340. [PMID: 35227823 PMCID: PMC9398956 DOI: 10.1053/j.ajkd.2021.12.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 12/16/2021] [Indexed: 01/27/2023]
Abstract
RATIONALE & OBJECTIVE Nonadherence to medical regimens increases the risk of graft loss among adolescent and young adult recipients of kidney transplants. Interventions that improve adherence may decrease rejection rates, but their perceived costs are a barrier to clinical implementation. We developed a model to assess the cost-effectiveness of an adherence promotion strategy, the Medication Adherence Promotion System (MAPS). STUDY DESIGN Simulation-based. Data sources included published articles indexed in Medline or referenced in bibliographies of relevant English-language articles. Data on costs and outcomes were taken from a single clinical center. SETTING & POPULATION US adolescent patients after their first kidney transplant. INTERVENTION Usual posttransplant care versus usual care plus MAPS. OUTCOME Effectiveness measured in quality-adjusted life years (QALYs) and costs measured in 2020 US dollars. MODEL, PERSPECTIVE, & TIMEFRAME Markov state transition decision model. We used a health care system perspective with a lifelong time horizon. RESULTS In the base-case analysis, MAPS was more effective and less costly than usual care. MAPS cost $9,106 per patient less than usual care and resulted in a gain of 0.32 QALYs. In probabilistic sensitivity analyses, MAPS was cost saving 100% of the time. Extending results to a program level with 100 patients, any adherence promotion intervention similar in effectiveness to MAPS would cost less than $50,000/QALY if the start-up costs were <$2.5 million and annual costs <$188,000. Strategies with costs similar to MAPS that reduce the risk of rejection by as little as 3% would also have similar cost-effectiveness. LIMITATIONS Estimates of components and costs for MAPS were based on a single center. CONCLUSIONS Adherence promotion strategies with costs similar to MAPS can be cost-effective as long as they reduce rejection rates by at least 3%. This model can be applied to study the cost-effectiveness of adherence promotion strategies with varying costs and outcomes.
Collapse
Affiliation(s)
- Charles D Varnell
- Division of Nephrology & Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; James M. Anderson Center for Health Systems Excellence, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio.
| | - Kristin L Rich
- Division of Behavioral and Clinical Psychology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio
| | - Avani C Modi
- Division of Behavioral and Clinical Psychology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio
| | - David K Hooper
- Division of Nephrology & Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; James M. Anderson Center for Health Systems Excellence, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio
| | - Mark H Eckman
- Division of General Internal Medicine and the Center for Clinical Effectiveness, University of Cincinnati, Cincinnati, Ohio.
| |
Collapse
|
20
|
Ponticelli C, Citterio F. Non-Immunologic Causes of Late Death-Censored Kidney Graft Failure: A Personalized Approach. J Pers Med 2022; 12:1271. [PMID: 36013220 PMCID: PMC9410103 DOI: 10.3390/jpm12081271] [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: 04/01/2022] [Revised: 07/28/2022] [Accepted: 07/28/2022] [Indexed: 11/29/2022] Open
Abstract
Despite continuous advances in surgical and immunosuppressive protocols, the long-term survival of transplanted kidneys is still far from being satisfactory. Antibody-mediated rejection, recurrent autoimmune diseases, and death with functioning graft are the most frequent causes of late-kidney allograft failure. However, in addition to these complications, a number of other non-immunologic events may impair the function of transplanted kidneys and directly or indirectly lead to their failure. In this narrative review, we will list and discuss the most important nonimmune causes of late death-censored kidney graft failure, including quality of the donated kidney, adherence to prescriptions, drug toxicities, arterial hypertension, dyslipidemia, new onset diabetes mellitus, hyperuricemia, and lifestyle of the renal transplant recipient. For each of these risk factors, we will report the etiopathogenesis and the potential consequences on graft function, keeping in mind that in many cases, two or more risk factors may negatively interact together.
Collapse
Affiliation(s)
| | - Franco Citterio
- Renal Transplant Unit, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Università Cattolica Sacro Cuore, 00168 Roma, Italy
| |
Collapse
|
21
|
Proteomics for Biomarker Discovery for Diagnosis and Prognosis of Kidney Transplantation Rejection. Proteomes 2022; 10:proteomes10030024. [PMID: 35893765 PMCID: PMC9326686 DOI: 10.3390/proteomes10030024] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 06/27/2022] [Accepted: 06/28/2022] [Indexed: 02/07/2023] Open
Abstract
Renal transplantation is currently the treatment of choice for end-stage kidney disease, enabling a quality of life superior to dialysis. Despite this, all transplanted patients are at risk of allograft rejection processes. The gold-standard diagnosis of graft rejection, based on histological analysis of kidney biopsy, is prone to sampling errors and carries high costs and risks associated with such invasive procedures. Furthermore, the routine clinical monitoring, based on urine volume, proteinuria, and serum creatinine, usually only detects alterations after graft histologic damage and does not differentiate between the diverse etiologies. Therefore, there is an urgent need for new biomarkers enabling to predict, with high sensitivity and specificity, the rejection processes and the underlying mechanisms obtained from minimally invasive procedures to be implemented in routine clinical surveillance. These new biomarkers should also detect the rejection processes as early as possible, ideally before the 78 clinical outputs, while enabling balanced immunotherapy in order to minimize rejections and reducing the high toxicities associated with these drugs. Proteomics of biofluids, collected through non-invasive or minimally invasive analysis, e.g., blood or urine, present inherent characteristics that may provide biomarker candidates. The current manuscript reviews biofluids proteomics toward biomarkers discovery that specifically identify subclinical, acute, and chronic immune rejection processes while allowing for the discrimination between cell-mediated or antibody-mediated processes. In time, these biomarkers will lead to patient risk stratification, monitoring, and personalized and more efficient immunotherapies toward higher graft survival and patient quality of life.
Collapse
|
22
|
Krstic N, Multani K, Wishart DS, Blydt-Hansen T, Cohen Freue GV. The impact of methodological choices when developing predictive models using urinary metabolite data. Stat Med 2022; 41:3511-3526. [PMID: 35567357 DOI: 10.1002/sim.9431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 04/15/2022] [Accepted: 04/26/2022] [Indexed: 11/08/2022]
Abstract
The continuous evolution of metabolomics over the past two decades has stimulated the search for metabolic biomarkers of many diseases. Metabolomic data measured from urinary samples can provide rich information of the biological events triggered by organ rejection in pediatric kidney transplant recipients. With additional validation, metabolic markers can be used to build clinically useful diagnostic tools. However, there are many methodological steps ranging from data processing to modeling that can influence the performance of the resulting metabolomic classifiers. In this study we focus on the comparison of various classification methods that can handle the complex structure of metabolomic data, including regularized classifiers, partial least squares discriminant analysis, and nonlinear classification models. We also examine the effectiveness of a physiological normalization technique widely used in the clinical and biochemical literature but not extensively analyzed and compared in urine metabolomic studies. While the main objective of this work is to interrogate metabolomic data of pediatric kidney transplant recipients to improve the diagnosis of T cell-mediated rejection (TCMR), we also analyze three independent datasets from other disease conditions to investigate the generalizability of our findings.
Collapse
Affiliation(s)
- Nikolas Krstic
- Department of Statistics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Kevin Multani
- Department of Statistics, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Physics, Stanford University, Stanford, California, USA
| | - David S Wishart
- Departments of Computing Science and Biological Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Tom Blydt-Hansen
- Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Gabriela V Cohen Freue
- Department of Statistics, University of British Columbia, Vancouver, British Columbia, Canada
| |
Collapse
|
23
|
Vonbrunn E, Angeloni M, Büttner-Herold M, Müller-Deile J, Heller K, Bleich E, Söllner S, Amann K, Ferrazzi F, Daniel C. Can Gene Expression Analysis in Zero-Time Biopsies Predict Kidney Transplant Rejection? Front Med (Lausanne) 2022; 9:793744. [PMID: 35433772 PMCID: PMC9005644 DOI: 10.3389/fmed.2022.793744] [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: 10/12/2021] [Accepted: 02/14/2022] [Indexed: 11/13/2022] Open
Abstract
Zero-time biopsies are taken to determine the quality of the donor organ at the time of transplantation. Histological analyses alone have so far not been able to identify parameters that allow the prediction of subsequent rejection episodes or graft survival. This study investigated whether gene expression analyses of zero-time biopsies might support this prediction. Using a well-characterized cohort of 26 zero-time biopsies from renal transplant patients that include 4 living donor (LD) and 22 deceased donor (DD) biopsies that later developed no rejection (Ctrl, n = 7), delayed graft function (DGF, n = 4), cellular (T-cell mediated rejection; TCMR, n = 8), or antibody-mediated rejection (ABMR, n = 7), we analyzed gene expression profiles for different types of subsequent renal transplant complication. To this end, RNA was isolated from formalin-fixed, paraffin-embedded (FFPE) sections and gene expression profiles were quantified. Results were correlated with transplant data and B-cell, and plasma cell infiltration was assessed by immunofluorescence microscopy. Both principal component analysis and clustering analysis of gene expression data revealed marked separation between LDs and DDs. Differential expression analysis identified 185 significant differentially expressed genes (adjusted p < 0.05). The expression of 68% of these genes significantly correlated with cold ischemia time (CIT). Furthermore, immunoglobulins were differentially expressed in zero-time biopsies from transplants later developing rejection (TCMR + ABMR) compared to non-rejected (Ctrl + DGF) transplants. In addition, immunoglobulin expression did not correlate with CIT but was increased in transplants with previous acute renal failure (ARF). In conclusion, gene expression profiles in zero-time biopsies derived from LDs are markedly different from those of DDs. Pre-transplant ARF increased immunoglobulin expression, which might be involved in triggering later rejection events. However, these findings must be confirmed in larger cohorts and the role of early immunoglobulin upregulation in zero-biopsies needs further clarification.
Collapse
Affiliation(s)
- Eva Vonbrunn
- Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg and University Hospital, Erlangen, Germany
| | - Miriam Angeloni
- Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg and University Hospital, Erlangen, Germany
| | - Maike Büttner-Herold
- Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg and University Hospital, Erlangen, Germany
| | - Janina Müller-Deile
- Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nuremberg and University Hospital, Erlangen, Germany
| | - Katharina Heller
- Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nuremberg and University Hospital, Erlangen, Germany
| | - Erik Bleich
- Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg and University Hospital, Erlangen, Germany
| | - Stefan Söllner
- Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg and University Hospital, Erlangen, Germany
| | - Kerstin Amann
- Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg and University Hospital, Erlangen, Germany
| | - Fulvia Ferrazzi
- Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg and University Hospital, Erlangen, Germany.,Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg and University Hospital, Erlangen, Germany
| | - Christoph Daniel
- Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg and University Hospital, Erlangen, Germany
| |
Collapse
|
24
|
Madill-Thomsen KS, Abouljoud M, Bhati C, Ciszek M, Durlik M, Feng S, Foroncewicz B, Francis I, Grąt M, Jurczyk K, Klintmalm G, Krasnodębski M, McCaughan G, Miquel R, Montano-Loza A, Moonka D, Mucha K, Myślak M, Pączek L, Perkowska-Ptasińska A, Piecha G, Reichman T, Sanchez-Fueyo A, Tronina O, Wawrzynowicz-Syczewska M, Więcek A, Zieniewicz K, Halloran PF. The molecular phenotypes of injury, steatohepatitis, and fibrosis in liver transplant biopsies in the INTERLIVER study. Am J Transplant 2022; 22:909-926. [PMID: 34780106 DOI: 10.1111/ajt.16890] [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: 06/01/2021] [Revised: 10/19/2021] [Accepted: 10/21/2021] [Indexed: 01/25/2023]
Abstract
To extend previous molecular analyses of rejection in liver transplant biopsies in the INTERLIVER study (ClinicalTrials.gov #NCT03193151), the present study aimed to define the gene expression selective for parenchymal injury, fibrosis, and steatohepatitis. We analyzed genome-wide microarray measurements from 337 liver transplant biopsies from 13 centers. We examined expression of genes previously annotated as increased in injury and fibrosis using principal component analysis (PCA). PC1 reflected parenchymal injury and related inflammation in the early posttransplant period, slowly regressing over many months. PC2 separated early injury from late fibrosis. Positive PC3 identified a distinct mildly inflamed state correlating with histologic steatohepatitis. Injury PCs correlated with liver function and histologic abnormalities. A classifier trained on histologic steatohepatitis predicted histologic steatohepatitis with cross-validated AUC = 0.83, and was associated with pathways reflecting metabolic abnormalities distinct from fibrosis. PC2 predicted histologic fibrosis (AUC = 0.80), as did a molecular fibrosis classifier (AUC = 0.74). The fibrosis classifier correlated with matrix remodeling pathways with minimal overlap with those selective for steatohepatitis, although some biopsies had both. Genome-wide assessment of liver transplant biopsies can not only detect molecular changes induced by rejection but also those correlating with parenchymal injury, steatohepatitis, and fibrosis, offering potential insights into disease mechanisms for primary diseases.
Collapse
Affiliation(s)
| | | | - Chandra Bhati
- Virginia Commonwealth University, Richmond, Virginia, USA
| | - Michał Ciszek
- Department of Immunology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Magdalena Durlik
- Department of Transplant Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Sandy Feng
- University of California San Francisco, San Francisco, California, USA
| | - Bartosz Foroncewicz
- Department of Immunology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | | | - Michał Grąt
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Krzysztof Jurczyk
- Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, Szczecin, Poland
| | | | - Maciej Krasnodębski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Geoff McCaughan
- Centenary Research Institute, Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, The University of Sydney, Sydney, New South Wales, Australia
| | | | | | | | - Krzysztof Mucha
- Department of Immunology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | - Marek Myślak
- Department of Clinical Interventions, Department of Nephrology and Kidney Transplantation SPWSZ Hospital, Pomeranian Medical University, Szczecin, Poland
| | - Leszek Pączek
- Department of Immunology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | | | - Grzegorz Piecha
- Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia, Katowice, Poland
| | | | | | - Olga Tronina
- Department of Transplant Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Marta Wawrzynowicz-Syczewska
- Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, Szczecin, Poland
| | - Andrzej Więcek
- Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia, Katowice, Poland
| | - Krzysztof Zieniewicz
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | | |
Collapse
|
25
|
Yatim KM, Azzi JR. Novel Biomarkers in Kidney Transplantation. Semin Nephrol 2022; 42:2-13. [DOI: 10.1016/j.semnephrol.2022.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
|
26
|
Catar RA, Wischnewski O, Chen L, Heidecke H, Rutz C, Schülein R, Dragun D, Philippe A, Kusch A. Non-HLA antibodies targeting angiotensin II type 1 receptors and endothelin-1 type A receptors impair endothelial repair via a β2-arrestin link to the mTOR pathway. Kidney Int 2021; 101:498-509. [PMID: 34757123 DOI: 10.1016/j.kint.2021.09.029] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 09/02/2021] [Accepted: 09/10/2021] [Indexed: 01/03/2023]
Abstract
Functional non-HLA antibodies (antibodies to non-human leukocyte antigens) targeting the G protein-coupled receptors angiotensin II type 1 receptor (AT1R) and endothelin-1 type A receptor (ETAR) are implicated in the pathogenesis of transplant vasculopathy. While ERK signaling (a regulator of cell growth) may represent a general cellular response to agonist stimulation, the molecular link between receptor stimulation and development of vascular obliteration has not been fully established. Here we hypothesize involvement of the versatile adaptor proteins, β-arrestins, and the major regulator of cell growth, PI3K/mTOR signaling, in impaired endothelial repair. To test this, human microvascular endothelial cells were treated with AT1R/ETAR antibodies isolated from patients with kidney transplant vasculopathy. These antibodies activated both mTOR complexes via AT1R and ETAR in a PI3K-dependent and ERK-independent manner. The mTOR inhibitor, rapamycin, completely abolished activation of mTORC1 and mTORC2 after long-term treatment with receptor antibodies. Imaging studies revealed that β2- but not β1-arrestin was recruited to ETAR in response to ET1 and patient antibodies but not with antibodies isolated from healthy individuals. Silencing of β2-arrestin by siRNA transfection significantly reduced ERK1/2 and mTORC2 activation. Non-HLA antibodies impaired endothelial repair by AT1R- and ETAR-induced mTORC2 signaling. Thus, we provide evidence that functional AT1R/ETAR antibodies induce ERK1/2 and mTOR signaling involving β2-arrestin in human microvascular endothelium. Hence, our data may provide a translational rational for mTOR inhibitors in combination with receptor blockers in patients with non-HLA receptor recognizing antibodies.
Collapse
Affiliation(s)
- Rusan Ali Catar
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Medizinische Klinik m. S. Nephrologie und internistische Intensivmedizin, Berlin, Germany; Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Cardiovascular Research, Charitéplatz 1, Berlin, Germany.
| | - Oskar Wischnewski
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Medizinische Klinik m. S. Nephrologie und internistische Intensivmedizin, Berlin, Germany
| | - Lei Chen
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Medizinische Klinik m. S. Nephrologie und internistische Intensivmedizin, Berlin, Germany; Department of Nephrology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai City, Guandong Province, People's Republic of China
| | | | - Claudia Rutz
- Leibniz Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V., Berlin, Germany
| | - Ralf Schülein
- Leibniz Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V., Berlin, Germany
| | - Duska Dragun
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Medizinische Klinik m. S. Nephrologie und internistische Intensivmedizin, Berlin, Germany; Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Cardiovascular Research, Charitéplatz 1, Berlin, Germany; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, Charitéplatz 1, Berlin, Germany
| | - Aurélie Philippe
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Medizinische Klinik m. S. Nephrologie und internistische Intensivmedizin, Berlin, Germany; Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Cardiovascular Research, Charitéplatz 1, Berlin, Germany; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, Charitéplatz 1, Berlin, Germany
| | - Angelika Kusch
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Medizinische Klinik m. S. Nephrologie und internistische Intensivmedizin, Berlin, Germany; Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Cardiovascular Research, Charitéplatz 1, Berlin, Germany; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, Charitéplatz 1, Berlin, Germany; DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany.
| |
Collapse
|
27
|
Cornell LD. Histopathologic Features of Antibody Mediated Rejection: The Banff Classification and Beyond. Front Immunol 2021; 12:718122. [PMID: 34646262 PMCID: PMC8503253 DOI: 10.3389/fimmu.2021.718122] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 09/07/2021] [Indexed: 01/27/2023] Open
Abstract
Antibody mediated rejection (ABMR) in the kidney can show a wide range of clinical presentations and histopathologic patterns. The Banff 2019 classification currently recognizes four diagnostic categories: 1. Active ABMR, 2. Chronic active ABMR, 3. Chronic (inactive) ABMR, and 4. C4d staining without evidence of rejection. This categorization is limited in that it does not adequately represent the spectrum of antibody associated injury in allograft, it is based on biopsy findings without incorporating clinical features (e.g., time post-transplant, de novo versus preformed DSA, protocol versus indication biopsy, complement inhibitor drugs), the scoring is not adequately reproducible, and the terminology is confusing. These limitations are particularly relevant in patients undergoing desensitization or positive crossmatch kidney transplantation. In this article, I discuss Banff criteria for these ABMR categories, with a focus on patients with pre-transplant DSA, and offer a framework for considering the continuum of allograft injury associated with donor specific antibody in these patients.
Collapse
Affiliation(s)
- Lynn D Cornell
- Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
| |
Collapse
|
28
|
Abstract
Despite the overall success of heart transplantation as a definitive treatment for endstage heart failure, cardiac allograft rejection remains an important cause of morbidity and mortality. Endomyocardial biopsy has been the standard of care for rejection monitoring, but is associated with several diagnostic limitations and serious procedural complications. The use of molecular diagnostics has emerged over the past decade as a tool to potentially circumvent some of these limitations. We present an update on novel molecular approaches to detecting transplant rejection, focusing on 4 categories: microarray technology, gene expression profiling, cell-free DNA and microRNA.
Collapse
Affiliation(s)
- Lillian Benck
- Department of Cardiology, Cedars-Sinai Smidt Heart Institute
| | - Takuma Sato
- Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine
| | - Jon Kobashigawa
- Department of Cardiology, Cedars-Sinai Smidt Heart Institute
| |
Collapse
|
29
|
Ali AA, Almukhtar SE, Abd KH, Saleem ZSM, Sharif DA, Hughson MD. The causes and frequency of kidney allograft failure in a low-resource setting: observational data from Iraqi Kurdistan. BMC Nephrol 2021; 22:272. [PMID: 34364378 PMCID: PMC8349141 DOI: 10.1186/s12882-021-02486-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 07/28/2021] [Indexed: 12/18/2022] Open
Abstract
Background In the developing world, transplantation is the most common long-term treatment for patients with end-stage renal disease, but rates and causes of graft failure are uncertain. Methods This was a retrospective outcomes study of renal transplant patients seen in Iraqi Kurdistan nephrology clinics in the year 2019. In 2019, 871 renal transplant patients were registered and outcomes followed through 12/31/2020. Indicated renal biopsies were obtained on 431 patients at 1 day to 18 years post-transplantation. Outcomes were compared with United States Renal Data System (USRDS) living donor reports. Results All donors were living. The recipient age was 38.5 ± 13.3 years, 98.2% were < 65 years old, 3.7% had previous transplants, and 2.8% had pretransplant donor-specific antibodies (DSA). Gehan-Breslow estimated failure rates for all-cause, return to HD, and death with functional graft were 6.0, 4.2, and 1.9% at 1 year and 18.1, 13.7, and 5.1% at 5 years post-engraftment (USRDS 2000; 1 year: 7.0, 5.0, 2.6%; 5 year: 22.3, 15.2, 10.6%. USRDS 2010; 1 year: 3.7, 2.4, 1.4%; 5 year: 15.3, 9.6, 7.3%). The median graft survival was 15 years. Acute tubular injury (ATI), infarction, and acute T cell-mediated rejection accounted for 22.2% of graft loss, with > 75% of these failures taking place in the first year. Most graft failures occurred late, at a median post-transplant time of 1125 (interquartile range, 365–2555) days, and consisted of interstitial fibrosis and tubular atrophy (IF/TA) (23.8%), transplant glomerulopathy (13.7%), and acquired active antibody-mediated rejection (12.0%). The significant predictors of graft loss were C4d + biopsies (P < 0.01) and advanced IF/TA (P < 0.001). Conclusions Kurdistan transplant patients had graft failure rates similar to living donors reported by the USRDS for the year 2000 but higher than reported for 2010. Compared to USRDS 2010, Kurdistan patients had a moderate excess of HD failures at one and 5 years post-engraftment. Nevertheless, prolonged survival is the norm, with chronic disorders and acquired DSA being the leading causes of graft loss.
Collapse
Affiliation(s)
- Alaa Abbas Ali
- University of Sulaimani College of Medicine, Quirga Road, Sulaimani, Iraq
| | | | - Kais H Abd
- University of Dohuk College of Medicine, Dohuk, Iraq
| | | | - Dana A Sharif
- University of Sulaimani College of Medicine, Quirga Road, Sulaimani, Iraq
| | - Michael D Hughson
- University of Sulaimani College of Medicine, Quirga Road, Sulaimani, Iraq.
| |
Collapse
|
30
|
Connor KL, O'Sullivan ED, Marson LP, Wigmore SJ, Harrison EM. The Future Role of Machine Learning in Clinical Transplantation. Transplantation 2021; 105:723-735. [PMID: 32826798 DOI: 10.1097/tp.0000000000003424] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The use of artificial intelligence and machine learning (ML) has revolutionized our daily lives and will soon be instrumental in healthcare delivery. The rise of ML is due to multiple factors: increasing access to massive datasets, exponential increases in processing power, and key algorithmic developments that allow ML models to tackle increasingly challenging questions. Progressively more transplantation research is exploring the potential utility of ML models throughout the patient journey, although this has not yet widely transitioned into the clinical domain. In this review, we explore common approaches used in ML in solid organ clinical transplantation and consider opportunities for ML to help clinicians and patients. We discuss ways in which ML can aid leverage of large complex datasets, generate cutting-edge prediction models, perform clinical image analysis, discover novel markers in molecular data, and fuse datasets to generate novel insights in modern transplantation practice. We focus on key areas in transplantation in which ML is driving progress, explore the future potential roles of ML, and discuss the challenges and limitations of these powerful tools.
Collapse
Affiliation(s)
- Katie L Connor
- Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.,Edinburgh Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom.,Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Eoin D O'Sullivan
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Lorna P Marson
- Edinburgh Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom.,Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Stephen J Wigmore
- Edinburgh Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom.,Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Ewen M Harrison
- Centre for Medical Informatics, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom
| |
Collapse
|
31
|
Impact of Belatacept Conversion on Renal Function, Histology, and Gene Expression in Kidney Transplant Patients With Chronic Active Antibody-mediated Rejection. Transplantation 2021; 105:660-667. [PMID: 32510913 DOI: 10.1097/tp.0000000000003278] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND Here, we present our initial experience with a prospective protocol of belatacept conversion in patients with chronic active antibody-mediated rejection (caAMR) and a high degree of chronicity at the time of diagnosis. METHODS We converted 19 patients (mean age, 45 ± 12 y) with biopsy-proven caAMR from tacrolimus to belatacept at a median of 44 months post-kidney transplant. RESULTS At a median of 29 months (interquartile range, 16-46 mo) postconversion, death-censored graft and patient survivals were 89% and 95%, respectively. When compared to a 1:2 propensity-matched control cohort from the INSERM U970 registry maintained on calcineurin inhibitor, the belatacept group had progressive improvement (P = 0.02) in estimated glomerular filtration rate from a mean of 33.9 ± 10 at baseline to 37.8 ± 13 at 6 months and 38.5 ± 12 mL/min/1.73 m2 at 12 months postconversion, as compared to a steady decline noted in the controls (36.2 [baseline] → 33.1 [6 mo] → 32.7 mL/min/1.73 m2 [12 mo] of follow-up). A paired histologic comparison of preconversion and postconversion (performed at median 9.5 mo postconversion) biopsies showed no worsening in microvascular inflammation or chronicity. The paired tissue gene expression analysis showed improved mean total rejection score (0.68 ± 0.26-0.56 ± 0.33; P = 0.02) and a trend toward improved antibody-mediated rejection score (0.64 ± 0.34-0.56 ± 0.39; P = 0.06). CONCLUSIONS Here, we report that in patients diagnosed with caAMR who were not subjected to intensive salvage immunosuppressive therapies, isolated belatacept conversion alone was associated with stabilization in renal function. These results are bolstered by molecular evidence of improved inflammation.
Collapse
|
32
|
Seyahi N, Ozcan SG. Artificial intelligence and kidney transplantation. World J Transplant 2021; 11:277-289. [PMID: 34316452 PMCID: PMC8290997 DOI: 10.5500/wjt.v11.i7.277] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 05/17/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
Artificial intelligence and its primary subfield, machine learning, have started to gain widespread use in medicine, including the field of kidney transplantation. We made a review of the literature that used artificial intelligence techniques in kidney transplantation. We located six main areas of kidney transplantation that artificial intelligence studies are focused on: Radiological evaluation of the allograft, pathological evaluation including molecular evaluation of the tissue, prediction of graft survival, optimizing the dose of immunosuppression, diagnosis of rejection, and prediction of early graft function. Machine learning techniques provide increased automation leading to faster evaluation and standardization, and show better performance compared to traditional statistical analysis. Artificial intelligence leads to improved computer-aided diagnostics and quantifiable personalized predictions that will improve personalized patient care.
Collapse
Affiliation(s)
- Nurhan Seyahi
- Department of Nephrology, Istanbul University-Cerrahpaşa, Cerrahpaşa Medical Faculty, Istanbul 34098, Fatih, Turkey
| | - Seyda Gul Ozcan
- Department of Internal Medicine, Istanbul University-Cerrahpaşa, Cerrahpaşa Medical Faculty, Istanbul 34098, Fatih, Turkey
| |
Collapse
|
33
|
Miyairi S, Ueda D, Yagisawa T, Okada D, Keslar KS, Tanabe K, Dvorina N, Valujskikh A, Baldwin WM, Hazen SL, Fairchild RL. Recipient myeloperoxidase-producing cells regulate antibody-mediated acute versus chronic kidney allograft rejection. JCI Insight 2021; 6:148747. [PMID: 34081629 PMCID: PMC8410093 DOI: 10.1172/jci.insight.148747] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 05/27/2021] [Indexed: 11/17/2022] Open
Abstract
Antibody-mediated rejection (ABMR) continues to be a major problem undermining the success of kidney transplantation. Acute ABMR of kidney grafts is characterized by neutrophil and monocyte margination in the tubular capillaries and by graft transcripts indicating NK cell activation, but the myeloid cell mechanisms required for acute ABMR have remained unclear. Dysregulated donor-specific antibody (DSA) responses with high antibody titers are induced in B6.CCR5-/- mice transplanted with complete MHC-mismatched A/J kidneys and are required for rejection of the grafts. This study tested the role of recipient myeloid cell production of myeloperoxidase (MPO) in the cellular and molecular components of acute ABMR. Despite induction of equivalent DSA titers, B6.CCR5-/- recipients rejected A/J kidneys between days 18 and 25, with acute ABMR, whereas B6.CCR5-/-MPO-/- recipients rejected the grafts between days 46 and 54, with histopathological features of chronic graft injury. On day 15, myeloid cells infiltrating grafts from B6.CCR5-/- and B6.CCR5-/-MPO-/- recipients expressed marked phenotypic and functional transcript differences that correlated with the development of acute versus chronic allograft injury, respectively. Near the time of peak DSA titers, activation of NK cells to proliferate and express CD107a was decreased within allografts in B6.CCR5-/-MPO-/- recipients. Despite high titers of DSA, depletion of neutrophils reproduced the inhibition of NK cell activation and decreased macrophage infiltration but increased monocytes producing MPO. Overall, recipient myeloid cells producing MPO regulate graft-infiltrating monocyte/macrophage function and NK cell activation that are required for DSA-mediated acute kidney allograft injury, and their absence switches DSA-mediated acute pathology and graft outcomes to chronic ABMR.
Collapse
Affiliation(s)
- Satoshi Miyairi
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
| | - Daisuke Ueda
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Takafumi Yagisawa
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
| | - Daigo Okada
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
| | - Karen S. Keslar
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Kazunari Tanabe
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
| | - Nina Dvorina
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Anna Valujskikh
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - William M. Baldwin
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Stanley L. Hazen
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Robert L. Fairchild
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| |
Collapse
|
34
|
Romphruk AV, Simtong P, Suntornnipat J, Sudwilai Y, Cheunta S, Chan-On C, Leelayuwat C. Prevalence and impact of HLA and MICA allele mismatching on donor-specific antibodies induction in kidney transplant rejection. Nephrology (Carlton) 2021; 26:833-841. [PMID: 34197005 DOI: 10.1111/nep.13921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 06/07/2021] [Accepted: 06/25/2021] [Indexed: 11/26/2022]
Abstract
AIM Donor-recipient antigen mismatching for anti-human leucocyte antigen (HLA) and MICA is one of the risk factors for antibody induction leading to graft rejection. Our aim was to analyze the incidence and specificity of the different DSAs developing and to investigate the impact of HLA and MICA allele mismatches on antibody production in kidney transplant patients experiencing antibody-mediated rejection (AMR). METHODS We retrospectively reviewed 253 consecutive recipients of kidney transplant who were diagnosed as experiencing AMR. RESULTS Our results showed that around 27% of our patients were positive for DSAs over a median follow-up period of 24 months. Antibody to HLA-DQ7 was the most prevalent DSA detected. The allele mismatch number was significantly lower for DQ loci than -A and -B loci (DQ vs. A, p < .001; DQ vs. B, p = .002). Considering each HLA antigen, the incidence rate of DQ-DSA [41.9 (32.92-51.46; 95%CI)] was much higher than the rate observed for DSA directed to -A, -DR and -B loci. Half of the recipients in the DQ-DSA-only group, and the DQ-DSA together with non-DQ group, had MFI > 5000. Only one case developed de novo MICA-DSA (MICA002). CONCLUSION Our study indicates that mismatching for HLA and MICA alleles leads to the development of HLA and MICA antibodies in some kidney transplant recipients. We have also demonstrated that DSA to the DQ locus is the most prevalent in kidney transplant patients with AMR. Thus, matching the DQ locus in kidney allocation algorithms may reduce post-transplant development of DSA.
Collapse
Affiliation(s)
- Amornrat V Romphruk
- Blood Transfusion Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.,The Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - Piyapong Simtong
- The Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand.,Department of Clinical Immunology and Transfusion Sciences, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - Jidpinan Suntornnipat
- Biomedical Sciences Program, Faculty of Graduate School, Khon Kaen University, Khon Kaen, Thailand
| | - Yupaporn Sudwilai
- Blood Transfusion Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Siriluk Cheunta
- Blood Transfusion Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Chitranon Chan-On
- Internal Medicine Department, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Chanvit Leelayuwat
- The Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand.,Department of Clinical Immunology and Transfusion Sciences, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| |
Collapse
|
35
|
Woodle ES, Gill JS, Clark S, Stewart D, Alloway R, First R. Early Corticosteroid Cessation vs Long-term Corticosteroid Therapy in Kidney Transplant Recipients: Long-term Outcomes of a Randomized Clinical Trial. JAMA Surg 2021; 156:307-314. [PMID: 33533901 DOI: 10.1001/jamasurg.2020.6929] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Importance The complications of corticosteroids make the inclusion of these drugs in immunosuppressive protocols for kidney transplant patients undesirable. However, cessation of corticosteroids is associated with a higher risk of short-term rejection, and the long-term outcomes of patients withdrawn from corticosteroids remain uncertain. Objective To compare long-term kidney transplant outcomes of patients randomized to continue or withdraw corticosteroids. Design, Setting, and Participants This prospective multicenter randomized double-blind placebo-controlled trial was conducted between November 1999 and December 2002 with linkage to a mandatory national registry with validated outcome ascertainment until June 8, 2018. The study included 28 kidney transplant centers in the United States, including 386 low- to moderate-immune risk adult recipients of a living or deceased donor kidney transplant without delayed graft function or short-term rejection in the first week after transplant. Analyses were intention to treat. Analysis began September 2018 and ended June 2019. Interventions Patients were randomized to receive tacrolimus and mycophenolate mofetil with or without corticosteroids 7 days after transplant. Main Outcomes and Measures Kidney allograft failure from any cause including death and allograft failure censored for patient death defined by the requirement for long-term dialysis or repeat transplant. Results Of 385 patients, 191 were assigned to withdraw from corticosteroids (mean [SD] age, 46.5 [12.1] years), and 194 patients were assigned to continued corticosteroids (mean [SD] age, 46.3 [12.6] years). The median (interquartile range) follow-up time was 15.8 (12.0-16.3) years after transplant. The adjusted hazard ratios of allograft failure from any cause including death was 0.83 (95% CI, 0.62-1.10; P = .19) and for allograft failure censored for patient death was 0.78 (95% CI, 0.52-1.19; P = .25) and did not differ between the patients assigned to withdraw from corticosteroids vs assigned to continued corticosteroids. Results were consistent in a per-protocol analysis among 223 patients who continued the trial-assigned treatment of corticosteroid withdrawal (n = 114) or corticosteroids (n = 109) through at least 5 years after transplant. The outcomes of trial participants in either treatment group did not differ from similarly treated contemporary registry patients who met trial eligibility criteria and were treated with the same immunosuppressive drugs. Conclusions and Relevance Long-term corticosteroids may not be necessary as part of a calcineurin-based multiple drug immunosuppressive regimen in low- to moderate-immune risk kidney transplant recipients.
Collapse
Affiliation(s)
- E Steve Woodle
- College of Medicine, University of Cincinnati, Cincinnati, Ohio
| | - John S Gill
- Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada.,Centre for Health Evaluation and Outcome Sciences, University of British Columbia, Vancouver, British Columbia, Canada.,Division of Nephrology, Tufts-New England Medical Center, Boston, Massachusetts
| | - Stephanie Clark
- Providence Health Care Research Institute, Vancouver, British Columbia, Canada
| | | | - Rita Alloway
- College of Medicine, University of Cincinnati, Cincinnati, Ohio
| | - Roy First
- Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| |
Collapse
|
36
|
Liu L, Sun X, Yuan C, Liu H. Relationship between HLA-DRB1 gene polymorphism and breast cancer: A protocol for systematic review and meta-analysis. Medicine (Baltimore) 2021; 100:e25078. [PMID: 33761666 PMCID: PMC9282000 DOI: 10.1097/md.0000000000025078] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 02/16/2021] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Breast cancer is one of the common malignant tumors in women, which seriously affects women's physical and mental health and even life-threatening. The occurrence and development of breast cancer are closely related to genetic factors. Many studies have shown that human leukocyte antigen DRB1 is associated with the development of breast cancer, but lack evidence. This study aims to systematically evaluate the relationship between HLA-DRB1 gene polymorphism and breast cancer. METHODS The retrieval time of this study was from the establishment of the database to February 2021. The retrieval databases included CNKI, Wanfang, VIP and China Biomedical Database, PubMed, Embase, Web of Science, and the Cochrane Library. The retrieval objects were observational studies on the relationship between HLA-DRB1 gene polymorphism and breast cancer (including case--control studies, cross-sectional studies, and cohort studies). The language restrictions were English and Chinese. Two researchers independently extracted the data and assessed the quality of the included studies, and Stata 16.0 software was used for statistical analysis. RESULTS This study will systematically evaluate the relationship between HLA-DRB1 gene polymorphism and breast cancer based on existing studies. CONCLUSION This study will explore the early warning signal of breast cancer genetic susceptibility, and provide evidence-based medical evidence for clarifying the role of HLA-DRB1 gene polymorphism in breast cancer. OSF REGISTRATION NUMBER DOI 10.17605/OSF.IO/847FQ.
Collapse
Affiliation(s)
- Linlin Liu
- Department of Integrated TCM and Western Medicine, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Xu Sun
- Department of Integrated TCM and Western Medicine, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Chenxi Yuan
- Department of Integrated TCM and Western Medicine, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Huaimin Liu
- Department of Integrated TCM and Western Medicine, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| |
Collapse
|
37
|
Marimuthu C, Pushpa Rani V. Elucidating the role of cell-mediated inflammatory cytokines on allogeneic mouse-derived nucleus pulposus mesenchymal stem cells. J Food Biochem 2021; 45:e13681. [PMID: 33694170 DOI: 10.1111/jfbc.13681] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/11/2021] [Accepted: 02/16/2021] [Indexed: 12/28/2022]
Abstract
In this present study, our aim was to evaluate the cell-mediated specific anti-donor antibody and its associated inflammatory cytokine secretion along with its succeeding effects on Nucleus pulposus-derived mesenchymal stem cells (NPMSCs). Tissue from the NP compartment of 12 normal mice was isolated, expanded in cell culture, and the cell phenotypes were confirmed by flow cytometry. Multipotent differentiation and its specific gene expression analysis were confirmed by reverse transcriptase PCR. T and B cells were monitored for both donor and recipient mouse and further analysis of anti-donor antibody secretion was confirmed by lymphocyte crossmatch. In conjunction with anti-donor-specific antibody analysis, the associated inflammatory cytokine expression was analyzed by ELISA. In co-culture, cell-mediated antibody secretion was elevated in T and B cells positive mouse group, when compared to control mouse group. Allogeneic-derived donor NPMSCs were found to be stimulated the secretion of pro-inflammatory cytokines and the level of pro-inflammatory cytokines showed reduced expression in control mouse serum. In co-culture group the concentration of the cell-mediated pro- and anti-inflammatory cytokines found to be increased. PRACTICAL APPLICATIONS: Mesenchymal stem cell exhibit good regeneration capacity for many types of disease, and the mechanism belongs to regeneration is not clear. In intervertebral disc, the nucleus pulposus-derived mesenchymal stem cells showed a better regeneration capacity. On the contrary, the NP cells-based therapy, the Mesenchymal stem cells showed expanded anabolic and reduced catabolic activity together with induced anti-inflammatory effect. In this study, the T & B cells were used to evaluate the anti-donor antibody secretion and also to study how it stimulates the production of anti-donor antibodies against the donor cells. Finally, it was found that T & B cells lead the synthesis of inflammatory cytokines are IL-1, IL-6, and TNF-α. From this study, the results proved that the cell-mediated pro- and anti-inflammatory cytokines to be monitored in allogeneic stem cells-based therapy of intervertebral disc degeneration.
Collapse
Affiliation(s)
- Chinnarasu Marimuthu
- Department of Advanced Zoology and Biotechnology, Loyola College, Chennai, India
| | - Vedham Pushpa Rani
- Department of Advanced Zoology and Biotechnology, Loyola College, Chennai, India
| |
Collapse
|
38
|
Nieuwenhuijs-Moeke GJ, Bosch DJ, Leuvenink HG. Molecular Aspects of Volatile Anesthetic-Induced Organ Protection and Its Potential in Kidney Transplantation. Int J Mol Sci 2021; 22:ijms22052727. [PMID: 33800423 PMCID: PMC7962839 DOI: 10.3390/ijms22052727] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 02/25/2021] [Accepted: 03/03/2021] [Indexed: 12/16/2022] Open
Abstract
Ischemia reperfusion injury (IRI) is inevitable in kidney transplantation and negatively impacts graft and patient outcome. Reperfusion takes place in the recipient and most of the injury following ischemia and reperfusion occurs during this reperfusion phase; therefore, the intra-operative period seems an attractive window of opportunity to modulate IRI and improve short- and potentially long-term graft outcome. Commonly used volatile anesthetics such as sevoflurane and isoflurane have been shown to interfere with many of the pathophysiological processes involved in the injurious cascade of IRI. Therefore, volatile anesthetic (VA) agents might be the preferred anesthetics used during the transplantation procedure. This review highlights the molecular and cellular protective points of engagement of VA shown in in vitro studies and in vivo animal experiments, and the potential translation of these results to the clinical setting of kidney transplantation.
Collapse
Affiliation(s)
- Gertrude J. Nieuwenhuijs-Moeke
- Department of Anesthesiology, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands;
- Correspondence: ; Tel.: +31-631623075
| | - Dirk J. Bosch
- Department of Anesthesiology, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands;
| | - Henri G.D. Leuvenink
- Department of Surgery, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands;
| |
Collapse
|
39
|
Molecular Analysis of Renal Allograft Biopsies: Where Do We Stand and Where Are We Going? Transplantation 2021; 104:2478-2486. [PMID: 32150035 DOI: 10.1097/tp.0000000000003220] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
A renal core biopsy for histological evaluation is the gold standard for diagnosing renal transplant pathology. However, renal biopsy interpretation is subjective and can render insufficient precision, making it difficult to apply a targeted therapeutic regimen for the individual patient. This warrants a need for additional methods assessing disease state in the renal transplant. Significant research activity has been focused on the role of molecular analysis in the diagnosis of renal allograft rejection. The identification of specific molecular expression patterns in allograft biopsies related to different types of allograft injury could provide valuable information about the processes underlying renal transplant dysfunction and can be used for the development of molecular classifier scores, which could improve our diagnostic and prognostic ability and could guide treatment. Molecular profiling has the potential to be more precise and objective than histological evaluation and may identify injury even before it becomes visible on histology, making it possible to start treatment at the earliest time possible. Combining conventional diagnostics (histology, serology, and clinical data) and molecular evaluation will most likely offer the best diagnostic approach. We believe that the use of state-of-the-art molecular analysis will have a significant impact in diagnostics after renal transplantation. In this review, we elaborate on the molecular phenotype of both acute and chronic T cell-mediated rejection and antibody-mediated rejection and discuss the additive value of molecular profiling in the setting of diagnosing renal allograft rejection and how this will improve transplant patient care.
Collapse
|
40
|
Miyairi S, Baldwin WM, Valujskikh A, Fairchild RL. Natural Killer Cells: Critical Effectors During Antibody-mediated Rejection of Solid Organ Allografts. Transplantation 2021; 105:284-290. [PMID: 32384380 DOI: 10.1097/tp.0000000000003298] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Antibody-mediated rejection (AMR) is an important cause of graft loss and continues to present a formidable obstacle to successful transplantation. Unresolved problems continue to be the absence of effective strategies to ablate the donor-specific antibody (DSA) response as well as to attenuate the antibody-mediated graft tissue injury. While the properties of DSA that cause greater graft tissue injury and the characteristic microvascular pathology of the graft injury are well documented, the mechanisms underlying the injury mediated by the antibodies remains unclear. Recent transcriptome interrogation of kidney and heart biopsies procured during ongoing AMR has indicated the expression of genes associated with natural killer (NK) cell activation that is absent during T cell-mediated rejection. The expression of NK cell transcripts during AMR correlates with the presence of CD56+ cells in the microcirculation inflammation observed during AMR. Several mouse models have recently demonstrated the role of NK cells in antibody-mediated chronic vasculopathy in heart allografts and the requirement for NK cell activation during acute AMR of kidney allografts. In the latter model, NK cell activation within kidney allografts is regulated by the activation of myeloid cells producing myeloperoxidase. Overall, the studies to date indicate that AMR constitutes a complex series of DSA-induced interactions with components of the innate immune response. The innate immune participants and their expressed effector functions resulting in the rejection are beginning to be identified. The identification of these components should uncover novel targets that can be used to attenuate acute graft tissue injury in the presence of DSA.
Collapse
Affiliation(s)
- Satoshi Miyairi
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | | | | | | |
Collapse
|
41
|
Profiling the Resident and Infiltrating Monocyte/Macrophages during Rejection following Kidney Transplantation. J Immunol Res 2020; 2020:5746832. [PMID: 33015198 PMCID: PMC7525314 DOI: 10.1155/2020/5746832] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 08/10/2020] [Accepted: 08/24/2020] [Indexed: 01/08/2023] Open
Abstract
Immune tolerance research is essential for kidney transplantation. Other than antibody and T cell-mediated immune rejection, macrophage-mediated innate immunity plays an important role in the onset phase of transplantation rejection. However, due to the complexity of the kidney environment as well as its diversity and low abundance, studies pertaining to monocyte/macrophages in kidney transplantation require further elucidation. In this study, kidney samples taken from healthy human adults and biopsy specimens from patients undergoing rejection following kidney transplantation were analysed and studied. By conducting a single-cell RNA analysis, the type and status of monocyte/macrophages in kidney transplantation were described, in which monocyte/macrophages were observed to form two different subpopulations: resident and infiltrating monocyte/macrophages. Furthermore, previously defined genes were mapped to all monocyte/macrophage types in the kidney and enriched the differential genes of the two main subpopulations using gene expression databases. Considering that various cases of rejection may be of the monocyte/macrophage type, the present data may serve as a reference for studies regarding immune tolerance following kidney transplantation.
Collapse
|
42
|
Mengel M, Loupy A, Haas M, Roufosse C, Naesens M, Akalin E, Clahsen‐van Groningen MC, Dagobert J, Demetris AJ, Duong van Huyen J, Gueguen J, Issa F, Robin B, Rosales I, Von der Thüsen JH, Sanchez‐Fueyo A, Smith RN, Wood K, Adam B, Colvin RB. Banff 2019 Meeting Report: Molecular diagnostics in solid organ transplantation-Consensus for the Banff Human Organ Transplant (B-HOT) gene panel and open source multicenter validation. Am J Transplant 2020; 20:2305-2317. [PMID: 32428337 PMCID: PMC7496585 DOI: 10.1111/ajt.16059] [Citation(s) in RCA: 132] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 04/19/2020] [Accepted: 04/27/2020] [Indexed: 02/06/2023]
Abstract
This meeting report from the XV Banff conference describes the creation of a multiorgan transplant gene panel by the Banff Molecular Diagnostics Working Group (MDWG). This Banff Human Organ Transplant (B-HOT) panel is the culmination of previous work by the MDWG to identify a broadly useful gene panel based on whole transcriptome technology. A data-driven process distilled a gene list from peer-reviewed comprehensive microarray studies that discovered and validated their use in kidney, liver, heart, and lung transplant biopsies. These were supplemented by genes that define relevant cellular pathways and cell types plus 12 reference genes used for normalization. The 770 gene B-HOT panel includes the most pertinent genes related to rejection, tolerance, viral infections, and innate and adaptive immune responses. This commercially available panel uses the NanoString platform, which can quantitate transcripts from formalin-fixed paraffin-embedded samples. The B-HOT panel will facilitate multicenter collaborative clinical research using archival samples and permit the development of an open source large database of standardized analyses, thereby expediting clinical validation studies. The MDWG believes that a pathogenesis and pathway based molecular approach will be valuable for investigators and promote therapeutic decision-making and clinical trials.
Collapse
Affiliation(s)
- Michael Mengel
- Department of Laboratory Medicine and PathologyUniversity of AlbertaEdmontonCanada
| | - Alexandre Loupy
- Paris Translational Research Center for Organ TransplantationINSERM U970 and Necker HospitalUniversity of ParisParisFrance
| | - Mark Haas
- Department of Pathology and Laboratory MedicineCedars‐Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Candice Roufosse
- Department of Immunology and InflammationImperial College London and North West London PathologyLondonUK
| | - Maarten Naesens
- Department of Microbiology, Immunology and TransplantationKU LeuvenLeuvenBelgium,Department of NephrologyUniversity Hospitals LeuvenLeuvenBelgium
| | - Enver Akalin
- Montefiore‐Einstein Center for TransplantationMontefiore Medical CenterBronxNew YorkUSA
| | | | - Jessy Dagobert
- Paris Translational Research Center for Organ TransplantationINSERM U970 and Necker HospitalUniversity of ParisParisFrance
| | - Anthony J. Demetris
- Department of PathologyUniversity of Pittsburgh Medical CenterMontefiore, PittsburghPennsylvaniaUSA
| | - Jean‐Paul Duong van Huyen
- Paris Translational Research Center for Organ TransplantationINSERM U970 and Necker HospitalUniversity of ParisParisFrance
| | - Juliette Gueguen
- Paris Translational Research Center for Organ TransplantationINSERM U970 and Necker HospitalUniversity of ParisParisFrance
| | - Fadi Issa
- Nuffield Department of Surgical SciencesUniversity of OxfordOxfordUK
| | - Blaise Robin
- Paris Translational Research Center for Organ TransplantationINSERM U970 and Necker HospitalUniversity of ParisParisFrance
| | - Ivy Rosales
- Department of PathologyMassachusetts General HospitalHarvard Medical SchoolBostonMassachusettsUSA
| | | | | | - Rex N. Smith
- Department of PathologyMassachusetts General HospitalHarvard Medical SchoolBostonMassachusettsUSA
| | - Kathryn Wood
- Nuffield Department of Surgical SciencesUniversity of OxfordOxfordUK
| | - Benjamin Adam
- Department of Laboratory Medicine and PathologyUniversity of AlbertaEdmontonCanada
| | - Robert B. Colvin
- Department of PathologyMassachusetts General HospitalHarvard Medical SchoolBostonMassachusettsUSA
| |
Collapse
|
43
|
Wilhelm M, Kaur A, Wernli M, Hirsch HH. BK Polyomavirus-Specific CD8 T-Cell Expansion In Vitro Using 27mer Peptide Antigens for Developing Adoptive T-Cell Transfer and Vaccination. J Infect Dis 2020; 223:1410-1422. [PMID: 32857163 DOI: 10.1093/infdis/jiaa546] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Accepted: 08/22/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND BK polyomavirus (BKPyV) remains a significant cause of premature kidney transplant failure. In the absence of effective antivirals, current treatments rely on reducing immunosuppression to regain immune control over BKPyV replication. Increasing BKPyV-specific CD8 T cells correlate with clearance of BKPyV DNAemia in kidney transplant patients. We characterized a novel approach for expanding BKPyV-specific CD8 T cells in vitro using 27mer-long synthetic BKPyV peptides, different types of antigen-presenting cells, and CD4 T cells. METHODS Langerhans cells and immature or mature monocyte-derived dendritic cells (Mo-DCs) were generated from peripheral blood mononuclear cells of healthy blood donors, pulsed with synthetic peptide pools consisting of 36 overlapping 27mers (27mP) or 180 15mers (15mP). BKPyV-specific CD8 T-cell responses were assessed by cytokine release assays using 15mP or immunodominant 9mers. RESULTS BKPyV-specific CD8 T cells expanded using 27mP and required mature Mo-DCs (P = .0312) and CD4 T cells (P = .0156) for highest responses. The resulting BKPyV-specific CD8 T cells proliferated, secreted multiple cytokines including interferon γ and tumor necrosis factor α, and were functional (CD107a+/PD1-) and cytotoxic. CONCLUSIONS Synthetic 27mP permit expanding BKPyV-specific CD8 T-cell responses when pulsing mature Mo-DCs in presence of CD4 T cells, suggesting novel and safe approaches to vaccination and adoptive T-cell therapies for patients before and after kidney transplantation.
Collapse
Affiliation(s)
- Maud Wilhelm
- Transplantation and Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Amandeep Kaur
- Transplantation and Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Marion Wernli
- Transplantation and Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Hans H Hirsch
- Transplantation and Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland.,Clinical Virology, Laboratory Medicine, University Hospital Basel, Basel, Switzerland.,Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland
| |
Collapse
|
44
|
Chutipongtanate A, Prukviwat S, Pongsakul N, Srisala S, Kamanee N, Arpornsujaritkun N, Gesprasert G, Apiwattanakul N, Hongeng S, Ittichaikulthol W, Sumethkul V, Chutipongtanate S. Effects of Desflurane and Sevoflurane anesthesia on regulatory T cells in patients undergoing living donor kidney transplantation: a randomized intervention trial. BMC Anesthesiol 2020; 20:215. [PMID: 32854613 PMCID: PMC7450591 DOI: 10.1186/s12871-020-01130-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Accepted: 08/20/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Volatile anesthetic agents used during surgery have immunomodulatory effects which could affect postoperative outcomes. Recognizing that regulatory T cells (Tregs) plays crucial roles in transplant tolerance and high peripheral blood Tregs associated with stable kidney graft function, knowing which volatile anesthetic agents can induce peripheral blood Tregs increment would have clinical implications. This study aimed to compare effects of desflurane and sevoflurane anesthesia on peripheral blood Tregs induction in patients undergoing living donor kidney transplantation. METHODS A prospective, randomized, double-blind trial in living donor kidney transplant recipients was conducted at a single center, tertiary-care, academic university hospital in Thailand during August 2015 - June 2017. Sixty-six patients were assessed for eligibility and 40 patients who fulfilled the study requirement were equally randomized and allocated to desflurane versus sevoflurane anesthesia during transplant surgery. The primary outcome included absolute changes of peripheral blood CD4+CD25+FoxP3+Tregs which measured by flow cytometry and expressed as the percentage of the total population of CD4+ T lymphocytes at pre-exposure (0-h) and post-exposure (2-h and 24-h) to anesthetic gas. P-value < 0.05 denoted statistical significance. RESULTS Demographic data were comparable between groups. No statistical difference of peripheral blood Tregs between desflurane and sevoflurane groups observed at the baseline pre-exposure (3.6 ± 0.4% vs. 3.1 ± 0.4%; p = 0.371) and 2-h post-exposure (3.0 ± 0.3% vs. 3.5 ± 0.4%; p = 0.319). At 24-h post-exposure, peripheral blood Tregs was significantly higher in desflurane group (5.8 ± 0.5% vs. 4.1 ± 0.3%; p = 0.008). Within group analysis showed patients receiving desflurane, but not sevoflurane, had 2.7% increase in peripheral blood Treg over 24-h period (p < 0.001). CONCLUSION This study provides the clinical trial-based evidence that desflurane induced peripheral blood Tregs increment after 24-h exposure, which could be beneficial in the context of kidney transplantation. Mechanisms of action and clinical advantages of desflurane anesthesia based on Treg immunomodulation should be investigated in the future. TRIAL REGISTRATION ClinicalTrials.gov, NCT02559297 . Registered 22 September 2015 - retrospectively registered.
Collapse
Affiliation(s)
- Arpa Chutipongtanate
- Department of Anesthesiology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand
| | - Sasichol Prukviwat
- Department of Anesthesiology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand
| | - Nutkridta Pongsakul
- Pediatric Translational Research Unit, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand
| | - Supanart Srisala
- Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand
| | - Nakarin Kamanee
- Department of Anesthesiology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand
| | - Nuttapon Arpornsujaritkun
- Vascular and Transplantation Unit, Department of Surgery, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand
| | - Goragoch Gesprasert
- Vascular and Transplantation Unit, Department of Surgery, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand
| | - Nopporn Apiwattanakul
- Division of Infectious Disease, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand
| | - Suradej Hongeng
- Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand
| | - Wichai Ittichaikulthol
- Department of Anesthesiology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand
| | - Vasant Sumethkul
- Division of Nephrology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand
| | - Somchai Chutipongtanate
- Pediatric Translational Research Unit, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand.
- Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand.
| |
Collapse
|
45
|
Aziz F, Mandelbrot D, Parajuli S, Al-Qaoud T, Redfield R, Kaufman D, Odorico JS. Alloimmunity in pancreas transplantation. Curr Opin Organ Transplant 2020; 25:322-328. [PMID: 32692039 DOI: 10.1097/mot.0000000000000776] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
PURPOSE OF REVIEW Despite significant improvement in pancreas allograft survival, rejection continues to be a major clinical problem. This review will focus on emerging literature related to the impact of pretransplant and de-novo DSA (dnDSA) in pancreas transplant recipients, and the diagnosis and treatment of T-cell-medicated rejection (TCMR) and antibody-mediated rejection (ABMR) in this complex group of patients. RECENT FINDINGS Recent data suggest that pretransplant DSA and the emergence of dnDSA in pancreas transplant recipients are both associated with increased risk of ABMR. The pancreas allograft biopsy is essential for the specific diagnosis of TCMR and/or ABMR, distinguish rejection from other causes of graft dysfunction, and to guide-targeted therapy. This distinction is important especially in the setting of solitary pancreas transplants but also in simultaneous pancreas-kidney transplants where solid evidence has now emerged demonstrating discordant biopsy findings. Treatment of rejection in a functioning pancreas can prolong allograft survival. SUMMARY The accurate and timely diagnosis of active alloimmune destruction in pancreas transplant recipients is paramount to preserving graft function in the long term. This review will discuss new, rapidly evolving information that is valuable for the physician caring for these patients to achieve optimal immunological outcomes.
Collapse
Affiliation(s)
- Fahad Aziz
- Department of Medicine, Division of Nephrology
| | | | | | - Talal Al-Qaoud
- Department of Surgery, Division of Transplantation, University of Wisconsin-Madison School of Medicine and Public Health, the University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA
| | - Robert Redfield
- Department of Surgery, Division of Transplantation, University of Wisconsin-Madison School of Medicine and Public Health, the University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA
| | - Dixon Kaufman
- Department of Surgery, Division of Transplantation, University of Wisconsin-Madison School of Medicine and Public Health, the University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA
| | - Jon S Odorico
- Department of Surgery, Division of Transplantation, University of Wisconsin-Madison School of Medicine and Public Health, the University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA
| |
Collapse
|
46
|
Kumar D, Yakubu I, Safavi F, Levy M, Moinuddin I, Kimball P, Kamal L, King A, Massey D, Halloran P, Gupta G. Lack of Histological and Molecular Signature Response to Tocilizumab in Kidney Transplants with Chronic Active Antibody Mediated Rejection: A Case Series. KIDNEY360 2020; 1:663-670. [PMID: 35372943 DOI: 10.34067/kid.0000182019] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 04/21/2020] [Indexed: 02/08/2023]
Abstract
Background Traditional therapies for caAbMR have unclear efficacy with significant side effects in recipients of kidney transplants (KTs). A recent single-center case series suggested tocilizumab (TCZ) could stabilize renal function and improve microvascular inflammation. Here we report our findings of the use of TCZ in patients with caAbMR. Methods Ten adult recipients of KTs with biopsy-proven caAbMR were treated with TCZ at 8 mg/kg per month. Patients were monitored for adverse events, and therapy was interrupted in the setting of serious infections. Six patients (60%) underwent post-treatment biopsies. Results Patients (mean age of 43 years) were initiated on TCZ at a median of 36 months post-KT. A majority of patients were black (70%), underwent regrafts (40%), and were sensitized (mean cPRA=41%). Patients received a median of six doses of TCZ (range=3-10). At a median follow-up of 12 months (range=8-24 months), renal function did not show improvement (mean eGFR, 42±18 ml/min per 1.73 m2 to 37±24 ml/min per 1.73 m2; P=0.27). The slope of decline in eGFR remained unchanged (-0.14±0.9 to -0.33±1.1; P=0.25). There was no improvement in mean MVI (g+ptc) (4.8±1.4 to 4.2±2.0; P=0.39) scores or Molecular Microscope Diagnostic System (MMDx) AbMR scores (0.79±0.17 to 0.78±0.26; P=0.86). There was a numeric worsening of chronicity (ci+ct) scores (2.5±0.8 to 3.3±1.7; P=0.38) and MMDx atrophy fibrosis scores (0.36±0.24 to 0.58±0.15; P=0.21). Patient survival was 90%, with one patient death due to complications from a hip infection. Overall death-censored graft survival was 80%, with two graft losses in patients who had recurrent infections requiring hospitalization. Conclusions In this early experience, we report a lack of efficacy and toxicity with the use of TCZ for caAbMR. Prospective clinical trials are needed to clarify the role of IL-6 blockade and the possibility of increased incidence of infections in patients with caAbMR who are treated with TCZ.
Collapse
Affiliation(s)
- Dhiren Kumar
- Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, Virginia
| | - Idris Yakubu
- Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, Virginia
| | - Frough Safavi
- Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, Virginia
| | - Marlon Levy
- Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, Virginia
| | - Irfan Moinuddin
- Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, Virginia
| | - Pamela Kimball
- Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, Virginia
| | - Layla Kamal
- Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, Virginia
| | - Anne King
- Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, Virginia
| | - Davis Massey
- Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, Virginia
| | - Philip Halloran
- Alberta Transplant Applied Genomics Center, Edmonton, Alberta, Canada
| | - Gaurav Gupta
- Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, Virginia
| |
Collapse
|
47
|
Liu Y, Hu J, Liu D, Zhou S, Liao J, Liao G, Yang S, Guo Z, Li Y, Li S, Chen H, Guo Y, Li M, Fan L, Li L, Lin A, Zhao M. Single-cell analysis reveals immune landscape in kidneys of patients with chronic transplant rejection. Am J Cancer Res 2020; 10:8851-8862. [PMID: 32754283 PMCID: PMC7392010 DOI: 10.7150/thno.48201] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 06/18/2020] [Indexed: 12/11/2022] Open
Abstract
Rationale: Single-cell RNA sequencing (scRNA-seq) has provided an unbiased assessment of specific profiling of cell populations at the single-cell level. Conventional renal biopsy and bulk RNA-seq only average out the underlying differences, while the extent of chronic kidney transplant rejection (CKTR) and how it is shaped by cells and states in the kidney remain poorly characterized. Here, we analyzed cells from CKTR and matched healthy adult kidneys at single-cell resolution. Methods: High-quality transcriptomes were generated from three healthy human kidneys and two CKTR biopsies. Unsupervised clustering analysis of biopsy specimens was performed to identify fifteen distinct cell types, including major immune cells, renal cells and a few types of stromal cells. Single-sample gene set enrichment (ssGSEA) algorithm was utilized to explore functional differences between cell subpopulations and between CKTR and normal cells. Results: Natural killer T (NKT) cells formed five subclasses, representing CD4+ T cells, CD8+ T cells, cytotoxic T lymphocytes (CTLs), regulatory T cells (Tregs) and natural killer cells (NKs). Memory B cells were classified into two subtypes, representing reverse immune activation. Monocytes formed a classic CD14+ group and a nonclassical CD16+ group. We identified a novel subpopulation [myofibroblasts (MyoF)] in fibroblasts, which express collagen and extracellular matrix components. The CKTR group was characterized by increased numbers of immune cells and MyoF, leading to increased renal rejection and fibrosis. Conclusions: By assessing functional differences of subtype at single-cell resolution, we discovered different subtypes that correlated with distinct functions in CKTR. This resource provides deeper insights into CKTR biology that will be helpful in the diagnosis and treatment of CKTR.
Collapse
|
48
|
Chong AS. Mechanisms of organ transplant injury mediated by B cells and antibodies: Implications for antibody-mediated rejection. Am J Transplant 2020; 20 Suppl 4:23-32. [PMID: 32538534 PMCID: PMC7482418 DOI: 10.1111/ajt.15844] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Revised: 02/06/2020] [Accepted: 02/19/2020] [Indexed: 01/25/2023]
Abstract
Recent adjustments to the histological diagnosis and the introduction of molecular classification are providing renewed support for the paradigm that antibody-mediated rejection (ABMR) is an important clinical problem for which there is an urgent need for better therapies. Acute ABMR is observed when the graft is exposed to rapid increases in high-titer donor-specific antibodies (DSA) that are most often generated as anamnestic responses in sensitized recipients or de novo responses in nonsensitized patients who are nonadherent. Chronic ABMR is associated with slower increases in DSA, which may be high or low titer and transient or persistent. These DSA elicit cycles of injury and repair that manifest as multilamination of the peritubular capillary basement membrane or arteriopathy manifesting as intimal fibrosis. Mitigating the problem of AMBR requires the anamnestic and de novo DSA responses to be prevented and established DSA responses to be reversed. To this end, a better understanding of the immunobiology of DSA production is necessary and also the development of assays capable of detecting early humoral immune responses.Recent advances in understanding the immunobiology of B cells and areas requiring further investigation that might lead to new therapies or better diagnosis are discussed in this review.
Collapse
Affiliation(s)
- Anita S Chong
- Section of Transplantation, Department of Surgery, University of Chicago, Chicago, Illinois, USA
| |
Collapse
|
49
|
Jeong HJ. Diagnosis of renal transplant rejection: Banff classification and beyond. Kidney Res Clin Pract 2020; 39:17-31. [PMID: 32164120 PMCID: PMC7105630 DOI: 10.23876/j.krcp.20.003] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 02/10/2020] [Accepted: 02/19/2020] [Indexed: 12/20/2022] Open
Abstract
Diagnosis of renal transplant rejection is dependent on interpretation of renal allograft biopsies. The Banff Classification of Allograft Pathology, which was developed as a standardized working classification system in 1991, has contributed to the standardization of definitions for histologic injuries resulting from renal allograft rejections and provided a universal grading system for assessing these injuries. It has also helped to provide insight into the underlying pathogenic mechanisms that contribute to transplant rejection. In addition to histological and immunologic parameters, molecular tools are now being used to facilitate the diagnosis of rejection. In this review, I will discuss morphologic features of renal transplant rejections as well as major revisions and pitfalls of the Banff classification system, and provide future perspectives.
Collapse
Affiliation(s)
- Hyeon Joo Jeong
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
| |
Collapse
|
50
|
Trailin A, Hruba P, Viklicky O. Molecular Assessment of Kidney Allografts: Are We Closer to a Daily Routine? Physiol Res 2020; 69:215-226. [PMID: 32199018 DOI: 10.33549/physiolres.934278] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Kidney allograft pathology assessment has been traditionally based on clinical and histological criteria. Despite improvements in Banff histological classification, the diagnostics in particular cases is problematic reflecting a complex pathogenesis of graft injuries. With the advent of molecular techniques, polymerase-chain reaction, oligo- and microarray technologies allowed to study molecular phenotypes of graft injuries, especially acute and chronic rejections. Moreover, development of the molecular microscope diagnostic system (MMDx) to assess kidney graft biopsies, represents the first clinical application of a microarray-based method in transplantation. Whether MMDx may replace conventional pathology is the subject of ongoing research, however this platform is particularly useful in complex histological findings and may help clinicians to guide the therapy.
Collapse
Affiliation(s)
- A Trailin
- Department of Nephrology, Transplant Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
| | | | | |
Collapse
|