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1
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Lee D, Polkinghorne KR, Pilmore H, Mulley WR. Mycophenolate Dose Reduction in Tacrolimus-based Regimens and Long-term Kidney Transplant Outcomes in Australia and New Zealand. Transplant Direct 2024; 10:e1659. [PMID: 38881745 PMCID: PMC11177819 DOI: 10.1097/txd.0000000000001659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 04/03/2024] [Accepted: 04/03/2024] [Indexed: 06/18/2024] Open
Abstract
Background Mycophenolate dose reduction (MDR) is associated with acute rejection and transplant failure in kidney transplant recipients (KTRs). The optimal dose to prevent rejection and reduce complications remains poorly defined in tacrolimus-based regimens. Methods We assessed adult KTRs from 2005 to 2017 initiated on mycophenolate mofetil 2 g/d, tacrolimus, and prednisolone from the Australia and New Zealand Dialysis and Transplant Registry. KTRs with rejection within the first 30 d posttransplant were excluded. The primary outcome was time to first rejection between 30 d and 2 y posttransplant. Mycophenolate dose was modeled as a time-varying covariate using Cox proportional hazards regression. Secondary outcomes included assessment of early MDR to <1.5 g/d within the first 6 mo posttransplant and subsequent patient and death-censored graft survival. Results In the primary analysis, 3590 KTRs were included. Compared with mycophenolate dose of ≥2 g/d, both 1.0-<1.5 and <1 g/d were associated with an increased risk of rejection during the 2 y posttransplant (hazard ratio [HR] 1.67; 95% confidence interval [CI], 1.29-2.16; P < 0.001 and HR 2.06; 95% CI, 1.36-3.13; P = 0.001, respectively) but not 1.5-<2 g/d (HR 1.20; 95% CI, 0.94-1.53; P = 0.14). Early MDR to <1.5 g/d occurred in 45.3% of KTRs and was an independent risk factor for death-censored graft failure (HR 1.32; 95% CI, 1.05-1.66; P = 0.016) but not death (HR 1.18; 95% CI, 0.97-1.44; P = 0.10), during a median follow-up of 5.0 (interquartile range, 2.6-8.5) y. Conclusions Early MDR was a risk factor for subsequent rejection and graft failure in KTRs receiving contemporary tacrolimus-based regimens.
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Affiliation(s)
- Darren Lee
- Department of Renal Medicine, Eastern Health Clinic School, Monash University, Box Hill, VIC, Australia
- Department of Nephrology, Austin Health, Heidelberg, VIC, Australia
| | - Kevan R Polkinghorne
- Department of Nephrology, Monash Health, Clayton, VIC, Australia
- Department of Medicine, Monash University, Clayton, VIC, Australia
- Department Epidemiology and Preventative Medicine, Monash University, Clayton, VIC, Australia
- Department of Medicine, Centre for Inflammatory Diseases, Monash University, Clayton, VIC, Australia
| | - Helen Pilmore
- Department of Renal Medicine, Auckland City Hospital, Auckland, New Zealand
| | - William R Mulley
- Department of Nephrology, Monash Health, Clayton, VIC, Australia
- Department of Medicine, Centre for Inflammatory Diseases, Monash University, Clayton, VIC, Australia
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2
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Gonzalez FM, Cohens FG. Predicting outcomes after kidney transplantation: Can Pareto's rules help us to do so? World J Transplant 2024; 14:90149. [PMID: 38576758 PMCID: PMC10989466 DOI: 10.5500/wjt.v14.i1.90149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 01/13/2024] [Accepted: 02/05/2024] [Indexed: 03/15/2024] Open
Abstract
Kidney transplantation is the best option for kidney replacement therapy, even considering that most of the times the grafts do not survive as long as their recipients. In the Khalil et al's experience, published in this issue of the Journal, they analyze their second kidney graft survival and describe those significant predictors of early loss. This editorial comments on the results and put in perspec tive that most of the times, long-term graft survival could be inadvertently jeopardized if the immunosuppressive therapy is reduced or withdrawn for any reason, and that it could happen frequently if the transplant physician intends to innovate with the clinical care without proper evidence-based data.
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Affiliation(s)
- Fernando M Gonzalez
- Department of Nephrology, Faculty of Medicine, Universidad de Chile, Santiago 7500922, Chile
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3
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Han JW, Choi JY, Jung ES, Kim JH, Cho HS, Yoo JS, Sung PS, Jang JW, Yoon SK, Choi HJ, You YK. Association between the early high level of serum tacrolimus and recurrence of hepatocellular carcinoma in ABO-incompatible liver transplantation. World J Gastrointest Surg 2023; 15:2727-2738. [PMID: 38222009 PMCID: PMC10784835 DOI: 10.4240/wjgs.v15.i12.2727] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 10/18/2023] [Accepted: 12/01/2023] [Indexed: 12/27/2023] Open
Abstract
BACKGROUND Clinical factors predicting graft survival (GS) after ABO-incompatible (ABOi) liver transplantation (LT), and differences between recipients with and without hepatocellular carcinoma (HCC) are unclear. AIM To analyze the impact of serial serum tacrolimus trough concentration in recipients with or without HCC) in ABOi living-donor liver transplantation (LDLT). METHODS We analyzed a historical cohort of 89 recipients who underwent ABOi LDLT, including 47 patients with HCC. RESULTS The 1-, 3-, 5-, and 10-year GS rates were 85.9%, 73.3%, 71.4%, and 71.4%, respectively, and there were no significant differences between HCC and non-HCC recipients. In multivariate Cox-regression analyses, tacrolimus trough concentrations below 5.4 ng/mL at 24 wk post-LT, in addition to the antibody-mediated rejection (AMR) were associated with poor-graft outcomes. In HCC patients, AMR [hazard ratio (HR) = 63.20, P < 0.01] and HCC recurrence (HR = 20.72, P = 0.01) were significantly associated with poor graft outcomes. HCCs outside Milan criteria, and tacrolimus concentrations at 4 wk post-LT > 7.3 ng/mL were significant predictive factors for HCC recurrence. After propensity score matching, patients with high tacrolimus concentrations at 4 wk had significantly poor recurrence-free survival. CONCLUSION Elevated tacrolimus levels at 4 wk after ABOi LDLT have been found to correlate with HCC recurrence. Therefore, careful monitoring and control of tacrolimus levels are imperative in ABOi LT recipients with HCC.
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Affiliation(s)
- Ji Won Han
- Department of Internal Medicine, The Catholic University of Korea, Seoul 06591, South Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
| | - Jong Young Choi
- Department of Internal Medicine, The Catholic University of Korea, Seoul 06591, South Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
| | - Eun Sun Jung
- Department of Hospital Pathology, The Catholic University of Korea, Seoul 06591, South Korea
| | - Ji Hoon Kim
- Department of Internal Medicine, The Catholic University of Korea, Seoul 06591, South Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
| | - Hee Sun Cho
- Department of Internal Medicine, The Catholic University of Korea, Seoul 06591, South Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
| | - Jae-Sung Yoo
- Department of Internal Medicine, The Catholic University of Korea, Seoul 06591, South Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
| | - Pil Soo Sung
- Department of Internal Medicine, The Catholic University of Korea, Seoul 06591, South Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
| | - Jeong Won Jang
- Department of Internal Medicine, The Catholic University of Korea, Seoul 06591, South Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
| | - Seung Kew Yoon
- Department of Internal Medicine, The Catholic University of Korea, Seoul 06591, South Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
| | - Ho Joong Choi
- Department of Surgery, The Catholic University of Korea, Seoul 06591, South Korea
| | - Young Kyoung You
- Department of Surgery, The Catholic University of Korea, Seoul 06591, South Korea
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4
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McGovern KE, Sonar SA, Watanabe M, Coplen CP, Bradshaw CM, Nikolich JŽ. The aging of the immune system and its implications for transplantation. GeroScience 2023:10.1007/s11357-022-00720-2. [PMID: 36626019 PMCID: PMC9838392 DOI: 10.1007/s11357-022-00720-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 12/21/2022] [Indexed: 01/11/2023] Open
Abstract
By the last third of life, most mammals, including humans, exhibit a decline in immune cell numbers, immune organ structure, and immune defense of the organism, commonly known as immunosenescence. This decline leads to clinical manifestations of increased susceptibility to infections, particularly those caused by emerging and reemerging microorganisms, which can reach staggering levels-infection with SARS-CoV-2 has been 270-fold more lethal to older adults over 80 years of age, compared to their 18-39-year-old counterparts. However, while this would be expected to be beneficial to situations where hyporeactivity of the immune system may be desirable, this is not always the case. Here, we discuss the cellular and molecular underpinnings of immunosenescence as they pertain to outcomes of solid organ and hematopoietic transplantation.
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Affiliation(s)
- Kathryn E McGovern
- Department of Immunobiology, University of Arizona, Tucson, AZ, 85724, USA
- Arizona Center On Aging, The University of Arizona, University of Arizona College of Medicine-Tucson, Tucson, AZ, 85724, USA
- BIO5 Institute, University of Arizona, Tucson, AZ, USA
| | - Sandip A Sonar
- Department of Immunobiology, University of Arizona, Tucson, AZ, 85724, USA
- Arizona Center On Aging, The University of Arizona, University of Arizona College of Medicine-Tucson, Tucson, AZ, 85724, USA
| | - Makiko Watanabe
- Department of Immunobiology, University of Arizona, Tucson, AZ, 85724, USA
- Arizona Center On Aging, The University of Arizona, University of Arizona College of Medicine-Tucson, Tucson, AZ, 85724, USA
| | - Christopher P Coplen
- Department of Immunobiology, University of Arizona, Tucson, AZ, 85724, USA
- Arizona Center On Aging, The University of Arizona, University of Arizona College of Medicine-Tucson, Tucson, AZ, 85724, USA
| | - Christine M Bradshaw
- Department of Immunobiology, University of Arizona, Tucson, AZ, 85724, USA
- Arizona Center On Aging, The University of Arizona, University of Arizona College of Medicine-Tucson, Tucson, AZ, 85724, USA
| | - Janko Ž Nikolich
- Department of Immunobiology, University of Arizona, Tucson, AZ, 85724, USA.
- Arizona Center On Aging, The University of Arizona, University of Arizona College of Medicine-Tucson, Tucson, AZ, 85724, USA.
- BIO5 Institute, University of Arizona, Tucson, AZ, USA.
- The Aegis Consortium for Pandemic-free Future, University of Arizona Health Sciences, University of Arizona, Tucson, 85719, USA.
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5
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Dugbartey GJ, Sener A. Organ Toxicity by Immunosuppressive Drugs in Solid Organ Transplantation. RECENT ADVANCES IN THERAPEUTIC DRUG MONITORING AND CLINICAL TOXICOLOGY 2022:255-271. [DOI: 10.1007/978-3-031-12398-6_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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6
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Park Y, Lee H, Eum SH, Kim HD, Ko EJ, Yang CW, Chung BH. Intrapatient Variability in Tacrolimus Trough Levels Over 2 Years Affects Long-Term Allograft Outcomes of Kidney Transplantation. Front Immunol 2021; 12:746013. [PMID: 34659243 PMCID: PMC8514869 DOI: 10.3389/fimmu.2021.746013] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 09/09/2021] [Indexed: 11/13/2022] Open
Abstract
This study aimed to determine the impact of tacrolimus (TAC) trough level (C0) intrapatient variability (IPV) over a period of 2 years after kidney transplantation (KT) on allograft outcomes. In total, 1,143 patients with low immunologic risk were enrolled. The time-weighted coefficient variability (TWCV) of TAC-C0 was calculated, and patients were divided into tertile groups (T1: < 24.6%, T2: 24.6%–33.7%, T3: ≥ 33.7%) according to TAC-C0-TWCV up to post-transplant 1st year. They were classified into the low/low, low/high, high/low, and high/high groups based on a TAC-C0-TWCV value of 33.7% during post-transplant 0–1st and 1st–2nd years. The allograft outcomes among the three tertile and four TAC-C0-TWCV groups were compared. The T3 group had the highest rate of death-censored allograft loss (DCGL), and T3 was considered an independent risk factor for DCGL. The low/low group had the lowest and the high/high group had the highest risk for DCGL. Moreover, patients with a mean TAC-C0 of ≥5 ng/ml in the high/high group were at the highest risk for DCGL. Thus, TAC-IPV can significantly affect allograft outcomes even with a high mean TAC-C0. Furthermore, to improve allograft outcomes, a low TAC-IPV should be maintained even after the first year of KT.
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Affiliation(s)
- Yohan Park
- Division of Nephrology, Department of Internal Medicine, Konyang University Hospital, College of Medicine, Konyang University, Daejeon, South Korea.,Transplantation Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Hanbi Lee
- Transplantation Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Sang Hun Eum
- Transplantation Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Hyung Duk Kim
- Transplantation Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Eun Jeong Ko
- Transplantation Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Chul Woo Yang
- Transplantation Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Byung Ha Chung
- Transplantation Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
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7
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Süsal C, Aykut G, Morath C, Fichtner A, Unterrainer C, Scherer S, Tran TH, Mehrabi A, Zeier M, Tönshoff B. Relevance of donor-specific antibody monitoring after kidney transplantation: Findings from the Collaborative Transplant Study and the Heidelberg Transplant Center. HLA 2020; 94 Suppl 2:11-15. [PMID: 31403240 DOI: 10.1111/tan.13665] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 08/06/2019] [Accepted: 08/09/2019] [Indexed: 01/13/2023]
Abstract
Monitoring of donor-specific HLA antibodies (DSA) has become part of the clinical routine in kidney transplantation. This paper gives a brief overview on data from the Collaborative Transplant Study (CTS) and the Heidelberg Transplant Center on the clinical relevance of post-transplant DSA monitoring in patients undergoing renal transplantation. The obtained findings underline the importance of DSA monitoring in the post-operative course in immunologically high-risk patients and patients with deterioration of graft function. Especially in patients with a pre-activated immune system, a gap in the immunosuppressive therapy appear to lead to persistence, reappearance or de novo occurrence of strong, complement-activating DSA, resulting in severe antibody-mediated rejection (AMR) and, without timely intervention, in AMR-related graft loss.
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Affiliation(s)
- Caner Süsal
- Institute of Immunology, Heidelberg University Hospital, Heidelberg, Germany
| | - Güclü Aykut
- Institute of Immunology, Heidelberg University Hospital, Heidelberg, Germany
| | - Christian Morath
- Nephrology Division, Heidelberg University Hospital, Heidelberg, Germany
| | - Alexander Fichtner
- Department of Pediatrics I, Heidelberg University Hospital, Heidelberg, Germany
| | | | - Sabine Scherer
- Institute of Immunology, Heidelberg University Hospital, Heidelberg, Germany
| | - Thuong H Tran
- Institute of Immunology, Heidelberg University Hospital, Heidelberg, Germany
| | - Arianeb Mehrabi
- Department of General, Visceral, and Transplant Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Martin Zeier
- Nephrology Division, Heidelberg University Hospital, Heidelberg, Germany
| | - Burkhard Tönshoff
- Department of Pediatrics I, Heidelberg University Hospital, Heidelberg, Germany
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8
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Rennie TJW, Petrie M, Metcalfe W, Walbaum D, Joss N, Barton E, Marson L, Clancy MJ, Henderson L, Traynor JP, Geddes CG, Phelan PJ. The impact of age on patient tolerance of mycophenolate following kidney transplantation. Nephrology (Carlton) 2020; 25:566-574. [PMID: 32323461 DOI: 10.1111/nep.13718] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 03/31/2020] [Accepted: 04/02/2020] [Indexed: 11/28/2022]
Abstract
BACKGROUND In Scotland, standard maintenance immunosuppression following kidney transplantation consists of mycophenolate (MPA), tacrolimus and prednisolone irrespective of recipient age. We analyzed the tolerability of this immunosuppression regimen and the association with transplant outcomes. METHODS A national, multicentre retrospective analysis of patients transplanted in 2015 and 2016, comparing graft function, acute rejection, significant infection rates and immunosuppression dosing between patients aged 18 and 59 years (Group 1) and ≥60 years (Group 2). RESULTS Of the 490 patients, 26% were aged ≥60 years. Acute rejection (AR) rates at 1 year were 15% and 11% in Groups 1 and 2, respectively. Full-dose MPA was poorly tolerated with 53% in Group 1 and 77% in Group 2 requiring dose reduction or cessation. Female gender and age ≥60 years were independent predictors for MPA dose changes. One year following MPA dose reduction, AR risk was low (5%) in Group 2, however, those remaining on full dose MPA had a 79% increased rate of serious infections. CONCLUSION The majority of renal transplant recipients aged ≥60 fail to tolerate full-dose MPA. In this group, MPA dose reduction is associated with low rejection rates, but full-dose MPA is associated with high infection rates. We suggest that a tailored approach to immunosuppression in elderly recipients incorporating lower doses of MPA may be appropriate.
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Affiliation(s)
| | - Michaela Petrie
- Renal Department, NHS Lothian - Royal Infirmary Edinburgh, Edinburgh, UK
| | - Wendy Metcalfe
- Renal Department, NHS Lothian - Royal Infirmary Edinburgh, Edinburgh, UK.,The Scottish Renal Registry, Meridian Court, ISD Scotland, Glasgow, UK
| | - David Walbaum
- Renal Department, NHS Grampian, Aberdeen Royal Infirmary, Aberdeen, UK
| | - Nicola Joss
- Renal Department, NHS Highland, Raigmore Hospital, Inverness, UK
| | - Ellen Barton
- School of Medicine, The University of Edinburgh, Edinburgh, UK
| | - Lorna Marson
- Renal Department, NHS Lothian - Royal Infirmary Edinburgh, Edinburgh, UK.,Division of Health Sciences, The University of Edinburgh, Edinburgh, UK
| | - Marc J Clancy
- Department of Renal Transplantation, NHS Great Glasgow and Clyde - Queen Elizabeth University Hospital, Glasgow, UK
| | - Lorna Henderson
- Renal Department, NHS Lothian - Royal Infirmary Edinburgh, Edinburgh, UK
| | - Jamie P Traynor
- The Scottish Renal Registry, Meridian Court, ISD Scotland, Glasgow, UK.,Department of Renal Transplantation, NHS Great Glasgow and Clyde - Queen Elizabeth University Hospital, Glasgow, UK
| | - Colin G Geddes
- Department of Renal Transplantation, NHS Great Glasgow and Clyde - Queen Elizabeth University Hospital, Glasgow, UK
| | - Paul J Phelan
- Renal Department, NHS Lothian - Royal Infirmary Edinburgh, Edinburgh, UK
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9
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Dreyer GJ, de Fijter JW. Transplanting the Elderly: Mandatory Age- and Minimal Histocompatibility Matching. Front Immunol 2020; 11:359. [PMID: 32226428 PMCID: PMC7080649 DOI: 10.3389/fimmu.2020.00359] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 02/14/2020] [Indexed: 12/16/2022] Open
Abstract
Worldwide over 40% of patients receiving renal replacement therapy (RRT) are aged 65 years or older, a number that is still increasing. Renal transplantation is the preferred RRT, providing substantial survival benefit over those remaining on dialysis, including the elderly. Only 3% of patients aged 65 years or older accepted on the waiting list actually received a kidney transplant offer within the Eurotransplant allocation region. To increase the chance for elderly to receive a timely kidney transplant, the Eurotransplant Senior Program was introduced. The ESP supports local allocation of older kidneys to older donors in order to decrease cold ischemia time, while disregarding former exchange principles based on matching for HLA antigens. As a consequence, more elderly received a kidney transplant and a relative higher incidence of acute rejection resulted in additional courses of high steroids and/or depleting antibody therapy. Since death with a functioning graft due to infections is the dominant reason of graft loss in elderly, more intense clinical immunosuppression to prevent or treat acute rejection is not a very attractive option. Therefore in elderly kidney transplant candidates, we advocate reintroduction of minimal histocompatibility criteria (i.e., HLA-DR matching) followed by age-matching with mandatory local/regional allocation to also facilitate short cold ischemia.
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Affiliation(s)
- Geertje J Dreyer
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, Netherlands
| | - Johan W de Fijter
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, Netherlands
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10
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Hofmann BB, Krapp N, Li Y, De La Torre C, Sol M, Braun JD, Kolibabka M, Pallavi P, Krämer BK, Yard BA, Kälsch AI. N-Octanoyl-Dopamine inhibits cytokine production in activated T-cells and diminishes MHC-class-II expression as well as adhesion molecules in IFNγ-stimulated endothelial cells. Sci Rep 2019; 9:19338. [PMID: 31853095 PMCID: PMC6920350 DOI: 10.1038/s41598-019-55983-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 11/29/2019] [Indexed: 01/06/2023] Open
Abstract
IFNγ enhances allograft immunogenicity and facilitates T-cell mediated rejection. This may cause interstitial fibrosis and tubular atrophy (IFTA), contributing to chronic allograft loss. We assessed if inhibition of T-cell activation by N-octanoyl dopamine (NOD) impairs adherence of activated T-cells to endothelial cells and the ability of activated T-cells to produce IFNγ. We also assessed if NOD affects IFNγ mediated gene expression in endothelial cells. The presence of NOD during T-cell activation significantly blunted their adhesion to unstimulated and cytokine stimulated HUVEC. Supernatants of these T-cells displayed significantly lower concentrations of TNFα and IFNγ and were less capable to facilitate T-cell adhesion. In the presence of NOD VLA-4 (CD49d/CD29) and LFA-1 (CD11a/CD18) expression on T-cells was reduced. NOD treatment of IFNγ stimulated HUVEC reduced the expression of MHC class II transactivator (CIITA), of MHC class II and its associated invariant chain CD74. Since IFTA is associated with T-cell mediated rejection and IFNγ to a large extent regulates immunogenicity of allografts, our current data suggest a potential clinical use of NOD in the treatment of transplant recipients. Further in vivo studies are warranted to confirm these in vitro findings and to assess the benefit of NOD on IFTA in clinically relevant models.
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Affiliation(s)
- Björn B Hofmann
- Department of Nephrology, Endocrinology and Rheumatology, Fifth Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Nicolas Krapp
- Department of Nephrology, Endocrinology and Rheumatology, Fifth Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Yingchun Li
- Department of Nephrology, Endocrinology and Rheumatology, Fifth Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Carolina De La Torre
- Center of Medical Research, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Marloes Sol
- Department of Medical Biology and Pathology, University Medical Center Groningen, Groningen, Netherlands
| | - Jana D Braun
- Department of Nephrology, Endocrinology and Rheumatology, Fifth Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Matthias Kolibabka
- Department of Nephrology, Endocrinology and Rheumatology, Fifth Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Prama Pallavi
- Department of Nephrology, Endocrinology and Rheumatology, Fifth Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Bernhard K Krämer
- Department of Nephrology, Endocrinology and Rheumatology, Fifth Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Benito A Yard
- Department of Nephrology, Endocrinology and Rheumatology, Fifth Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
| | - Anna-Isabelle Kälsch
- Department of Nephrology, Endocrinology and Rheumatology, Fifth Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
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11
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Süsal C, Döhler B. Late intra-patient tacrolimus trough level variability as a major problem in kidney transplantation: A Collaborative Transplant Study Report. Am J Transplant 2019; 19:2805-2813. [PMID: 30859672 DOI: 10.1111/ajt.15346] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 02/26/2019] [Accepted: 03/07/2019] [Indexed: 01/25/2023]
Abstract
Intra-patient variability (IPV) of tacrolimus trough level has been associated with poor outcome after kidney transplantation. These findings were derived from single-center analyses and restricted mainly to measurements early after transplantation. We analyzed in a multicenter effort whether high IPV of tacrolimus levels at posttransplant years 1, 2, and 3 was associated with impaired clinical outcome. More than 6600 patients who received a deceased donor kidney transplant during 2000-2014 and had a functioning graft for >3 years were studied. Graft survival was significantly impaired with increasing IPV (P < 0.001). As compared to patients with a low IPV of <30%, the risk of graft loss during years 4-6 increased 32% in patients with an IPV of 30% to 44% and 66% in patients with an IPV of ≥45% (P = 0.002 and P < 0.001). About one-third of patients showed an IPV of ≥30% with substantially impaired outcome. Even in patients with good outcome during the first 3 posttransplant years, a high IPV was associated with inferior graft survival. Our data indicate that a fluctuating tacrolimus trough level at years 1, 2, and 3 posttransplant is a major problem in kidney transplantation.
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Affiliation(s)
- Caner Süsal
- Institute of Immunology, Heidelberg University, Heidelberg, Germany
| | - Bernd Döhler
- Institute of Immunology, Heidelberg University, Heidelberg, Germany
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12
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Pretransplant Cancer in Kidney Recipients in Relation to Recurrent and De Novo Cancer Incidence Posttransplantation and Implications for Graft and Patient Survival. Transplantation 2019; 103:581-587. [PMID: 30418430 DOI: 10.1097/tp.0000000000002459] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Whether kidney transplant recipients who were treated for a malignant tumor before transplantation are at an increased risk of developing a tumor posttransplantation has not been adequately quantified and characterized. METHODS We studied more than 270 000 patients on whom pretransplant and posttransplant malignancy data were reported to the Collaborative Transplant Study. More than 4000 of these patients were treated for pretransplant malignancy. The posttransplant tumor incidence in these patients was compared to that in recipients without a pretransplant tumor. Cox regression, considering multiple confounders, was applied. RESULTS Significant increases in posttransplant tumor incidence with hazard ratio ranging from 2.10 to 5.47 (all P < 0.001) were observed for tumors in the site-specific pretransplant locations, suggesting tumor recurrences. There were also significantly increased de novo tumors in new locations with hazard ratio ranging from 1.28 to 1.89. Pretransplant basal cell carcinoma of the skin and male genital cancer were associated with significantly increased death-censored graft survival, suggesting impaired immune responsiveness against transplanted kidneys. Time interval from pretransplant tumor occurrence to transplantation and posttransplant mammalian target of rapamycin inhibitor treatment was not found to be of significant relevance in this study. CONCLUSIONS Patients who experienced a pretransplant tumor are at significant risk of tumor recurrence, regardless of the length of interval between tumor treatment and transplantation. There is also some increased risk for de novo tumors, suggesting impaired immune surveillance. Impaired tumor immunity appears to extend to a lower rate of transplant rejection because patients with pretransplant tumors tended to show improved death-censored graft survival.
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13
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Abstract
PURPOSE OF REVIEW Mesenchymal stromal cells (MSC) have emerged as one of the most promising candidates for immunomodulatory cell therapy in kidney transplantation. Here we describe novel insights into the MSC mechanism of action and provide an overview of initial safety and feasibility studies with MSC in kidney transplantation. RECENT FINDINGS Clinical studies of MSC-based cell therapy in kidney transplant recipients demonstrated the safety and feasibility of cell therapy and provide the first encouraging evidence of the efficacy of MSC in enabling the minimization of immunosuppressive drugs. In our initial experience with MSC-based therapy in kidney transplant recipients we carried out extensive clinical and immunological monitoring of MSC-treated patients and found possible biomarkers of MSC immunomodulation in some of them. Based on these biomarkers we identified a patient in whom complete discontinuation of immunosuppression has been achieved safely and successfully. SUMMARY Many issues should be addressed before MSC-based therapy becomes a standard treatment protocol for kidney transplantation. A better understanding of the MSC mechanism of action and the identification of biomarkers of response to therapy will inform the rational design of the most effective clinical protocol and the selection of patients amenable to safe immunosuppressive drug withdrawal.
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14
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Safety and Efficacy of Reduced Prolonged-release Tacrolimus Exposure in De Novo Kidney Transplantation: A Randomized, Open-label, Pilot Study in Asia-OPTIMIZE Study. Transplant Direct 2019; 5:e340. [PMID: 30993185 PMCID: PMC6445651 DOI: 10.1097/txd.0000000000000877] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Accepted: 12/11/2018] [Indexed: 11/26/2022] Open
Abstract
Background A multicenter, randomized, open-label, parallel group, pilot, 52-week study in Asian countries that assessed the renal function, efficacy, and safety of reduced-exposure versus standard-exposure prolonged-release tacrolimus (PR-T) in adult kidney transplant recipients (KTRs). Methods Posttransplantation, KTRs received PR-T from weeks 0 to 4 (initial dose, 0.2-0.3 mg/kg; target trough level, 6-10 ng/mL). At week 4, KTRs were randomized (1:1) to receive reduced-exposure PR-T (target 4-6 ng/mL, weeks 4-12; 3-5 ng/mL, weeks 12-52) or standard-exposure PR-T (target: 6-10 ng/mL, weeks 4-52). Primary end point: estimated glomerular filtration rate (eGFR) over 52 weeks. Secondary end points (week 52) included creatinine clearance, serum creatinine, graft/patient survival, biopsy-confirmed acute rejection (AR), composite of graft loss/patient death/biopsy-confirmed AR, and steroid-resistant AR. Treatment-emergent adverse events were recorded. Results Sixty-six KTRs received PR-T (reduced-exposure, n = 32; standard-exposure, n = 34) and were analyzed. After per-protocol dose adjustment, mean ± standard deviation tacrolimus trough level was lower with reduced- versus standard-exposure PR-T (week 52, 4.5 ± 1.1 ng/mL vs 8.0 ± 2.2 ng/mL). In the reduced- versus standard-exposure group, eGFR was similar at weeks 8 to 52 (overall least-square mean difference, -2.82; 95% confidence interval, -7.91 to 2.27; P = 0.272). At week 52, there was no significant difference in creatinine clearance (P = 0.375) or serum creatinine (P = 0.547) between groups. All grafts/patients survived, no steroid-resistant AR was reported, and 4 and 3 patients had AR in reduced- and standard-exposure groups, respectively. Drug-related treatment-emergent adverse events were reported in 34.4% and 38.2% of patients, respectively. Conclusions Reducing exposure to PR-T resulted in a clinically acceptable short-term safety profile and was generally as effective as standard tacrolimus exposure for Asian patients.
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15
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Veenhof H, Koster RA, Alffenaar JWC, van den Berg AP, de Groot MR, Verschuuren EA, Berger SP, Bakker SJ, Touw DJ. Clinical application of a dried blood spot assay for sirolimus and everolimus in transplant patients. ACTA ACUST UNITED AC 2019; 57:1854-1862. [DOI: 10.1515/cclm-2019-0053] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 03/08/2019] [Indexed: 11/15/2022]
Abstract
Abstract
Background
Monitoring of immunosuppressive drugs such as everolimus and sirolimus is important in allograft rejection prevention in transplant patients. Dried blood spots (DBS) sampling gives patients the opportunity to sample a drop of blood from a fingerprick at home, which can be sent to the laboratory by mail.
Methods
A total of 39 sirolimus and 44 everolimus paired fingerprick DBS and whole blood (WB) samples were obtained from 60 adult transplant patients for method comparison using Passing-Bablok regression. Bias was assessed using Bland-Altman. Two validation limits were pre-defined: limits of analytical acceptance were set at >67% of all paired samples within 20% of the mean of both samples and limits of clinical relevance were set in a multidisciplinary team at >80% of all paired samples within 15% of the mean of both samples.
Results
For both sirolimus and everolimus, Passing-Bablok regression showed no differences between WB and DBS with slopes of 0.86 (95% CI slope, 0.72–1.02) and 0.96 (95% CI 0.84–1.06), respectively. Only everolimus showed a significant constant bias of 4%. For both sirolimus and everolimus, limits of analytical acceptance were met (76.9% and 81.8%, respectively), but limits or clinical relevance were not met (77.3% and 61.5%, respectively).
Conclusions
Because pre-defined limits of clinical relevance were not met, this DBS sampling method for sirolimus and everolimus cannot replace WB sampling in our center at this time. However, if the clinical setting is compatible with less strict limits for clinical relevance, this DBS method is suitable for clinical application.
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Affiliation(s)
- Herman Veenhof
- Department of Clinical Pharmacy and Pharmacology , University of Groningen, University Medical Center Groningen , Groningen , The Netherlands
| | - Remco A. Koster
- Department of Clinical Pharmacy and Pharmacology , University of Groningen, University Medical Center Groningen , Groningen , The Netherlands
- PRA Health Sciences , Bioanalytical Laboratory , Assen , The Netherlands
| | - Jan-Willem C. Alffenaar
- Department of Clinical Pharmacy and Pharmacology , University of Groningen, University Medical Center Groningen , Groningen , The Netherlands
| | - Aad P. van den Berg
- Department of Gastroenterology and Hepatology , University of Groningen, University Medical Center Groningen , Groningen , The Netherlands
| | - Marco R. de Groot
- Department of Hematology , University of Groningen, University Medical Center Groningen , Groningen , The Netherlands
| | - Erik A.M. Verschuuren
- Department of Pulmonology and Tuberculosis , University of Groningen, University Medical Center Groningen , Groningen , The Netherlands
| | - Stefan P. Berger
- Department of Internal Medicine, Division of Nephrology , University of Groningen, University Medical Center Groningen , Groningen , The Netherlands
| | - Stephan J.L. Bakker
- Department of Internal Medicine, Division of Nephrology , University of Groningen, University Medical Center Groningen , Groningen , The Netherlands
| | - Daan J. Touw
- Department of Clinical Pharmacy and Pharmacology , University of Groningen, University Medical Center Groningen , Groningen , The Netherlands
- Department of Pharmacy, Section Pharmacokinetics, Toxicology and Targeting , University of Groningen , Groningen , The Netherlands , Phone: +31 503614071, Fax: +31 503612417
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Hanaoka K, Maeda M, Tsujimoto S, Oshima S, Fukahori H, Nakamura K, Noto T, Higashi Y, Hirose J, Takakura S, Morokata T. Benefits of a loading dose of tacrolimus on graft survival of kidney transplants in nonhuman primates. Transpl Immunol 2019. [DOI: 10.1016/j.trim.2018.10.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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17
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Lladó L, González-Castillo A, Fabregat J, Baliellas C, Ramos E, González-Vilatarsana E, Busquets J, Xiol X. Efficacy and Safety of Delayed Prolonged-Release Tacrolimus Initiation in De Novo Hepatitis C Virus-Negative Orthotopic Liver Transplant Recipients: A Single-Center, Single-Arm, Prospective Study. Ann Transplant 2019; 24:36-44. [PMID: 30655498 PMCID: PMC6346812 DOI: 10.12659/aot.912444] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Background Delaying initiation of tacrolimus after liver transplantation (LT) is a potential renal-sparing strategy. We assessed safety and efficacy of delayed initiation of prolonged-release tacrolimus (PR-T) in de novo LT. Material/Methods This was a single-center, single-arm, prospective, 12-month observational study of hepatitis C virus-negative orthotopic LT patients. Immunosuppression included PR-T (initially 0.1 or 0.2 mg/kg/day) initiated on Day 3 post LT, basiliximab (20 mg) on post-transplantation Day 0 and Day 4, and intraoperative corticosteroids (500 mg). Patients received maintenance corticosteroids and mycophenolate mofetil (MMF) according to center protocol. MMF dose was adjusted according to thrombocyte count. The primary endpoint was the estimated glomerular filtration rate (eGFR) measured using the Modification of Diet in Renal Disease 4-variable formula at 12 months. Secondary endpoints included biopsy-confirmed acute rejection (BCAR) and dialysis requirement. Adverse events were recorded. Results Sixty-nine patients (mean age 55.0 years) were included. Most patients started MMF on Day 1 (60.9%) or Day 2 (10.1%), and PR-T on Day 3 (55.1%) or Day 4 (29.0%). Mean tacrolimus trough levels (ng/mL) were: Day 7, 9.5±6.3; Day 10, 9.4±5.4; Month 1, 8.0±3.1; Month 3, 7.8±3.7; Month 6, 8.0±4.1; and Month 12, 7.2±3.1. Mean 12-month eGFR was 77.2±24.5 mL/min/1.73 m2; 72.5% of patients had eGFR >60 mL/min/1.73 m2 at 12 months; 89.9% had no eGFR measurements <40 mL/min/1.73 m2 during the study. Renal insufficiency (any eGFR <60 mL/min/1.73 m2) was diagnosed in 27.5% of patients; one patient required dialysis. There were no BCAR episodes; the infection rate was 36.2%, and 3 patients died. Overall, 19 patients (27.5%) developed de novo diabetes mellitus, 18 patients (26.1%) had hypercholesterolemia, and 12 patients (17.4%) had hypertriglyceridemia. Conclusions Quadruple therapy with delayed administration of PR-T was well tolerated and efficacious, and was associated with acceptable renal function over 12 months.
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Affiliation(s)
- Laura Lladó
- Liver Transplant Unit, University Hospital of Bellvitge, Barcelona, Spain
| | | | - Joan Fabregat
- Liver Transplant Unit, University Hospital of Bellvitge, Barcelona, Spain
| | - Carme Baliellas
- Liver Transplant Unit, University Hospital of Bellvitge, Barcelona, Spain
| | - Emilio Ramos
- Liver Transplant Unit, University Hospital of Bellvitge, Barcelona, Spain
| | | | - Juli Busquets
- Liver Transplant Unit, University Hospital of Bellvitge, Barcelona, Spain
| | - Xavier Xiol
- Liver Transplant Unit, University Hospital of Bellvitge, Barcelona, Spain
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18
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Advancing Transplantation: New Questions, New Possibilities in Kidney and Liver Transplantation. Transplantation 2018; 101 Suppl 2S:S1-S41. [PMID: 28125449 DOI: 10.1097/tp.0000000000001563] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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19
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Coemans M, Süsal C, Döhler B, Anglicheau D, Giral M, Bestard O, Legendre C, Emonds MP, Kuypers D, Molenberghs G, Verbeke G, Naesens M. Analyses of the short- and long-term graft survival after kidney transplantation in Europe between 1986 and 2015. Kidney Int 2018; 94:964-973. [PMID: 30049474 DOI: 10.1016/j.kint.2018.05.018] [Citation(s) in RCA: 189] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Revised: 04/26/2018] [Accepted: 05/17/2018] [Indexed: 12/21/2022]
Abstract
The evolution of kidney allograft survival remains insufficiently studied in the context of the changing donor and recipient demographics. Since European data are lacking we performed a cohort study (1986-2015) that, based on the Collaborative Transplant Study, included 108 787 recipients of brain-death kidney donors in 135 hospitals across 21 European countries. We analyzed the hazard rate of kidney failure after transplantation. Between 1986 and 1999, improvement in graft survival was more pronounced in the short term than in the long term: one-, five- and ten-year hazard rates after transplantation declined 64% (95% confidence interval, 61%-66%), 53% (49%-57%) and 45% (39%-50%), respectively. Between 2000 and 2015, hazard rates at one, five and ten years post-transplant declined respectively 22% (12-30%), 47% (36-56%) and 64% (45-76%). Improvement in graft survival in the first five years post-transplant was significantly less since 2000, while improvement after five years was comparable to before. During the 2000-2015 period improvement of graft survival was greater in the long than in the short term. These changes were independent of changing donor and recipient characteristics, and reflect the evolution in global kidney transplant management over the past decades. Unfortunately, after accounting for the evolution of donor and recipient characteristics, we found that short-term improvement in graft survival decreased since 2000, while long-term improvement remained unchanged in Europe. Thus, deceleration of short-term graft survival improvement in more recent years illustrates an unmet need for innovation.
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Affiliation(s)
- Maarten Coemans
- Department of Microbiology and Immunology, KU Leuven, University of Leuven, Leuven, Belgium; Leuven Biostatistics and Statistical Bioinformatics Centre, Leuven, Belgium
| | - Caner Süsal
- Institute of Immunology, University of Heidelberg, Heidelberg, Germany
| | - Bernd Döhler
- Institute of Immunology, University of Heidelberg, Heidelberg, Germany
| | - Dany Anglicheau
- Service de Néphrologie-Transplantation Adulte, Hôpital Necker, Paris, Université Paris Descartes & INSERM U 1151, Hôpital Necker, Paris, France
| | - Magali Giral
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France
| | - Oriol Bestard
- Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain
| | - Christophe Legendre
- Service de Néphrologie-Transplantation Adulte, Hôpital Necker, Paris, Université Paris Descartes & INSERM U 1151, Hôpital Necker, Paris, France
| | - Marie-Paule Emonds
- Department of Microbiology and Immunology, KU Leuven, University of Leuven, Leuven, Belgium; Histocompatibility and Immunogenetic Laboratory, Red Cross Flanders, Mechelen, Belgium
| | - Dirk Kuypers
- Department of Microbiology and Immunology, KU Leuven, University of Leuven, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Geert Molenberghs
- Leuven Biostatistics and Statistical Bioinformatics Centre, Leuven, Belgium
| | - Geert Verbeke
- Leuven Biostatistics and Statistical Bioinformatics Centre, Leuven, Belgium
| | - Maarten Naesens
- Department of Microbiology and Immunology, KU Leuven, University of Leuven, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
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20
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Wallin EF, Hill DL, Linterman MA, Wood KJ. The Calcineurin Inhibitor Tacrolimus Specifically Suppresses Human T Follicular Helper Cells. Front Immunol 2018; 9:1184. [PMID: 29904381 PMCID: PMC5990622 DOI: 10.3389/fimmu.2018.01184] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Accepted: 05/14/2018] [Indexed: 02/06/2023] Open
Abstract
Background T follicular helper (Tfh) cells are key players in the production of antibody-producing B cells via the germinal center reaction. Therapeutic strategies targeting Tfh cells are important where antibody formation is implicated in disease, such as transplant rejection and autoimmune diseases. We investigated the impact of the immunosuppressive agent tacrolimus on human Tfh cell differentiation and function in transplant recipients. Methods Paired blood and lymph node (LN) samples were obtained from 61 transplant recipients immediately prior to organ implantation. Living-donor recipients received a week of tacrolimus prior to kidney transplantation. Deceased-donor recipients served as controls, as tacrolimus was not administered until after the transplant operation. Flow cytometry was used to compare LN and circulating cell subsets. Results The calcineurin inhibitor (CNIs) tacrolimus specifically suppresses both LN Tfh cells and circulating Tfh cells, but not their regulatory counterparts or other CD4 T cell subsets. Conclusion Our findings suggest that CNIs may have a more important role in the prevention of antibody formation than previously understood and, therefore, have potential for antibody-associated conditions in which aberrant Tfh function has been implicated in disease.
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Affiliation(s)
- Elizabeth F Wallin
- Transplant Research Immunology Group, Nuffield Department Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Danika L Hill
- Lymphocyte Signalling ISP, Babraham Institute, Cambridge, United Kingdom.,Department of Immunology and Pathology, Monash University, Melbourne, VIC, Australia
| | | | - Kathryn J Wood
- Transplant Research Immunology Group, Nuffield Department Surgical Sciences, University of Oxford, Oxford, United Kingdom
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21
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Eskandary F, Regele H, Baumann L, Bond G, Kozakowski N, Wahrmann M, Hidalgo LG, Haslacher H, Kaltenecker CC, Aretin MB, Oberbauer R, Posch M, Staudenherz A, Handisurya A, Reeve J, Halloran PF, Böhmig GA. A Randomized Trial of Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection. J Am Soc Nephrol 2017; 29:591-605. [PMID: 29242250 DOI: 10.1681/asn.2017070818] [Citation(s) in RCA: 205] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 09/20/2017] [Indexed: 01/03/2023] Open
Abstract
Late antibody-mediated rejection (ABMR) is a leading cause of kidney allograft failure. Uncontrolled studies have suggested efficacy of the proteasome inhibitor bortezomib, but no systematic trial has been undertaken to support its use in ABMR. In this randomized, placebo-controlled trial (the Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection [BORTEJECT] Trial), we investigated whether two cycles of bortezomib (each cycle: 1.3 mg/m2 intravenously on days 1, 4, 8, and 11) prevent GFR decline by halting the progression of late donor-specific antibody (DSA)-positive ABMR. Forty-four DSA-positive kidney transplant recipients with characteristic ABMR morphology (median time after transplant, 5.0 years; pretransplant DSA documented in 19 recipients), who were identified on cross-sectional screening of 741 patients, were randomly assigned to receive bortezomib (n=21) or placebo (n=23). The 0.5-ml/min per 1.73 m2 per year (95% confidence interval, -4.8 to 5.8) difference detected between bortezomib and placebo in eGFR slope (primary end point) was not significant (P=0.86). We detected no significant differences between bortezomib- and placebo-treated groups in median measured GFR at 24 months (33 versus 42 ml/min per 1.73 m2; P=0.31), 2-year graft survival (81% versus 96%; P=0.12), urinary protein concentration, DSA levels, or morphologic or molecular rejection phenotypes in 24-month follow-up biopsy specimens. Bortezomib, however, associated with gastrointestinal and hematologic toxicity. In conclusion, our trial failed to show that bortezomib prevents GFR loss, improves histologic or molecular disease features, or reduces DSA, despite significant toxicity. Our results reinforce the need for systematic trials to dissect the efficiency and safety of new treatments for late ABMR.
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Affiliation(s)
| | | | - Lukas Baumann
- Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Gregor Bond
- Division of Nephrology and Dialysis, Department of Medicine III
| | | | - Markus Wahrmann
- Division of Nephrology and Dialysis, Department of Medicine III
| | | | | | | | | | | | - Martin Posch
- Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | | | | | - Jeff Reeve
- Alberta Transplant Applied Genomics Centre, University of Alberta, Edmonton, Alberta, Canada; and
| | - Philip F Halloran
- Alberta Transplant Applied Genomics Centre, University of Alberta, Edmonton, Alberta, Canada; and
| | - Georg A Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III,
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22
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Risk factors associated with the development of histocompatibility leukocyte antigen sensitization. Curr Opin Organ Transplant 2017; 21:447-52. [PMID: 27258577 DOI: 10.1097/mot.0000000000000336] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
PURPOSE OF REVIEW Despite excellent short-term kidney allograft survival rates, long-term outcomes have not improved. For years, the focus on improving these outcomes revolved around minimization or elimination of calcineurin toxicity. Despite our best efforts, approximately 5000 allografts are lost each year in the United States and results in a significant emotional burden for patients and financial burden for the healthcare system. RECENT FINDINGS Advancements in detection of donor-specific histocompatibility leukocyte antigen antibodies (DSAs) and improved assessment of allograft biopsy tissue have shown that the most common cause for graft failures is DSA-related antibody-mediated rejection. Sensitization is directly related to human tissue exposure prior to transplant. We now know that sensitization can occur in patients who are non compliant or poorly compliant with their calcineurin inhibitors. They develop de-novo DSAs, which are responsible for numerous allograft losses around the world. SUMMARY Given the current evidence, it is imperative that all transplant physicians recognize the importance of encouraging medication adherence to prevent the consequences of DSA-induced graft failure. However, little progress has been made in this area. Other potential therapeutic approaches based on B-cell depletion or modulation early posttransplant may help to reduce the risk for de-novo DSA development.
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23
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Massart A, Ghisdal L, Abramowicz M, Abramowicz D. Operational tolerance in kidney transplantation and associated biomarkers. Clin Exp Immunol 2017; 189:138-157. [PMID: 28449211 DOI: 10.1111/cei.12981] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/19/2017] [Indexed: 12/30/2022] Open
Abstract
In the 1960s, our predecessors won a historical battle against acute rejection and ensured that transplantation became a common life-saving treatment. In parallel with this success, or perhaps because of it, we lost the battle for long-lived transplants, being overwhelmed with chronic immune insults and the toxicities of immunosuppression. It is likely that current powerful treatments block acute rejection, but at the same time condemn the few circulating donor cells that would have been able to elicit immunoregulatory host responses towards the allograft. Under these conditions, spontaneously tolerant kidney recipients - i.e. patients who maintain allograft function in the absence of immunosuppression - are merely accidents; they are scarce, mysterious and precious. Several teams pursue the goal of finding a biomarker that would guide us towards the 'just right' level of immunosuppression that avoids rejection while leaving some space for donor immune cells. Some cellular assays are attractive because they are antigen-specific, and provide a comprehensive view of immune responses toward the graft. These seem to closely follow patient regulatory capacities. However, these tests are cumbersome, and require abundant cellular material from both donor and recipient. The latest newcomers, non-antigen-specific recipient blood transcriptomic biomarkers, offer the promise that a practicable and simple signature may be found that overcomes the complexity of a system in which an infinite number of individual cell combinations can lead possibly to graft acceptance. Biomarker studies are as much an objective - identifying tolerant patients, enabling tolerance trials - as a means to deciphering the underlying mechanisms of one of the most important current issues in transplantation.
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Affiliation(s)
- A Massart
- Department of Nephrology, Dialysis, and Transplantation, CUB Hôpital Erasme and Institute of Interdisciplinary Research in Molecular and Human Biology (IRIBHM), Université Libre de Bruxelles, Brussels, Belgium
| | - L Ghisdal
- Department of Nephrology, Centre Hospitalier EpiCURA, Baudour, Belgium
| | - M Abramowicz
- Department of Human Genetics, CUB Hôpital Erasme and Institute of Interdisciplinary Research in Molecular and Human Biology (IRIBHM), Université Libre de Bruxelles, Brussels, Belgium
| | - D Abramowicz
- Department of Nephrology, Universitair Ziekenhuis Antwerpen and Antwerp University, Antwerp, Belgium
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Kälble F, Schaier M, Schäfer S, Süsal C, Zeier M, Sommerer C, Morath C. An update on chemical pharmacotherapy options for the prevention of kidney transplant rejection with a focus on costimulation blockade. Expert Opin Pharmacother 2017; 18:799-807. [DOI: 10.1080/14656566.2017.1323876] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Florian Kälble
- Division of Nephrology, University of Heidelberg, Heidelberg, Germany
| | - Matthias Schaier
- Division of Nephrology, University of Heidelberg, Heidelberg, Germany
| | - Sebastian Schäfer
- Division of Nephrology, University of Heidelberg, Heidelberg, Germany
| | - Caner Süsal
- Department of Transplantation Immunology, University of Heidelberg, Heidelberg, Germany
| | - Martin Zeier
- Division of Nephrology, University of Heidelberg, Heidelberg, Germany
| | - Claudia Sommerer
- Division of Nephrology, University of Heidelberg, Heidelberg, Germany
| | - Christian Morath
- Division of Nephrology, University of Heidelberg, Heidelberg, Germany
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25
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Practical Recommendations for Long-term Management of Modifiable Risks in Kidney and Liver Transplant Recipients: A Guidance Report and Clinical Checklist by the Consensus on Managing Modifiable Risk in Transplantation (COMMIT) Group. Transplantation 2017; 101:S1-S56. [PMID: 28328734 DOI: 10.1097/tp.0000000000001651] [Citation(s) in RCA: 205] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Short-term patient and graft outcomes continue to improve after kidney and liver transplantation, with 1-year survival rates over 80%; however, improving longer-term outcomes remains a challenge. Improving the function of grafts and health of recipients would not only enhance quality and length of life, but would also reduce the need for retransplantation, and thus increase the number of organs available for transplant. The clinical transplant community needs to identify and manage those patient modifiable factors, to decrease the risk of graft failure, and improve longer-term outcomes.COMMIT was formed in 2015 and is composed of 20 leading kidney and liver transplant specialists from 9 countries across Europe. The group's remit is to provide expert guidance for the long-term management of kidney and liver transplant patients, with the aim of improving outcomes by minimizing modifiable risks associated with poor graft and patient survival posttransplant.The objective of this supplement is to provide specific, practical recommendations, through the discussion of current evidence and best practice, for the management of modifiable risks in those kidney and liver transplant patients who have survived the first postoperative year. In addition, the provision of a checklist increases the clinical utility and accessibility of these recommendations, by offering a systematic and efficient way to implement screening and monitoring of modifiable risks in the clinical setting.
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Overweight Kidney Transplant Recipients Are at Risk of Being Overdosed Following Standard Bodyweight-Based Tacrolimus Starting Dose. Transplant Direct 2017; 3:e129. [PMID: 28361113 PMCID: PMC5367746 DOI: 10.1097/txd.0000000000000644] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 11/12/2016] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Bodyweight-based dosing of tacrolimus (Tac) is considered standard care, even though the available evidence is thin. An increasing proportion of transplant recipients is overweight, prompting the question if the starting dose should always be based on bodyweight. METHODS For this analysis, data were used from a randomized-controlled trial in which patients received either a standard Tac starting dose or a dose that was based on CYP3A5 genotype. The hypothesis was that overweight patients would have Tac overexposure following standard bodyweight-based dosing. RESULTS Data were available for 203 kidney transplant recipients, with a median body mass index (BMI) of 25.6 (range, 17.2-42.2). More than 50% of the overweight or obese patients had a Tac predose concentration above the target range. The CYP3A5 nonexpressers tended to be above target when they weighed more than 67.5 kg or had a BMI of 24.5 or higher. Dosing guidelines were proposed with a decrease up to 40% in Tac starting doses for different BMI groups. The dosing guideline for patients with an unknown genotype was validated using the fixed-dose versus concentration controlled data set. CONCLUSIONS This study demonstrates that dosing Tac solely on bodyweight results in overexposure in more than half of overweight or obese patients.
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Garces JC, Giusti S, Staffeld-Coit C, Bohorquez H, Cohen AJ, Loss GE. Antibody-Mediated Rejection: A Review. Ochsner J 2017; 17:46-55. [PMID: 28331448 PMCID: PMC5349636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023] Open
Abstract
BACKGROUND Chronic antibody injury is a serious threat to allograft outcomes and is therefore the center of active research. In the continuum of allograft rejection, the development of antibodies plays a critical role. In recent years, an increased recognition of molecular and histologic changes has provided a better understanding of antibody-mediated rejection (AMR), as well as potential therapeutic interventions. However, several pathways are still unknown, which accounts for the lack of efficacy of some of the currently available agents that are used to treat rejection. METHODS We review the current diagnostic criteria for AMR; AMR paradigms; and desensitization, treatment, and prevention strategies. RESULTS Chronic antibody-mediated endothelial injury results in transplant glomerulopathy, manifested as glomerular basement membrane duplication, double contouring, or splitting. Clinical manifestations of AMR include proteinuria and a rise in serum creatinine. Current strategies for the treatment of AMR include antibody depletion with plasmapheresis (PLEX), immunoadsorption (IA), immunomodulation with intravenous immunoglobulin (IVIG), and T cell- or B cell-depleting agents. Some treatment benefits have been found in using PLEX and IA, and some small nonrandomized trials have identified some benefits in using rituximab and the proteasome inhibitor-based therapy bortezomib. More recent histologic follow-ups of patients treated with bortezomib have not shown significant benefits in terms of allograft outcomes. Furthermore, no specific treatment approaches have been approved by the US Food and Drug Administration. Other agents used for more difficult rejections include bortezomib and eculizumab (an anti-C5 monoclonal antibody). CONCLUSION AMR is a fascinating field with ample opportunities for research and progress in the future. Despite the use of advanced techniques for the detection of human leukocyte antigen (HLA) or non-HLA donor-specific antibodies, alloimmune response remains an important barrier for successful long-term allograft function. Treatment of AMR with currently available therapies has produced a variety of results, some of them suboptimal, precluding the development of standardized protocols. New therapies are promising, but randomized controlled trials are needed to find surrogate markers and improve the efficacy of therapy.
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Affiliation(s)
- Jorge Carlos Garces
- Multi-Organ Transplant Institute, Ochsner Clinic Foundation, New Orleans, LA
- The University of Queensland School of Medicine, Ochsner Clinical School, New Orleans, LA
| | - Sixto Giusti
- Multi-Organ Transplant Institute, Ochsner Clinic Foundation, New Orleans, LA
- Department of Nephrology, Ochsner Clinic Foundation, New Orleans, LA
| | - Catherine Staffeld-Coit
- The University of Queensland School of Medicine, Ochsner Clinical School, New Orleans, LA
- Department of Nephrology, Ochsner Clinic Foundation, New Orleans, LA
| | - Humberto Bohorquez
- Multi-Organ Transplant Institute, Ochsner Clinic Foundation, New Orleans, LA
- The University of Queensland School of Medicine, Ochsner Clinical School, New Orleans, LA
| | - Ari J. Cohen
- Multi-Organ Transplant Institute, Ochsner Clinic Foundation, New Orleans, LA
- The University of Queensland School of Medicine, Ochsner Clinical School, New Orleans, LA
| | - George E. Loss
- Multi-Organ Transplant Institute, Ochsner Clinic Foundation, New Orleans, LA
- The University of Queensland School of Medicine, Ochsner Clinical School, New Orleans, LA
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Zhou Y, Li X, Liu Y, Sun Q. Maintenance immunosuppressants in the management of antibody-mediated renal allograft rejection: which regimen is best? Immunotherapy 2016; 9:47-55. [PMID: 28000532 DOI: 10.2217/imt-2016-0096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Antibody-mediated rejection (AMR) is a pivotal cause of long-term graft failure following renal transplantation. De novo donor-specific antibody reduction is essential to prevent AMR and improve long-term graft survival in renal transplant recipients. Although the number of early AMR episodes can be successfully controlled by attenuating de novo donor-specific antibodies, the long-term outcomes are unsatisfactory. Numerous studies have focused on new strategies to reverse AMR, but the available evidence suggests that maintenance immunosuppressive agents play important roles. This article reviews data on the use of various maintenance immunosuppressive strategies in the management of AMR, with a focus on antibody-mediated kidney transplant rejection. Its aim is to help provide options benefitting long-term graft survival in renal transplant recipients.
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Affiliation(s)
- Yiqun Zhou
- Medical Department, Shanghai Roche Pharmaceuticals Ltd, Shanghai 201203, China
| | - Xiaolan Li
- Medical Department, Shanghai Roche Pharmaceuticals Ltd, Shanghai 201203, China
| | - Yun Liu
- Medical Department, Shanghai Roche Pharmaceuticals Ltd, Shanghai 201203, China
| | - Qiquan Sun
- Department of Renal Transplantation, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510530, China
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Abstract
Over the last decade, several biomarkers and surrogate markers have surfaced as promising predictive markers of risk of rejection in solid organ transplantation. The monitoring of these markers can help to improve graft and recipient care by personalizing immunomodulatory therapies. The complex immune system response against an implanted graft can change during long-term follow-up, and the dynamic balance between effector and regulatory T-cell populations is a crucial factor in antidonor response, risk of rejection, and immunosuppression requirements. Therefore, at any time before and after transplantation, T-effector activity, which is associated with increased production and release of proinflammatory cytokines, can be a surrogate marker of the risk of rejection and need for immunosuppression. In addition, immunosuppressive drugs may have a different effect in each individual patient. The pharmacokinetics and pharmacodynamics of these drugs show high interpatient variability, and pharmacodynamic markers, strongly associated with the specific mechanism of action, can potentially be used to measure individual susceptibility to a specific immunosuppressive agent. The monitoring of a panel of valid biomarkers can improve patient stratification and the selection of immunosuppressive drugs. After transplantation, therapy can be adjusted based on the prediction of rejection episodes (maintained alloreactivity), the prognosis of allograft damage, and the individual's response to the drugs. This review will focus on current data indicating that changes in the T-cell production of the intracellular cytokines interferon-γ and interleukin-2 could be used to predict the risk of rejection and to guide immunosuppressive therapy in transplant recipients.
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Žilinská Z, Dedinská I, Breza J, Laca L. Impact of Trough Levels of Tacrolimus on Kidney Function and Graft Survival in Short and Longer Periods After Renal Transplantation. Transplant Proc 2016; 48:2637-2643. [PMID: 27788794 DOI: 10.1016/j.transproceed.2016.06.051] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Accepted: 06/22/2016] [Indexed: 01/05/2023]
Abstract
BACKGROUND Optimizing immunosuppressive treatment in the early posttransplant period is important for achieving long-term graft function and survival. MATERIAL AND METHODS There were 205 renal transplant recipients involved in this study. Patients were divided into groups according to the induction therapy (no induction vs basiliximab/daclizumab vs rabbit antithymocyte globulin), maintenance therapy at the time of transplantation (tacrolimus [TAC] vs cyclosporine), the average trough TAC levels in months 4 to 6 after TO and serum creatinine 5 years after renal transplantation. RESULTS The incidence of acute rejection was significantly higher in cyclosporine than in TAC group of patients (P = .0364). The average TAC levels on elapsed time after transplantation significantly decreased (P < .0001). Five years after renal transplantation, there were higher TAC levels (5.6 ± 0.7 ng/mL) in the group with "zero" low levels than in the group with "zero" high levels (4.6 ± 1.1 ng/mL), which was statistically significant (P < .0001). We did not find any difference in graft and patient survival in posttransplant years 2 to 5 according to TAC levels or the induction treatment. CONCLUSIONS In our study, we have confirmed that better graft function 5 years after transplantation was connected with higher trough tacrolimus levels on elapsed time after renal transplantation.
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Affiliation(s)
- Z Žilinská
- Department of Urology with Kidney Transplant Center, University Hospital Bratislava, Bratislava, Slovak Republic
| | - I Dedinská
- Surgery Clinic and Transplant Center, University Hospital Martin and Jessenius Faculty of Medicine, Martin, Slovak Republic.
| | - J Breza
- Department of Urology with Kidney Transplant Center, University Hospital Bratislava, Bratislava, Slovak Republic
| | - L Laca
- Surgery Clinic and Transplant Center, University Hospital Martin and Jessenius Faculty of Medicine, Martin, Slovak Republic
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The Influence of Immunosuppressive Agents on the Risk of De Novo Donor-Specific HLA Antibody Production in Solid Organ Transplant Recipients. Transplantation 2016; 100:39-53. [PMID: 26680372 PMCID: PMC4683034 DOI: 10.1097/tp.0000000000000869] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Production of de novo donor-specific antibodies (dnDSA) is a major risk factor for acute and chronic antibody-mediated rejection and graft loss after all solid organ transplantation. In this article, we review the data available on the risk of individual immunosuppressive agents and their ability to prevent dnDSA production. Induction therapy with rabbit antithymocyte globulin may achieve a short-term decrease in dnDSA production in moderately sensitized patients. Rituximab induction may be beneficial in sensitized patients, and in abrogating rebound antibody response in patients undergoing desensitization or treatment for antibody-mediated rejection. Use of bortezomib for induction therapy in at-risk patients is of interest, but the benefits are unproven. In maintenance regimens, nonadherent and previously sensitized patients are not suitable for aggressive weaning protocols, particularly early calcineurin inhibitor withdrawal without lymphocyte-depleting induction. Early conversion to mammalian target of rapamycin inhibitor monotherapy has been reported to increase the risk of dnDSA formation, but a combination of mammalian target of rapamycin inhibitor and reduced-exposure calcineurin inhibitor does not appear to alter the risk. Early steroid therapy withdrawal in standard-risk patients after induction has no known dnDSA penalty. The available data do not demonstrate a consistent effect of mycophenolic acid on dnDSA production. Risk minimization for dnDSA requires monitoring of adherence, appropriate risk stratification, risk-based immunosuppression intensity, and prospective DSA surveillance.
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van Gelder T, Hesselink DA. Mycophenolate revisited. Transpl Int 2016; 28:508-15. [PMID: 25758949 DOI: 10.1111/tri.12554] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Revised: 02/03/2015] [Accepted: 03/06/2015] [Indexed: 12/11/2022]
Abstract
The patent of mycophenolate mofetil (MMF) has expired, and for enteric-coated mycophenolate sodium (EC-MPS), this will happen in 2017. In the twenty years these drugs have been used, they have become extremely popular. In this review, the reasons for the popularity of mycophenolate are discussed, including the benefits compared to azathioprine. MMF and EC-MPS are therapeutically equivalent. Although neither is considered to be a narrow therapeutic index drug, this should not lead to careless switching between the innovator drug and generic formulations, or between one generic formulation and another. The pipeline of new immunosuppressive drugs is dry, and it is very likely that we will be using mycophenolate for many more years to come as a first-line immunosuppressive drug in our transplant population. Whether or not the development of donor-specific anti-HLA antibodies is related to drug exposure (mycophenolic acid concentrations) remains to be investigated.
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Affiliation(s)
- Teun van Gelder
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center, Rotterdam, The Netherlands; Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
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Su VC, Greanya ED, Ensom MHH. Impact of Mycophenolate Mofetil Dose Reduction on Allograft Outcomes in Kidney Transplant Recipients on Tacrolimus-Based Regimens: A Systematic Review. Ann Pharmacother 2015; 45:248-57. [PMID: 21304036 DOI: 10.1345/aph.1p456] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVE To systematically evaluate the clinical consequences of mycophenolate dose reduction in renal transplant recipients on tacrolimus-based regimens. DATA SOURCES PubMed (1949-July 2010), EMBASE (1980-July 2010), Cochrane Database of Systematic Reviews, International Pharmaceutical Abstracts, and Web of Science were searched using the terms mycophenolate mofetil, tacrolimus, dose reduction, and kidney and/or renal transplant. References from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION Studies reporting on rejection rate, allograft survival, or renal function were included and ranked according to the US Preventive Services Task Force classification; excluded were studies that were dose-finding or used cyclosporine only, involved patients on enteric-coated mycophenolate sodium or those with multiorgan transplant, or provided no information on concomitant immunosuppressants. Data extracted were study design, sample size, immunosuppression regimen, type of transplant, and allograft outcomes. DATA SYNTHESIS Of 13 studies included, 1 was level I evidence, 3 were level II-2, 6 were level II-3, and 3 were level III evidence. Three focused on tacrolimus-based regimens, whereas 7 included either cyclosporine or tacrolimus. The only prospective, randomized, multicenter trial demonstrated that early taper of mycophenolate dosage to 1 g/day can be utilized without increased risk of rejection, compared with late tapering, but the rejection rate was high (30-40%). Overall, we found conflicting evidence regarding the impact of mycophenolate dose reduction on rejection rate and allograft loss and that discontinuing mycophenolate led to an increased risk of graft loss as high as 8 fold. Allograft survival was lowest in patients with gastrointestinal complications and those in whom mycophenolate was discontinued, compared with patients with neither gastrointestinal complications nor mycophenolate discontinuation. CONCLUSIONS Weak evidence suggests that mycophenolate dose modifications, either reduction or discontinuation, may increase rejection rate and graft loss; however, this is more apparent in cyclosporine-based regimens. Prospective, well-designed trials are necessary to definitively determine the impact of dose reduction in renal transplant recipients on tacrolimus-based regimens.
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Affiliation(s)
- Victoria Ch Su
- Victoria CH Su BSc (Pharm) ACPR, PharmD student, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Erica D Greanya
- Erica D Greanya BSc (Pharm) ACPR PharmD, Pharmacy Specialist-Solid Organ Transplantation, Vancouver General Hospital, Vancouver; Clinical Assistant Professor, Faculty of Pharmaceutical Sciences, The University of British Columbia
| | - Mary H H Ensom
- Mary HH Ensom BSc (Pharm) PharmD FASHP FCCP FCSHP FCAHS, Professor and Director, Doctor of Pharmacy Program, Faculty of Pharmaceutical Sciences, and Distinguished University Scholar, The University of British Columbia; Clinical Pharmacy Specialist, Children's and Women's Health Centre of British Columbia, Vancouver
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Ferjani H, El Abassi H, Ben Salem I, Guedri Y, Abid S, Achour A, Bacha H. The evaluate and compare the effects of the Tacrolimus and Sirolimus on the intestinal system using an intestinal cell culture model. Toxicol Mech Methods 2015; 26:54-60. [DOI: 10.3109/15376516.2015.1090514] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Ji SM, Xie KN, Chen JS, Wen JQ, Cheng DR, Cheng DP, Li X, Ni XF, Liu ZH. Retrospective evaluation of the effect of mycophenolate mofetil dosage on survival of kidney grafts based on biopsy results. Transplant Proc 2015; 46:3383-9. [PMID: 25498056 DOI: 10.1016/j.transproceed.2014.09.107] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2014] [Revised: 08/21/2014] [Accepted: 09/17/2014] [Indexed: 11/28/2022]
Abstract
INTRODUCTION Plasma concentration monitoring is commonly used to adjust immunosuppressant dosage in transplant recipients, but adjustment is often based on clinical experience rather than rigorous quantitative indicators. METHODS We examined the effect of mycophenolate mofetil (MMF) dosage on graft survival by pathologic and immunologic analysis of 88 kidney recipients who were given a postoperative immunosuppressive regimen of tacrolimus (FK506), MMF, and corticosteroids. Patients were given a conventional dosage (≥1.5 g/d; n = 40) or a reduced dosage (n = 48) of MMF owing to postoperative adverse side effects. RESULTS The reduced-dose group included patients given low doses (≤1.0 g/d; n = 27), ultra-low doses (≤0.5 g/d; n = 15), and those who discontinued MMF (n = 6). The dose reduction group had increased acute rejection, chronic rejection, and graft dysfunction, poorer pathologic scores, and increased cell infiltration of graft tissue (CD4, CD8, CD68, and CD138 positivity) and expression of interleukin-2R and HLA-DR. Finally, hazard analysis indicated that patients given low doses and ultra-low doses of MMF had poorer long-term kidney grafts survival (hazard ratios of 1.52 and 1.78, respectively). CONCLUSIONS These results indicate the importance of using an appropriate dosage of MMF in kidney transplant recipients.
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Affiliation(s)
- S-M Ji
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - K-N Xie
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - J-S Chen
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - J-Q Wen
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | | | - D-P Cheng
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - X Li
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - X-F Ni
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Z-H Liu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China. zhihong--
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Flechner SM. Optimizing immunosuppression: who can do more with less? Transpl Int 2015; 29:20-2. [PMID: 26310496 DOI: 10.1111/tri.12676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 08/20/2015] [Indexed: 11/28/2022]
Affiliation(s)
- Stuart M Flechner
- Glickman Urological and Kidney Institute, Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA
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Bodnár Z, Sipka S, Tidrenczel E, Amador Marchante M. [Ten years' experience in the research of abdominal compartment syndrome (2004-2014)]. Orv Hetil 2015; 155:1820-30. [PMID: 25344852 DOI: 10.1556/oh.2014.30030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Intra-abdominal hypertension and abdominal compartment syndrome are frequent findings among severe surgical ill patients. In spite of the fast diagnostic methods and effective therapeutic procedures the mortality is high. The causing factors lead to increased intra-abdominal pressure and abdominal compartment syndrome. It can be defined as adverse physiologic consequences that occur as a result of an acute increase in the intra-abdominal pressure. The most common causes are retroperitoneal haemorrhage, pancreatitis, bowel obstruction, tense ascites, peritonitis and serious visceral edema due to massive fluid resuscitation. The affected systems are cardiovascular, respiratory, renal, central nervous systems, splanchnic organs, and finally the whole body. The diagnostic method is the intra-abdominal pressure monitoring. The bases of the treatment are adequate fluid resuscitation, non-surgical management and decompression. The authors review the topic including the international and Hungarian references based on their ten years experience.
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Affiliation(s)
- Zsolt Bodnár
- Torrevieja Egyetemi Oktatókórház (Hospital de Torrevieja) Általános Sebészeti Osztály (Servicio de Cirugía General) Carretera CV-95, s/n 03186 Torrevieja (Alicante) Spanyolország
| | - Sándor Sipka
- Debreceni Egyetem, Orvos- és Egészségtudományi Centrum Belgyógyászati Intézet, Regionális Immunológiai Laboratórium Debrecen
| | - Edit Tidrenczel
- Torrevieja Egyetemi Oktatókórház (Hospital de Torrevieja) Sürgősségi Betegellátó Osztály Torrevieja (Alicante) Spanyolország
| | - Maria Amador Marchante
- Torrevieja Egyetemi Oktatókórház (Hospital de Torrevieja) Általános Sebészeti Osztály (Servicio de Cirugía General) Carretera CV-95, s/n 03186 Torrevieja (Alicante) Spanyolország
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Bestard O, Sarwal MM. Antibody-mediated rejection in young kidney transplant recipients: the dilemma of noncompliance and insufficient immunosuppression. Pediatr Nephrol 2015; 30:397-403. [PMID: 25503324 DOI: 10.1007/s00467-014-3020-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Revised: 11/09/2014] [Accepted: 11/10/2014] [Indexed: 11/29/2022]
Abstract
BACKGROUND Antibody-mediated rejection (ABMR) is a recognized cause of late kidney allograft loss. Although ABMR may occur despite appropriate chronic immunosuppressive therapy, non-adherence both facilitates and accelerates the activation of the effector phase of the humoral immune response against the donor tissue, leading in turn to progressive kidney allograft rejection. Given the poor efficacy of rescue therapies for both acute and chronic late ABMR, establishing appropriate preventive strategies at different times before and after transplantation is a critical management goal. CASE-DIAGNOSIS/TREATMENT In this report, we discuss the differential diagnoses and management of ABMR based on the clinical case report of a young kidney transplant recipient with progressive ABMR due to poor immunosuppressive adherence. In the absence of sensitive and specific non-invasive monitoring tools for alloimmune activation, the clinical dilemma in the management of the adolescent patient lies in differentiating between suboptimal prescribed immunosuppression and deliberate non-adherence to adequate immunosuppression dosing. Despite the advent of therapies to reduce ABMR injury, the graft is destined for untimely functional loss. CONCLUSIONS New biomarkers and tools for the accurate characterization of alloimmune risk before and after transplantation, and serial testing for de novo changes in circulating donor-specific alloantibodies, are urgently needed to support the delivery of optimized immunosuppression exposure.
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Affiliation(s)
- Oriol Bestard
- Renal Transplant Unit, Nephrology Department, Bellvitge University Hospital, IDIBELL, Barcelona, Spain,
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Clinical relevance of HLA antibody monitoring after kidney transplantation. J Immunol Res 2014; 2014:845040. [PMID: 25374891 PMCID: PMC4211317 DOI: 10.1155/2014/845040] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Accepted: 09/10/2014] [Indexed: 11/18/2022] Open
Abstract
In kidney transplantation, antibody-mediated allograft injury caused by donor HLA-specific antibodies (DSA) has recently been identified as one of the major causes of late graft loss. This paper gives a brief overview on the impact of DSA development on graft outcome in organ transplantation with a focus on risk factors for de novo alloantibody induction and recently published guidelines for monitoring of DSA during the posttransplant phase.
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40
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15-year follow-up of a multicenter, randomized, calcineurin inhibitor withdrawal study in kidney transplantation. Transplantation 2014; 98:47-53. [PMID: 24521775 DOI: 10.1097/01.tp.0000442774.46133.71] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Calcineurin inhibitors (CNIs) are essential immunosuppressive drugs after renal transplantation. Because of nephrotoxicity, withdrawal has been a challenge since their introduction. METHODS A randomized multicenter trial included 212 kidney patients transplanted between 1997 and 1999. All patients were initially treated with mycophenolate mofetil (MMF), cyclosporine A (CsA), and prednisone (pred). At 6 months after transplantation, 63 patients were randomized for MMF/pred, 76 for MMF/CsA, and 73 for MMF/CsA/pred. Within 18 months after randomization 23 patients experienced a rejection episode: MMF/pred (27.0%), MMF/CsA (6.8%) and MMF/CsA/pred (1.4%) (P<0.001). RESULTS During 15 years of follow-up, 73 patients died with a functioning graft, and 43 patients lost their graft. Ninety-six were alive with a functioning graft. Intention-to-treat analysis did not show a significant difference in patient and graft survival. In multivariate analysis, death-censored graft survival was significantly associated with serum creatinine at 6 months after transplantation and maximum PRA but not with the randomization group. CNI withdrawal did not result in a reduced incidence of or death by malignancy or cardiovascular disease. Death-censored graft survival was significantly worse in those patients randomized for CNI withdrawal that had to be reverted to CNI. Independent of randomization group, compared with no rejection, death-censored graft survival was significantly worse in 23 patients with acute rejection after randomization. CONCLUSION Fifteen years after conversion to a CNI free regimen, there was no benefit regarding graft and patient survival or regarding prevalence of or death by comorbidities. However, rejection shortly after CNI withdrawal was associated with decreased graft survival.
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Langone A, Shihab F, Pankewycz O, Doria C, Wiland A, McCague K, Chan L. Long-term dosing patterns of enteric-coated mycophenolate sodium or mycophenolate mofetil with tacrolimus after renal transplantation. Clin Transplant 2014; 28:961-7. [PMID: 24893821 DOI: 10.1111/ctr.12392] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/01/2014] [Indexed: 11/29/2022]
Abstract
MORE was a four-yr, prospective, observational study at 40 transplant centers in the US. Data were analyzed to evaluate changes in mycophenolic acid (MPA) dosing over time in 904 de novo kidney transplant recipients receiving enteric-coated mycophenolate sodium (EC-MPS, n = 616) or mycophenolate mofetil (MMF, n = 288) with tacrolimus. Induction therapy and steroid treatment were similar in the two subpopulations. The proportion of patients receiving the maximal recommended MPA dose was 80.5%, 43.9%, 39.2%, 34.6%, and 30.1% at baseline and years 1, 2, 3, and 4, respectively. More patients received the maximal recommended MPA dose with EC-MPS vs. MMF at month 1 (79.2% vs. 71.7%, p = 0.016), month 3 (68.5% vs. 56.9%, p = 0.001), and month 6 (52.9% vs. 44.0%, p = 0.028). Multivariate analysis showed the risk of biopsy-proven acute rejection, graft loss or death to be similar for EC-MPS vs. MMF. Estimated glomerular filtration rate (GFR) was similar with EC-MPS vs. MMF at all time points. There were no significant differences in any category of adverse event between the EC-MPS and MMF cohorts during follow-up, including gastrointestinal events. In conclusion, MPA dose was maintained more effectively in the first six months after kidney transplantation using EC-MPS vs. MMF, without an increase in adverse events.
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Wedel J, Hottenrott MC, Stamellou E, Breedijk A, Tsagogiorgas C, Hillebrands JL, Yard BA. N-Octanoyl dopamine transiently inhibits T cell proliferation via G1 cell-cycle arrest and inhibition of redox-dependent transcription factors. J Leukoc Biol 2014; 96:453-62. [PMID: 24929005 DOI: 10.1189/jlb.3a0813-455r] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Recently, we developed a nonhemodynamic dopamine derivative, NOD, which has profound anti-inflammatory effects in vitro. As NOD also protects rats from ischemic AKI, the present study tested whether NOD is able to modulate cellular immunity for potential use as a T cell-suppressive agent. To this end, T cells were stimulated by anti-CD3/CD28 or PMA/ionomycin in the presence or absence of different concentrations of NOD. T cell proliferation, activation markers, intracellular cytokine expression, and activation of transcription factors were assessed. Whereas T cell proliferation was inhibited significantly by NOD at Day 3, proliferation was restored at Day 7 or later depending on the NOD concentration used. Inhibition of proliferation was reflected by a diminished CD25 expression and switch from naive to memory T cells. Early TCR activation events were unaffected, yet NF-κB and AP-1 were strongly inhibited by NOD. The inhibitory effect of NOD seemed to be dependent on its redox activity, as NOT, a redox-inactive NOD derivate, did not influence proliferation. NOD displayed synergistic effects with CNIs on T cell proliferation. Our data demonstrate that NOD displays T cell-suppressive activity. In keeping with its anti-inflammatory action and its beneficial effect on ischemia-induced AKI, NOD may be an interesting drug candidate to prevent CNI-related side-effects.
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Affiliation(s)
- Johannes Wedel
- Departments of Medicine, Nephrology, Endocrinology, Diabetology, Rheumatology and
| | - Maximillia C Hottenrott
- Anesthesia and Critical Care, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; and
| | - Eleni Stamellou
- Departments of Medicine, Nephrology, Endocrinology, Diabetology, Rheumatology and
| | - Annette Breedijk
- Departments of Medicine, Nephrology, Endocrinology, Diabetology, Rheumatology and
| | - Charalambos Tsagogiorgas
- Anesthesia and Critical Care, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; and
| | - Jan-Luuk Hillebrands
- Department of Pathology and Medical Biology, Pathology Section, University of Groningen, University Medical Center, Groningen, The Netherlands
| | - Benito A Yard
- Departments of Medicine, Nephrology, Endocrinology, Diabetology, Rheumatology and
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Klawitter J, Klawitter J, Schmitz V, Shokati T, Epshtein E, Thurman JM, Christians U. Mycophenolate mofetil enhances the negative effects of sirolimus and tacrolimus on rat kidney cell metabolism. PLoS One 2014; 9:e86202. [PMID: 24497939 PMCID: PMC3907404 DOI: 10.1371/journal.pone.0086202] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2013] [Accepted: 12/08/2013] [Indexed: 12/12/2022] Open
Abstract
Background and Purpose Mycophenolate mofetil (MMF) per se is not known to have negative effects on the kidney. MMF alone or in combination with sirolimus, can be the basis of calcineurin inhibitor (CNI)-free, kidney sparing drug protocols. However, long-term outcomes in patients on MMF/SRL seem to be inferior to those treated with regimens that include the CNI tacrolimus (TAC) due to an increased risk of allo-immune reactions. Interestingly, potential enhancement of the negative effects of SRL and TAC on the kidney by MMF has never been considered. Experimental Approach It was our aim to study the effects of TAC, SRL and MMF alone and evaluate their interactions when combined on the rat kidney. For this purpose we used a comprehensive molecular marker approach including measurements of urinary 8-isoprostane concentrations (oxidative stress marker) and changes of urinary metabolite patterns (1H-NMR spectroscopy) and comparing these markers to renal function (glomerular filtration rate (GFR)) and morphologic alterations (histology). Key Results While MMF alone did not impact GFR, its interaction with SRL and TAC led to a significant decrease of rats’ renal function. The decline went in parallel with a significant increase in urinary isoprostane concentrations and an enhancement of negative effects on urinary metabolite patterns. Conclusions In broad summary, the present study showed that MMF may enhance the negative effects of TAC on kidney function and may even display nephrotoxic properties when combined with SRL.
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Affiliation(s)
- Jelena Klawitter
- Department of Anesthesiology, University of Colorado, Aurora, Colorado, United States of America
- Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado, United States of America
- * E-mail:
| | - Jost Klawitter
- Department of Anesthesiology, University of Colorado, Aurora, Colorado, United States of America
| | - Volker Schmitz
- Department of Anesthesiology, University of Colorado, Aurora, Colorado, United States of America
- Department of General-, Visceral- and Transplantation Surgery, Charité, Campus Virchow, Berlin, Germany
| | - Touraj Shokati
- Department of Anesthesiology, University of Colorado, Aurora, Colorado, United States of America
| | - Ekaterina Epshtein
- Department of Anesthesiology, University of Colorado, Aurora, Colorado, United States of America
| | - Joshua M. Thurman
- Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado, United States of America
| | - Uwe Christians
- Department of Anesthesiology, University of Colorado, Aurora, Colorado, United States of America
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Salisbury EM, Game DS, Lechler RI. Transplantation tolerance. Pediatr Nephrol 2014; 29:2263-72. [PMID: 24213880 PMCID: PMC4212135 DOI: 10.1007/s00467-013-2659-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Revised: 10/01/2013] [Accepted: 10/04/2013] [Indexed: 01/26/2023]
Abstract
Although transplantation has been a standard medical practice for decades, marked morbidity from the use of immunosuppressive drugs and poor long-term graft survival remain important limitations in the field. Since the first solid organ transplant between the Herrick twins in 1954, transplantation immunology has sought to move away from harmful, broad-spectrum immunosuppressive regimens that carry with them the long-term risk of potentially life-threatening opportunistic infections, cardiovascular disease, and malignancy, as well as graft toxicity and loss, towards tolerogenic strategies that promote long-term graft survival. Reports of "transplant tolerance" in kidney and liver allograft recipients whose immunosuppressive drugs were discontinued for medical or non-compliant reasons, together with results from experimental models of transplantation, provide the proof-of-principle that achieving tolerance in organ transplantation is fundamentally possible. However, translating the reconstitution of immune tolerance into the clinical setting is a daunting challenge fraught with the complexities of multiple interacting mechanisms overlaid on a background of variation in disease. In this article, we explore the basic science underlying mechanisms of tolerance and review the latest clinical advances in the quest for transplantation tolerance.
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Affiliation(s)
- Emma M. Salisbury
- Section of Immunobiology, Division of Immunology and Inflammation, Department of Medicine, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, South Kensington Campus, Exhibition Road, London, SW7 2AZ UK
| | - David S. Game
- Department of Renal Medicine, Guy’s and St. Thomas’ NHS Foundation Trust, Guy’s Hospital, Great Maze Pond, London, SE1 9RT UK
| | - Robert I. Lechler
- King’s Health Partners Academic Health Sciences Centre, King’s College London, London, WC2R 2LS UK
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Abstract
Late kidney transplant dysfunction may be a harbinger of graft failure. For many years, calcineurin inhibitor toxicity was felt to be the main cause for graft dysfunction with fibrosis and transplant loss. Recently this idea has come into question. With the observation that peritubular capillary C4d staining in kidney allografts may indicate antibody-mediated injury in conjunction with biopsy study findings, an appreciation for antibody-mediated rejection as a major cause of late graft dysfunction and loss has emerged. Twenty percent to 30% of patients develop de novo donor-specific antibodies after kidney transplantation. There are no US Food and Drug Administration-approved treatments for antibody-mediated rejection, nor have any randomized controlled trials assessed efficacy. Off-label treatment strategies include some combination of plasma exchange, intravenous immunoglobulin, and rituximab. Other approaches, including splenectomy, bortezomib, and eculizumab, have also been tried.
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Salvadori M, Bertoni E. Is it time to give up with calcineurin inhibitors in kidney transplantation? World J Transplant 2013; 3:7-25. [PMID: 24175203 PMCID: PMC3782241 DOI: 10.5500/wjt.v3.i2.7] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Revised: 04/17/2013] [Accepted: 05/09/2013] [Indexed: 02/05/2023] Open
Abstract
Calcineurin inhibitors (CNIs) represent today a cornerstone for the maintenance immunosuppressive treatment in solid organ transplantation. Nevertheless, several attempts have been made either to minimize their dosage or to avoid CNIs at all because these drugs have the severe side effect of chronic nephrotoxicity. This issue represents a frontier for renal transplantation. The principal problem is to understanding whether the poor outcome over the long-term may be ascribed to CNIs nephrotoxicity or to the inability of these drugs to control the acute and chronic rejection B cells mediated. The authors analyze extensively all the international trials attempting to withdraw, minimize or avoid the use of CNIs. Few trials undertaken in low risk patients with an early conversion from CNIs to proliferation signal inhibitors were successful, but the vast majority of trials failed to improve CNIs side effects. To date the use of a new drug, a co-stimulation blocker, seems promising in avoiding CNIs with similar efficacy, better glomerular filtration rate and an improved metabolic profile. Moreover the use of this drug is not associated with the development of donor-specific anti-human leukocyte antigen antibodies. This point has a particular relevance, because the failure of CNIs to realize good outcomes in renal transplantation has recently ascribed to their inability to control the acute and chronic rejections B-cell mediated. This paper analyzes all the recent studies that have been done on this issue that represents the real frontier that should be overcome to realize better results over the long-term after transplantation.
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Süsal C, Opelz G, Morath C. Role and Value of Luminex(®)-Detected HLA Antibodies before and after Kidney Transplantation. ACTA ACUST UNITED AC 2013; 40:190-5. [PMID: 23922544 DOI: 10.1159/000351314] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2013] [Accepted: 02/22/2013] [Indexed: 12/18/2022]
Abstract
SUMMARY The complement-dependent lymphocytotoxicity (CDC) method has been the classical technique to detect human leukocyte antigen (HLA) antibodies in sera of patients who are listed for kidney transplantation. Because of the drawbacks of CDC, such as low sensitivity and low resolution in characterizing antibody specificities, the more specific ELISA technology was introduced in the 1990s which utilizes solubilized HLA molecules instead of lymphocytes. During the last 10 years, the introduction of the Luminex-based single antigen bead (L-SAB) technology, which uses recombinant single HLA molecules, allows detection and characterization of HLA antibodies at greater sensitivity than CDC and ELISA. A drawback associated with this technique is that the interpretation of results is demanding and requires comprehensive experience in HLA antibody diagnostics. Herein we discuss the current role and value of L-SAB technology in the clinical management of sensitized kidney transplant recipients.
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Affiliation(s)
- Caner Süsal
- Department of Transplant Immunology, University of Heidelberg, Heidelberg, Germany
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Schaefer SM, Süsal C, Sommerer C, Zeier M, Morath C. Current pharmacotherapeutical options for the prevention of kidney transplant rejection. Expert Opin Pharmacother 2013; 14:1029-41. [DOI: 10.1517/14656566.2013.788151] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Doria C, Greenstein S, Narayanan M, Ueda K, Wiland A, McCague K, Sankari B, Chan L. Association of mycophenolic acid dose with efficacy and safety events in kidney transplant patients receiving tacrolimus: an analysis of the Mycophenolic acid Observational REnal transplant registry. Clin Transplant 2012; 26:E602-11. [PMID: 23121178 PMCID: PMC3556697 DOI: 10.1111/ctr.12035] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/05/2012] [Indexed: 01/30/2023]
Abstract
Background Dose-finding studies for mycophenolic acid (MPA) in tacrolimus-treated kidney transplant patients are lacking. Methods Data from 901 de novo kidney transplant recipients enrolled in the prospective, non-interventional Mycophenolic acid Observational REnal (MORE) transplant registry were analyzed according to baseline daily MPA dose (<2000, 2000 or >2000 mg). Results The proportion of patients receiving 2000 and <2000 mg was 77.6% and 19.9% at baseline, 74.5% and 23.3% at month 1, 62.4% and 35.5% at month 3, 48.5% and 50.2% at month 6, and 44.1% and 55.2% at month 12. More patients were maintained on 2000 mg with enteric-coated mycophenolate sodium (EC-MPS) vs. mycophenolate mofetil (month 6, 52.7% vs. 43.0% [p = 0.02]; month 12, 47.3% vs. 39.4% [p = 0.08]). Multivariate modeling showed no significant effect of baseline MPA dose on 12-month risk of biopsy-proven acute rejection, graft loss or estimated GFR, or on safety events including MPA discontinuation other than a higher rate of gastrointestinal adverse events in patients with an initial MPA dose >2000 mg (p = 0.029) vs. 2000 mg. Conclusions These findings suggest that an initial MPA dose of <2000 mg does not compromise 12-month efficacy in tacrolimus-treated kidney transplants, but controlled trials are required and the lower threshold for MPA dose remains to be defined.
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Affiliation(s)
- Cataldo Doria
- Department of Transplant Surgery, Thomas Jefferson University Hospital, Philadelphia, PA 19107-5563, USA.
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Everolimus and sirolimus in combination with cyclosporine have different effects on renal metabolism in the rat. PLoS One 2012; 7:e48063. [PMID: 23118926 PMCID: PMC3485290 DOI: 10.1371/journal.pone.0048063] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2012] [Accepted: 09/19/2012] [Indexed: 01/05/2023] Open
Abstract
Enhancement of calcineurin inhibitor nephrotoxicity by sirolimus (SRL) is limiting the clinical use of this drug combination. We compared the dose-dependent effects of the structurally related everolimus (EVL) and sirolimus (SRL) alone, and in combination with cyclosporine (CsA), on the rat kidney. Lewis rats were treated by oral gavage for 28 days using a checkerboard dosing format (0, 3.0, 6.0 and 10.0 CsA and 0, 0.5, 1.5 and 3.0 mg/kg/day SRL or EVL, n = 4/dose combination). After 28 days, oxidative stress, energy charge, kidney histologies, glomerular filtration rates, and concentrations of the immunosuppressants were measured along with 1H-magnetic resonance spectroscopy (MRS) and gas chromatography- mass spectrometry profiles of cellular metabolites in urine. The combination of CsA with SRL led to higher urinary glucose concentrations and decreased levels of urinary Krebs cycle metabolites when compared to controls, suggesting that CsA+SRL negatively impacted proximal tubule metabolism. Unsupervised principal component analysis of MRS spectra distinguished unique urine metabolite patterns of rats treated with CsA+SRL from those treated with CsA+EVL and the controls. SRL, but not EVL blood concentrations were inversely correlated with urine Krebs cycle metabolite concentrations. Interestingly, the higher the EVL concentration, the closer urine metabolite patterns resembled those of controls, while in contrast, the combination of the highest doses of CsA+SRL showed the most significant differences in metabolite patterns. Surprisingly in this rat model, EVL and SRL in combination with CsA had different effects on kidney biochemistry, suggesting that further exploration of EVL in combination with low dose calcineurin inhibitors may be of potential benefit.
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