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Oliveras L, Coloma A, Lloberas N, Lino L, Favà A, Manonelles A, Codina S, Couceiro C, Melilli E, Sharif A, Hecking M, Guthoff M, Cruzado JM, Pascual J, Montero N. Immunosuppressive drug combinations after kidney transplantation and post-transplant diabetes: A systematic review and meta-analysis. Transplant Rev (Orlando) 2024; 38:100856. [PMID: 38723582 DOI: 10.1016/j.trre.2024.100856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 04/23/2024] [Accepted: 04/24/2024] [Indexed: 06/16/2024]
Abstract
Post-transplant diabetes mellitus (PTDM) is a frequent complication after kidney transplantation (KT). This systematic review investigated the effect of different immunosuppressive regimens on the risk of PTDM. We performed a systematic literature search in MEDLINE and CENTRAL for randomized controlled trials (RCTs) that included KT recipients with any immunosuppression and reported PTDM outcomes up to 1 October 2023. The analysis included 125 RCTs. We found no differences in PTDM risk within induction therapies. In de novo KT, there was an increased risk of developing PTDM with tacrolimus versus cyclosporin (RR 1.71, 95%CI [1.38-2.11]). No differences were observed between tacrolimus+mammalian target of rapamycin inhibitor (mTORi) and tacrolimus+MMF/MPA, but there was a tendency towards a higher risk of PTDM in the cyclosporin+mTORi group (RR 1.42, 95%CI [0.99-2.04]). Conversion from cyclosporin to an mTORi increased PTDM risk (RR 1.89, 95%CI [1.18-3.03]). De novo belatacept compared with a calcineurin inhibitor resulted in 50% lower risk of PTDM (RR 0.50, 95%CI [0.32-0.79]). Steroid avoidance resulted in 31% lower PTDM risk (RR 0.69, 95%CI [0.57-0.83]), whereas steroid withdrawal resulted in no differences. Immunosuppression should be decided on an individual basis, carefully weighing the risk of future PTDM and rejection.
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Affiliation(s)
- Laia Oliveras
- Hospital Universitari de Bellvitge, Nephrology Department. L'Hospitalet de Llobregat, Spain; Biomedical Research Institute (IDIBELL), Hospital Duran i Reynals, Barcelona, Spain
| | - Ana Coloma
- Hospital Universitari de Bellvitge, Nephrology Department. L'Hospitalet de Llobregat, Spain
| | - Nuria Lloberas
- Biomedical Research Institute (IDIBELL), Hospital Duran i Reynals, Barcelona, Spain
| | - Luis Lino
- Hospital Universitari de Bellvitge, Nephrology Department. L'Hospitalet de Llobregat, Spain
| | - Alexandre Favà
- Hospital Universitari de Bellvitge, Nephrology Department. L'Hospitalet de Llobregat, Spain
| | - Anna Manonelles
- Hospital Universitari de Bellvitge, Nephrology Department. L'Hospitalet de Llobregat, Spain; Biomedical Research Institute (IDIBELL), Hospital Duran i Reynals, Barcelona, Spain
| | - Sergi Codina
- Hospital Universitari de Bellvitge, Nephrology Department. L'Hospitalet de Llobregat, Spain; Biomedical Research Institute (IDIBELL), Hospital Duran i Reynals, Barcelona, Spain
| | - Carlos Couceiro
- Hospital Universitari de Bellvitge, Nephrology Department. L'Hospitalet de Llobregat, Spain; Biomedical Research Institute (IDIBELL), Hospital Duran i Reynals, Barcelona, Spain
| | - Edoardo Melilli
- Hospital Universitari de Bellvitge, Nephrology Department. L'Hospitalet de Llobregat, Spain; Biomedical Research Institute (IDIBELL), Hospital Duran i Reynals, Barcelona, Spain
| | - Adnan Sharif
- Department of Nephrology and Transplantation, University Hospitals Birmingham, Birmingham, United Kingdom; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Manfred Hecking
- Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Martina Guthoff
- Department of Diabetology, Endocrinology, Nephrology, University of Tübingen, Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
| | - Josep M Cruzado
- Hospital Universitari de Bellvitge, Nephrology Department. L'Hospitalet de Llobregat, Spain; Biomedical Research Institute (IDIBELL), Hospital Duran i Reynals, Barcelona, Spain
| | - Julio Pascual
- Hospital 12 de Octubre, Nephrology Department, Madrid, Spain.
| | - Nuria Montero
- Hospital Universitari de Bellvitge, Nephrology Department. L'Hospitalet de Llobregat, Spain; Biomedical Research Institute (IDIBELL), Hospital Duran i Reynals, Barcelona, Spain.
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Datrino LN, Boccuzzi ML, Silva RM, Castilho PHBT, Riva WJ, Rocha JS, Tustumi F. Safety and Efficacy of Mycophenolate Mofetil Associated With Tacrolimus for Kidney-pancreas and Kidney Transplantation: A Systematic Review and Meta-Analysis of Randomized Studies. Transplant Proc 2024; 56:1066-1076. [PMID: 38853029 DOI: 10.1016/j.transproceed.2024.05.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 05/13/2024] [Accepted: 05/17/2024] [Indexed: 06/11/2024]
Abstract
INTRODUCTION This study evaluated the efficacy and safety of mycophenolate mofetil (MMF) associated with tacrolimus (TAC) in patients undergoing kidney-pancreas and kidney transplants, in comparison with cyclosporine (CyA), azathioprine (AZA), everolimus (EVL), sirolimus (SRL), manitimus (MAN), mizoribine (MZR), and enteric-coated mycophenolate sodium (ECMPS) in combination or monotherapy. METHODS A systematic review and meta-analysis of randomized clinical trials was performed. The outcomes comprised acute rejection, graft loss, and adverse events. RESULTS Thirty studies were included. The main adverse events related to the TAC+MMF scheme were infection (36%; 95%CI: 26%-46%), including cytomegalovirus (CMV) (14%; 95%CI: 8%-20%); anemia (20%; 95%CI: 2%-37%); leukopenia (18%; 95%CI: 3%-33%); nausea (20%; 95%CI: 1%-39%); and diarrhea (26%; 95%CI:13%-40%). TAC+MMF was compared to the schemes AZA+TAC, CyA+AZA, CyA+MMF, CyA+SRL, ECMPS, EVL, MAN+TAC, MMF+SRL, MZR, TAC+AZA, TAC+EVR, TAC+MZR, TAC +SRL and TAC. TAC+MMF was associated with a lower risk of rejection than MMF monotherapy (RD: -0.24; 95%CI -0.46; -0.02). Comparing TAC+MMF with the other regimens, no significant difference was found for graft loss. TAC+MMF was associated with a higher risk of infections than MZR (RD: 0.174; 95%CI: 0.25; 0.323) and TAC monotherapy (RD: 0.07; 95%CI 0.003; 0.138). CONCLUSION Gastrointestinal and hematological adverse events and infections are the most common with TAC+MMF for kidney-pancreas and kidney. TAC+MMF effectively prevents acute cellular rejection, and alternatives with AZA, CyA, SRL, ECMPS, EVL, MAN, and MSR have similar efficacy and safety profiles. TAC monotherapy and MZR may be associated with a lower risk of infections.
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Affiliation(s)
| | - Matheus Lopes Boccuzzi
- Department of Evidenced-based Medicine, Centro Universitário Lusíada, Santos, SP, Brazil
| | - Rafael Matosinho Silva
- Department of Evidenced-based Medicine, Centro Universitário Lusíada, Santos, SP, Brazil
| | | | - Wagner José Riva
- Department of Evidenced-based Medicine, Centro Universitário Lusíada, Santos, SP, Brazil
| | - Jéssica Silva Rocha
- Department of Surgery, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Francisco Tustumi
- Department of Surgery, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil; Department of Gastroenterology, Universidade de São Paulo, São Paulo, SP, Brazil.
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Ciancio G, Gaynor JJ, Guerra G, Tabbara MM, Roth D, Kupin W, Mattiazzi A, Moni L, Burke GW. Long-term effects of average calcineurin inhibitor trough levels (over time) on renal function in a prospectively followed cohort of 150 kidney transplant recipients. Clin Transl Sci 2023; 16:2382-2393. [PMID: 37817405 PMCID: PMC10651634 DOI: 10.1111/cts.13639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 09/01/2023] [Indexed: 10/12/2023] Open
Abstract
More favorable clinical outcomes with medium-term follow-up have been reported among kidney transplant recipients receiving maintenance therapy consisting of "reduced-tacrolimus (TAC) dosing," mycophenolate mofetil (MMF), and low-dose corticosteroids. However, it is not clear whether long-term maintenance therapy with reduced-calcineurin inhibitor (CNI) dosing still leads to reduced renal function. A prospectively followed cohort of 150 kidney transplant recipients randomized to receive TAC/sirolimus (SRL) versus TAC/MMF versus cyclosporine microemulsion (CSA)/SRL, plus low-dose maintenance corticosteroids, now has 20 years of post-transplant follow-up. Average CNI trough levels over time among patients who were still alive with functioning grafts at 60, 120, and 180 months post-transplant were determined and ranked from smallest-to-largest for both TAC and CSA. Stepwise linear regression was used to determine whether these ranked average trough levels were associated with the patient's estimated glomerular filtration rate (eGFR) at those times, particularly after controlling for other significant multivariable predictors. Experiencing biopsy-proven acute rejection (BPAR) and older donor age were the two most significant multivariable predictors of poorer eGFR at 60, 120, and 180 months post-transplant (p < 000001 and 0.000003 for older donor age at 60 and 120 months; p = 0.00008 and <0.000001 for previous BPAR at 60 and 120 months). Assignment to CSA also implied a significantly poorer eGFR (but with less magnitudes of effect) in multivariable analysis at 60 and 120 months (p = 0.01 and 0.002). Higher ranked average CNI trough levels had no association with eGFR at any timepoint in either univariable or multivariable analysis (p > 0.70). Long-term maintenance therapy with reduced-CNI dosing does not appear to cause reduced renal function.
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Affiliation(s)
- Gaetano Ciancio
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
- Department of SurgeryLeonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
| | - Jeffrey J. Gaynor
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
- Department of SurgeryLeonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
| | - Giselle Guerra
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
- Division of Nephrology, Department of Medicine, Leonard M. Miller School of MedicineUniversity of MiamiMiamiFloridaUSA
| | - Marina M. Tabbara
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
| | - David Roth
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
- Division of Nephrology, Department of Medicine, Leonard M. Miller School of MedicineUniversity of MiamiMiamiFloridaUSA
| | - Warren Kupin
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
- Division of Nephrology, Department of Medicine, Leonard M. Miller School of MedicineUniversity of MiamiMiamiFloridaUSA
| | - Adela Mattiazzi
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
- Division of Nephrology, Department of Medicine, Leonard M. Miller School of MedicineUniversity of MiamiMiamiFloridaUSA
| | - Lissett Moni
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
- Department of SurgeryLeonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
| | - George W. Burke
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
- Department of SurgeryLeonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
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Granata S, Mercuri S, Troise D, Gesualdo L, Stallone G, Zaza G. mTOR-inhibitors and post-transplant diabetes mellitus: a link still debated in kidney transplantation. Front Med (Lausanne) 2023; 10:1168967. [PMID: 37250653 PMCID: PMC10213242 DOI: 10.3389/fmed.2023.1168967] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Accepted: 04/25/2023] [Indexed: 05/31/2023] Open
Abstract
The mammalian target of rapamycin inhibitors (mTOR-Is, Sirolimus, and Everolimus) are immunosuppressive drugs widely employed in kidney transplantation. Their main mechanism of action includes the inhibition of a serine/threonine kinase with a pivotal role in cellular metabolism and in various eukaryotic biological functions (including proteins and lipids synthesis, autophagy, cell survival, cytoskeleton organization, lipogenesis, and gluconeogenesis). Moreover, as well described, the inhibition of the mTOR pathway may also contribute to the development of the post-transplant diabetes mellitus (PTDM), a major clinical complication that may dramatically impact allograft survival (by accelerating the development of the chronic allograft damage) and increase the risk of severe systemic comorbidities. Several factors may contribute to this condition, but the reduction of the beta-cell mass, the impairment of the insulin secretion and resistance, and the induction of glucose intolerance may play a pivotal role. However, although the results of several in vitro and in animal models, the real impact of mTOR-Is on PTDM is still debated and the entire biological machinery is poorly recognized. Therefore, to better elucidate the impact of the mTOR-Is on the risk of PTDM in kidney transplant recipients and to potentially uncover future research topics (particularly for the clinical translational research), we decided to review the available literature evidence regarding this important clinical association. In our opinion, based on the published reports, we cannot draw any conclusion and PTDM remains a challenge. However, also in this case, the administration of the lowest possible dose of mTOR-I should also be recommended.
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Affiliation(s)
- Simona Granata
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Silvia Mercuri
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Dario Troise
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Loreto Gesualdo
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari, Bari, Italy
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Gianluigi Zaza
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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Frutos MÁ, Crespo M, Valentín MDLO, Alonso-Melgar Á, Alonso J, Fernández C, García-Erauzkin G, González E, González-Rinne AM, Guirado L, Gutiérrez-Dalmau A, Huguet J, Moral JLLD, Musquera M, Paredes D, Redondo D, Revuelta I, Hofstadt CJVD, Alcaraz A, Alonso-Hernández Á, Alonso M, Bernabeu P, Bernal G, Breda A, Cabello M, Caro-Oleas JL, Cid J, Diekmann F, Espinosa L, Facundo C, García M, Gil-Vernet S, Lozano M, Mahillo B, Martínez MJ, Miranda B, Oppenheimer F, Palou E, Pérez-Saez MJ, Peri L, Rodríguez O, Santiago C, Tabernero G, Hernández D, Domínguez-Gil B, Pascual J. Recommendations for living donor kidney transplantation. Nefrologia 2022; 42 Suppl 2:5-132. [PMID: 36503720 DOI: 10.1016/j.nefroe.2022.07.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 10/26/2021] [Indexed: 06/17/2023] Open
Abstract
This Guide for Living Donor Kidney Transplantation (LDKT) has been prepared with the sponsorship of the Spanish Society of Nephrology (SEN), the Spanish Transplant Society (SET), and the Spanish National Transplant Organization (ONT). It updates evidence to offer the best chronic renal failure treatment when a potential living donor is available. The core aim of this Guide is to supply clinicians who evaluate living donors and transplant recipients with the best decision-making tools, to optimise their outcomes. Moreover, the role of living donors in the current KT context should recover the level of importance it had until recently. To this end the new forms of incompatible HLA and/or ABO donation, as well as the paired donation which is possible in several hospitals with experience in LDKT, offer additional ways to treat renal patients with an incompatible donor. Good results in terms of patient and graft survival have expanded the range of circumstances under which living renal donors are accepted. Older donors are now accepted, as are others with factors that affect the decision, such as a borderline clinical history or alterations, which when evaluated may lead to an additional number of transplantations. This Guide does not forget that LDKT may lead to risk for the donor. Pre-donation evaluation has to centre on the problems which may arise over the short or long-term, and these have to be described to the potential donor so that they are able take them into account. Experience over recent years has led to progress in risk analysis, to protect donors' health. This aspect always has to be taken into account by LDKT programmes when evaluating potential donors. Finally, this Guide has been designed to aid decision-making, with recommendations and suggestions when uncertainties arise in pre-donation studies. Its overarching aim is to ensure that informed consent is based on high quality studies and information supplied to donors and recipients, offering the strongest possible guarantees.
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Affiliation(s)
| | - Marta Crespo
- Nephrology Department, Hospital del Mar, Barcelona, Spain
| | | | | | - Juana Alonso
- Nephrology Department, Hospital Regional Universitario de Málaga, Spain
| | | | | | - Esther González
- Nephrology Department, Hospital Universitario 12 Octubre, Spain
| | | | - Lluis Guirado
- Nephrology Department, Fundacio Puigvert, Barcelona, Spain
| | | | - Jorge Huguet
- RT Surgical Team, Fundació Puigvert, Barcelona, Spain
| | | | - Mireia Musquera
- Urology Department, Hospital Clinic Universitari, Barcelona, Spain
| | - David Paredes
- Donation and Transplantation Coordination Department, Hospital Clinic Universitari, Barcelona, Spain
| | | | - Ignacio Revuelta
- Nephrology and RT Department, Hospital Clinic Universitari, Barcelona, Spain
| | | | - Antonio Alcaraz
- Urology Department, Hospital Clinic Universitari, Barcelona, Spain
| | | | - Manuel Alonso
- Regional Transplantation Coordination, Seville, Spain
| | | | - Gabriel Bernal
- Nephrology Department, Hospital Universitario Virgen del Rocío, Seville, Spain
| | - Alberto Breda
- RT Surgical Team, Fundació Puigvert, Barcelona, Spain
| | - Mercedes Cabello
- Nephrology Department, Hospital Regional Universitario de Málaga, Spain
| | | | - Joan Cid
- Apheresis and Cell Therapy Unit, Haemotherapy and Haemostasis Department, Hospital Clinic Universitari, Barcelona, Spain
| | - Fritz Diekmann
- Nephrology and RT Department, Hospital Clinic Universitari, Barcelona, Spain
| | - Laura Espinosa
- Paediatric Nephrology Department, Hospital La Paz, Madrid, Spain
| | - Carme Facundo
- Nephrology Department, Fundacio Puigvert, Barcelona, Spain
| | | | | | - Miquel Lozano
- Apheresis and Cell Therapy Unit, Haemotherapy and Haemostasis Department, Hospital Clinic Universitari, Barcelona, Spain
| | | | | | | | | | - Eduard Palou
- Immunology Department, Hospital Clinic i Universitari, Barcelona, Spain
| | | | - Lluis Peri
- Urology Department, Hospital Clinic Universitari, Barcelona, Spain
| | | | | | | | - Domingo Hernández
- Nephrology Department, Hospital Regional Universitario de Málaga, Spain
| | | | - Julio Pascual
- Nephrology Department, Hospital del Mar, Barcelona, Spain.
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Effect of Sirolimus vs. Everolimus on CMV-Infections after Kidney Transplantation-A Network Meta-Analysis. J Clin Med 2022; 11:jcm11144216. [PMID: 35887977 PMCID: PMC9323040 DOI: 10.3390/jcm11144216] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 07/04/2022] [Accepted: 07/06/2022] [Indexed: 11/16/2022] Open
Abstract
(1) Background: Following renal transplantation, infection with cytomegalovirus (CMV) is a common and feared complication. mTOR-inhibitor (mTOR-I) treatment, either alone or in combination with calcineurininhibitors (CNIs), significantly reduces the CMV incidence after organ transplantation. As of now, there is no information on which mTOR-I, sirolimus (SIR) or everolimus (ERL), has a stronger anti-CMV effect. (2) Methods: The current literature was searched for prospective randomized controlled trials in renal transplantation. There were 1164 trials screened, of which 27 could be included (11,655 pts.). We performed a network meta-analysis to analyze the relative risk of different types of mTOR-I treatment on CMV infection 12 months after transplantation compared to CNI treatment. (3) Results: Four different types of mTOR-I treatment were analyzed in network meta-analyses—SIR mono, ERL mono, SIR with CNI, ERL with CNI. The mTOR-I treatment with the strongest anti-CMV effect compared to a regular CNI treatment was ERL in combination with a CNI (relative risk (RR) 0.27, confidence interval (CI) 0.22−0.32, p < 0.0001). The other mTOR-I therapy groups showed a slightly decreased anti-CMV efficacy (SIR monotherapy (mono): RR 0.35, CI 0.22−0.57, p < 0.001; SIR with CNI: RR 0.43, CI 0.29−0.64, p < 0.0001; ERL mono: RR 0.46, CI 0.22−0.93, p = 0.031). (4) Conclusions: The anti-CMV effect of both mTOR-Is (SRL and ERL) is highly effective, irrespective of the combination with other immunosuppressive drugs. Certain differences with respect to the potency against the CMV could be found between SRL and ERL. Data gained from this analysis seem to support that a combination of ERL and CNI has the most potent anti-CMV efficacy.
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Joharatnam-Hogan N, Morganstein DL. Diabetes and Cancer - optimising glycaemic control. J Hum Nutr Diet 2022; 36:504-513. [PMID: 35748508 DOI: 10.1111/jhn.13051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 05/31/2022] [Indexed: 01/08/2023]
Abstract
Diabetes and cancer are both common and increasingly prevalent conditions, but emerging epidemiological evidence confirms that the risk of developing a number of common cancers is increased in those with type 2 diabetes. The risk of cancer in type 1 diabetes is less clearly defined, and therefore this review will focus on type 2 diabetes. Emerging evidence also supports an influence of diabetes on outcomes of cancer treatment. However, this relationship is bi-directional, with cancer and its treatment impacting on glucose control, whilst there is also emerging evidence that diabetes care can deteriorate after a cancer diagnosis (summarised in Figure 1). Despite these clear links there is a lack of evidence to guide clinicians in how to manage patients with diabetes during their cancer treatment. Although recent UK guidelines have started to address this, with the development of guidance for the management of hyperglycaemia in cancer, there is a clear need for wider guidance on the management of multi-morbidity during cancer, including diabetes and obesity, to incorporate nutritional management We have therefore undertaken a narrative review of the evidence of links between type 2 diabetes and cancer incidence and outcomes, and discuss the challenges to diabetes care during cancer treatment. This article is protected by copyright. All rights reserved.
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Affiliation(s)
| | - Daniel L Morganstein
- Royal Marsden Hospital, Fulham Roal, London, SW3 6JJ, UK.,Chelsea and Westminster Hospital, 369 Fulham Road, London, SW10 9NH, UK
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Recomendaciones para el trasplante renal de donante vivo. Nefrologia 2022. [DOI: 10.1016/j.nefro.2021.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Graft Failure Due to Nonadherence among 150 Prospectively-Followed Kidney Transplant Recipients at 18 Years Post-transplant: Our Results and Review of the Literature. J Clin Med 2022; 11:jcm11051334. [PMID: 35268424 PMCID: PMC8911343 DOI: 10.3390/jcm11051334] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 02/23/2022] [Accepted: 02/24/2022] [Indexed: 01/15/2023] Open
Abstract
Background: We previously reported that graft failure due to nonadherence (GFNA) was a major cause of graft loss in kidney transplantation. Here, among 150 prospectively-followed kidney transplant recipients at 18 years post-transplant, we provide: updated (longer-term) estimates of cause-specific graft loss probabilities, risk factors for developing GFNA, and detailed characterizations of patients’ overt nonadherent (NA) behavior, including timing, extent, and clinical consequences. Methods: Determination of the patient becoming NA in taking his/her immunosuppressive medications, and the underlying cause of graft loss, were determined prospectively by the attending physicians. For never-functioning-graft, GFNA, GF due to causes other than NA (Other GF), and death with a functioning graft (DWFG), cumulative incidence functions were used to estimate the cumulative probabilities of cause-specific graft loss. Cox stepwise regression was used to determine significant multivariable predictors for the hazard rate of developing GFNA. Results: GFNA was a major cause of graft loss (22/150 patients), particularly among African-American and Hispanic recipients <50 years of age-at-transplant (20/56 experienced GFNA), with estimated percentages of such patients ever developing GFNA ranging between 36.9 and 41.5%. These patients were also at a higher risk of developing Other GF. For the remaining patients (2/94 experienced GFNA), estimated percentages of ever-developing GFNA were much lower (range: 0.0−6.7%). The major cause of graft loss among recipients ≥50 years of age was DWFG; GFNA rarely occurred among older recipients. In 21/22 GFNA patients, NA behavior lasted continuously from the time of developing NA until GFNA. In total, 28/150 patients became NA, and 67.9% (19/28) occurred beyond 36 months post-transplant. A total of 25 of 28 NA patients (89.3%) developed biopsy-proven acute rejection and/or chronic rejection that was directly attributed to the NA behavior. Lastly, 25/28 admitted to NA behavior, with financial and psychological components documented in 71.4% (20/28) and 96.4% (27/28) of NA cases, respectively. Conclusions: These results highlight the importance of performing serial monitoring of patients for overt NA behavior throughout their post-transplant follow-up. Financial and psychological components to NA behavior need to be simultaneously addressed with the goal of achieving complete avoidance/elimination of NA behavior among higher risk patients.
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T A M, Chng R, Yau WP. Efficacy and Safety of Tacrolimus-Based Maintenance Regimens in De Novo Kidney Transplant Recipients: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials. Ann Transplant 2021; 26:e933588. [PMID: 34963678 PMCID: PMC8721964 DOI: 10.12659/aot.933588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 11/19/2021] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND Tacrolimus is an established component of immunosuppressive regimens for kidney transplant recipients (KTRs); however, data comparing long-term outcomes between formulations are lacking. We conducted a systematic literature review and network meta-analysis assessing tacrolimus (primarily Advagraf [once-daily] and Prograf [twice-daily])-based maintenance regimens. MATERIAL AND METHODS Embase, MEDLINE, and Cochrane databases and congress proceedings were searched to identify studies of adult de novo KTRs who received tacrolimus-based therapy in phase II/III randomized controlled trials. Outcomes were acute rejection, graft/patient survival, and incidence of new-onset diabetes mellitus after transplantation (NODAT) and cytomegalovirus (CMV) infection. Bayesian network meta-analysis was used to analyze treatment effects on graft/patient survival. RESULTS Sixty-eight publications (61 primary) were included. Of 21 publications reporting graft rejection following Advagraf or Prograf treatment in ≥1 study arm, 12-month biopsy-proven acute rejection (BPAR) ranged from 3.3% with Prograf to 55.0% with mycophenolic acid (MPA)+corticosteroids (CS); >24 month BPAR ranged from 0% to 58.7% (the latter with bleselumab-based therapy). Fourteen publications reported graft loss following Advagraf (0-9.6%) or Prograf (0-7.5%). Patient mortality ≤24 months after transplantation (14 publications) ranged from 0% to 8.1% with Advagraf or Prograf. Advagraf+MPA+CS and reference treatment, Prograf+MPA+CS, were associated with a similar risk of graft loss (odds ratio 1.19; 95% credible-interval 0.51, 3.06) and mortality (odds ratio 1.21; 95% credible-interval 0.1557, 9.03). Incidence of NODAT and CMV varied by treatment arm. CONCLUSIONS Graft loss and patient mortality rates were generally comparable between Advagraf- and Prograf-based regimens. Further prospective studies are needed to evaluate longer-term outcomes.
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Affiliation(s)
- Manjunatha T A
- Department of Medical Affairs, Astellas Pharma Singapore Pte Ltd., Singapore, Singapore
| | - Rebecca Chng
- Department of Medical Affairs, Astellas Pharma Singapore Pte Ltd., Singapore, Singapore
| | - Wai-Ping Yau
- Department of Pharmacy, National University of Singapore, Singapore, Singapore
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11
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Zeng J, Zhong Q, Feng X, Li L, Feng S, Fan Y, Song T, Huang Z, Wang X, Lin T. Conversion From Calcineurin Inhibitors to Mammalian Target of Rapamycin Inhibitors in Kidney Transplant Recipients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Front Immunol 2021; 12:663602. [PMID: 34539621 PMCID: PMC8446650 DOI: 10.3389/fimmu.2021.663602] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 08/16/2021] [Indexed: 02/05/2023] Open
Abstract
Background A systematic review and meta-analysis were performed to investigate the efficacy and safety of conversion from calcineurin inhibitors (CNIs) to mammalian target of rapamycin inhibitors (mTORi) in kidney transplant recipients (KTRs). Methods MEDLINE, EMBASE, PubMed, and Cochrane Library were searched to identify randomized controlled trials (RCTs) that compared the continuation of CNI with conversion to mTORi therapy. Results Twenty-nine RCTs (5,747 KTRs) were included in our analysis. Meta-analysis of the glomerular filtration rate (SMD 0.20; 95%CI 0.10-0.31; P<0.01) and malignancy (RR 0.74; 95%CI 0.55-0.99; P=0.04) demonstrated a significant advantage of mTORi conversion over CNI continuation. However, the risk of acute rejection (RR 1.58; 95%CI 1.22-2.04; P<0.01), infection (RR 1.55; 95%CI 1.01-1.31; P=0.04), proteinuria (RR 1.87; 95%CI 1.34-2.59; P<0.01), leukopenia (RR 1.56; 95%CI 1.27-1.91; P<0.01), acne (RR 6.43; 95%CI 3.43-12.04; P<0.01), and mouth ulcer (RR 11.70; 95%CI 6.18-22.17; P<0.01) were higher in the mTORi group. More patients in the conversion group had to discontinue study medication (RR 2.52; 95%CI 1.75-3.63; P<0.01). There was no significant difference between the two groups with regard to death, graft loss, diabetes, chronic allograft nephropathy, and interstitial fibrosis/tubular atrophy. Conclusions Posttransplant patients have a better graft function and lower incidence of malignancy after conversion from CNI to mTORi therapy. However, this conversion strategy may be prevented by the higher drug discontinuation rate due to mTORi-associated adverse events, such as more acute rejection, infection, proteinuria, leukopenia, acne, and mouth ulcer, indicating that conversion therapy may only be a treatment option in selected patients.
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Affiliation(s)
- Jun Zeng
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.,Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Qiang Zhong
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.,Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaobing Feng
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.,Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Linde Li
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.,Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Shijian Feng
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.,Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yu Fan
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.,Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Turun Song
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.,Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Zhongli Huang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.,Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xianding Wang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.,Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Tao Lin
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.,Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
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12
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Jorgenson MR, Descourouez JL, Brady BL, Chandran MM, Do V, Kim M, Laub MR, Lichvar A, Park JM, Szczepanik A, Alloway RR. A call for transplant stewardship: The need for expanded evidence-based evaluation of induction and biologic-based cost-saving strategies in kidney transplantation and beyond. Clin Transplant 2021; 35:e14372. [PMID: 34033140 DOI: 10.1111/ctr.14372] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/15/2021] [Accepted: 05/19/2021] [Indexed: 12/14/2022]
Abstract
Rising expenditures threaten healthcare sustainability. While transplant programs are typically considered profitable, transplant medications are expensive and frequently targeted for cost savings. This review aims to summarize available literature supporting cost-containment strategies used in solid organ transplant. Despite widespread use of these tactics, we found the available evidence to be fairly low quality. Strategies mainly focus on induction, particularly rabbit antithymocyte globulin (rATG), given its significant cost and the lack of consensus surrounding dosing. While there is higher-quality evidence for high single-dose rATG, and dose-rounding protocols to reduce waste are likely low risk, more aggressive strategies, such as dosing rATG by CD3+ target-attainment or on ideal-body-weight, have less robust support and did not always attain similar efficacy outcomes. Extrapolation of induction dosing strategies to rejection treatment is not supported by any currently available literature. Cost-saving strategies for supportive therapies, such as IVIG and rituximab also have minimal literature support. Deferral of high-cost agents to the outpatient arena is associated with minimal risk and increases reimbursement, although may increase complexity and cost-burden for patients and infusion centers. The available evidence highlights the need for evaluation of unique patient-specific clinical scenarios and optimization of therapies, rather than simple blanket application of cost-saving initiatives in the transplant population.
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Affiliation(s)
- Margaret R Jorgenson
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, WI, USA
| | - Jillian L Descourouez
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, WI, USA
| | - Bethany L Brady
- Department of Pharmacy, Indiana University Health University Hospital, Indianapolis, IN, USA
| | - Mary M Chandran
- Department of Pharmacy, Children's Hospital of Colorado, Aurora, CO, USA
| | - Vincent Do
- Department of Pharmacy, Yale New Haven Hospital, New Haven, CT, USA
| | - Miae Kim
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Melissa R Laub
- Department of Pharmacy, Augusta University Medical Center, Augusta, GA, USA
| | - Alicia Lichvar
- Department of Pharmacy Practice and Surgery, University of Illinois at Chicago, Chicago, IL, USA
| | - Jeong M Park
- Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI, USA
| | - Amanda Szczepanik
- Department of Pharmacy, University of Maryland Medical Center, Baltimore, MD, USA
| | - Rita R Alloway
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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13
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Chevallier E, Jouve T, Rostaing L, Malvezzi P, Noble J. pre-existing diabetes and PTDM in kidney transplant recipients: how to handle immunosuppression. Expert Rev Clin Pharmacol 2020; 14:55-66. [PMID: 33196346 DOI: 10.1080/17512433.2021.1851596] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Preexisting diabetes (PD) and post-transplant diabetes mellitus (PTDM) are common and severe comorbidities posttransplantation. The immunosuppressive regimens are modifiable risk factors. AREAS COVERED We reviewed Pubmed and Cochrane database and we summarize the mechanisms and impacts of available immunosuppressive treatments on the risk of PD and PTDM. We also assess the possible management of these drugs to improve glycemic parameters while considering risks inherent in transplantation. EXPERT OPINION PD i) increases the risk of sepsis, ii) is an independent risk factor for infection-related mortality, and iii) increases acute rejection risk. Regarding PTDM development i) immunosuppressive strategies without corticosteroids significantly reduce the risk but the price may be a higher incidence of rejection; ii) minimization or rapid withdrawal of steroids are two valuable approaches; iii) the diabetogenic role of calcineurin inhibitors(CNIs) is also well-described and is more important for tacrolimus than for cyclosporine. Reducing tacrolimus-exposure may improve glycemic parameters but also has a higher risk of rejection. PTDM risk is higher in patients that receive sirolimus compared to mycophenolate mofetil. Finally, conversion from CNIs to belatacept may offer the best benefits to PTDM-recipients in terms of glycemic parameters, graft and patient-outcomes.
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Affiliation(s)
- Eloi Chevallier
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France
| | - Thomas Jouve
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France.,Université Grenoble Alpes , Grenoble, France
| | - Lionel Rostaing
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France.,Université Grenoble Alpes , Grenoble, France
| | - Paolo Malvezzi
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France
| | - Johan Noble
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France
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14
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Target-oriented delivery of self-assembled immunosuppressant cocktails prolongs allogeneic orthotopic liver transplant survival. J Control Release 2020; 328:237-250. [DOI: 10.1016/j.jconrel.2020.08.043] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 08/15/2020] [Accepted: 08/22/2020] [Indexed: 12/26/2022]
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15
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Ciancio G, Gaynor JJ, Guerra G, Roth D, Chen L, Kupin W, Mattiazzi A, Ortigosa-Goggins M, Moni L, Burke GW. Randomized trial of 3 maintenance regimens (TAC/SRL vs. TAC/MMF vs. CSA/SRL) with low-dose corticosteroids in primary kidney transplantation: 18-year results. Clin Transplant 2020; 34:e14123. [PMID: 33070366 DOI: 10.1111/ctr.14123] [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: 08/27/2020] [Revised: 10/05/2020] [Accepted: 10/10/2020] [Indexed: 12/21/2022]
Abstract
A randomized trial of 150 primary kidney transplant recipients, initiated in May 2000, compared tacrolimus (TAC)/sirolimus (SRL) vs. TAC/mycophenolate mofetil (MMF) vs. cyclosporine microemulsion (CSA)/SRL (N = 50/group). All patients received daclizumab induction and maintenance corticosteroids. With current median follow-up of 18 years post-transplant, biopsy-proven acute rejection (BPAR) occurred less often in TAC/MMF (26% (13/50)), vs. the TAC/SRL (36% (18/50)) and CSA/SRL (34% (17/50)) arms combined (p = .23), with statistical significance favoring TAC/MMF (p = .05) after controlling for the multivariable (Cox model) effects of recipient age, recipient race/ethnicity, and donor age. First BPAR rate was clearly more favorable for TAC/MMF after stratifying patients by having 0-1 (N = 72) vs. 2-3 (N = 78) unfavorable baseline characteristics (recipient age <50 years, African American or Hispanic recipient, and donor age ≥50 years) (p = .02). Mean estimated glomerular filtration rate (eGFR), using the CKD-EPI formula, was consistently higher for TAC/MMF, particularly after controlling for the multivariable effect of donor age, throughout the first 96 months post-transplant (p ≤ .008). These differences were translated into an observed more favorable graft failure due to immunologic cause (CAI/TG) rate for TAC/MMF (p = .06), although no significant differences in overall death-uncensored graft loss were observed. Previously reported significantly higher study drug discontinuation and requirement for antilipid therapy rates in the SRL-assigned arms were maintained over time. Overall, these results at 18 years post-transplant more definitively show that TAC/MMF should be the gold standard for achieving optimal, long-term maintenance immunosuppression in kidney transplantation.
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Affiliation(s)
- Gaetano Ciancio
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.,The Lillian Jean Kaplan Renal Transplant Center of the Division of Transplantation, The DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Jeffrey J Gaynor
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.,The Lillian Jean Kaplan Renal Transplant Center of the Division of Transplantation, The DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Giselle Guerra
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.,Division of Nephrology, Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - David Roth
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.,Division of Nephrology, Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Linda Chen
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.,The Lillian Jean Kaplan Renal Transplant Center of the Division of Transplantation, The DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Warren Kupin
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.,Division of Nephrology, Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Adela Mattiazzi
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.,Division of Nephrology, Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Mariella Ortigosa-Goggins
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.,Division of Nephrology, Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Lissett Moni
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.,The Lillian Jean Kaplan Renal Transplant Center of the Division of Transplantation, The DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - George W Burke
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.,The Lillian Jean Kaplan Renal Transplant Center of the Division of Transplantation, The DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
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16
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Arnol M, Naumovic R, Dimitrov EP, Racki S, Bucsa CA, Covic A, Mitic I, Vavic N, Radovanovic RMV, Zibar L, Bizilj S, Erculj V, Missoni TS, Stupica KT, Knotek M. Immunosuppressive regimens following kidney transplantation in five European countries: The observational RECORD study. TRANSPLANTATION REPORTS 2020. [DOI: 10.1016/j.tpr.2020.100061] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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17
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Hahn D, Hodson EM, Hamiwka LA, Lee VWS, Chapman JR, Craig JC, Webster AC. Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients. Cochrane Database Syst Rev 2019; 12:CD004290. [PMID: 31840244 PMCID: PMC6953317 DOI: 10.1002/14651858.cd004290.pub3] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Kidney transplantation is the therapy of choice for many patients with end-stage kidney disease (ESKD) with an improvement in survival rates and satisfactory short term graft survival. However, there has been little improvement in long-term survival. The place of target of rapamycin inhibitors (TOR-I) (sirolimus, everolimus), which have different modes of action from other commonly used immunosuppressive agents, in kidney transplantation remains uncertain. This is an update of a review first published in 2006. OBJECTIVES To evaluate the short and long-term benefits and harms of TOR-I (sirolimus and everolimus) when used in primary immunosuppressive regimens for kidney transplant recipients. SEARCH METHODS We searched the Cochrane Kidney and Transplant Register of Studies up to 20 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA All randomised controlled trials (RCTs) and quasi-RCTs in which drug regimens, containing TOR-I commenced within seven days of transplant, were compared to alternative drug regimens, were included without age restriction, dosage or language of report. DATA COLLECTION AND ANALYSIS Three authors independently assessed study eligibility, risk of bias, and extracted data. Results were reported as risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) with 95% CI for continuous outcomes. Statistical analyses were performed using the random-effects model. The certainty of the evidence was assessed using GRADE MAIN RESULTS: Seventy studies (17,462 randomised participants) were included; eight studies included two comparisons to provide 78 comparisons. Outcomes were reported at six months to three years post transplant. Risk of bias was judged to be low for sequence generation in 25 studies, for allocation concealment in 23 studies, performance bias in four studies, detection bias in 65 studies, attrition bias in 45 studies, selective reporting bias in 48 studies, and for other potential bias in three studies. Risk of bias was judged to be at high risk of bias for sequence generation in two studies, allocation concealment in two studies, performance bias in 61 studies, detection bias in one study, attrition bias in four studies, for selective reporting bias in 11 studies and for other potential risk of bias in 46 studies. Compared with CNI and antimetabolite, TOR-I with antimetabolite probably makes little or no difference to death (RR 1.31, 95% CI 0.87 to 1.98; 19 studies) or malignancies (RR 0.86, 95% CI 0.50 to 1.48; 10 studies); probably increases graft loss censored for death (RR 1.32, 95% CI 0.96 to 1.81; 15 studies), biopsy-proven acute rejection (RR 1.60, 95% CI 1.25 to 2.04; 15 studies), need to change treatment (RR 2.42, 95% CI 1.88 to 3.11; 14 studies) and wound complications (RR 2.56, 95% CI 1.94 to 3.36; 12 studies) (moderate certainty evidence); but reduces CMV infection (RR 0.43, 95% CI 0.29 to 0.63; 13 studies) (high certainty evidence). Compared with antimetabolites and CNI, TOR-I with CNI probably makes little or no difference to death (RR 1.06, 95% CI 0.84 to 1.33; 31 studies), graft loss censored for death (RR 1.09, 95% CI 0.82 to 1.45; 26 studies), biopsy-proven acute rejection (RR 0.95, 95% CI 0.81 to 1.12; 24 studies); and malignancies (RR 0.83, 95% CI 0.64 to 1.07; 17 studies); probably increases the need to change treatment (RR 1.56, 95% CI 1.28 to 1.90; 25 studies), and wound complications (RR 1.56, 95% CI 1.28 to 1.91; 17 studies); but probably reduces CMV infection (RR 0.44, 95% CI 0.34 to 0.58; 25 studies) (moderate certainty evidence). Lower dose TOR-I and standard dose CNI compared with higher dose TOR-I and reduced dose CNI probably makes little or no difference to death (RR 1.07, 95% CI 0.64 to 1.78; 9 studies), graft loss censored for death (RR 1.09, 95% CI 0.54 to 2.20; 8 studies), biopsy-proven acute rejection (RR 0.87, 95% CI 0.67 to 1.13; 8 studies), and CMV infection (RR 1.42, 95% CI 0.78 to 2.60; 5 studies) (moderate certainty evidence); and may make little or no difference to wound complications (RR 0.95, 95% CI 0.53 to 1.71; 3 studies), malignancies (RR 1.04, 95% CI 0.36 to 3.04; 7 studies), and the need to change treatments (RR 1.18, 95% CI 0.58 to 2.42; 5 studies) (low certainty evidence). Lower dose of TOR-I compared with higher doses probably makes little or no difference to death (RR 0.84, 95% CI 0.67 to 1.06; 13 studies), graft loss censored for death (RR 0.92, 95% CI 0.71 to 1.19; 12 studies), biopsy-proven acute rejection (RR 1.26, 95% CI 1.10 to 1.43; 11 studies), CMV infection (RR 0.87, 95% CI 0.63 to 1.21; 9 studies), wound complications (RR 0.92, 95% CI 0.66 to 1.29; 7 studies), and malignancy (RR 0.84, 95% CI 0.54 to 1.32; 10 studies) (moderate certainty evidence); and may make little or no difference to the need to change treatments (RR 0.91, 95% CI 0.78 to 1.05; 10 studies) (low certainty evidence). It is uncertain whether sirolimus and everolimus differ in their effects on kidney function and lipid levels because the certainty of the evidence is very low based on a single small study with only three months of follow-up. AUTHORS' CONCLUSIONS In studies with follow-up to three years, TOR-I with an antimetabolite increases the risk of graft loss and acute rejection compared with CNI and an antimetabolite. TOR-I with CNI potentially offers an alternative to an antimetabolite with CNI as rates of graft loss and acute rejection are similar between interventions and TOR-I regimens are associated with a reduced risk of CMV infections. Wound complications and the need to change immunosuppressive medications are higher with TOR-I regimens. While further new studies are not required, longer-term follow-up data from participants in existing methodologically robust RCTs are needed to determine how useful immunosuppressive regimens, which include TOR-I, are in maintaining kidney transplant function and survival beyond three years.
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Affiliation(s)
- Deirdre Hahn
- The Children's Hospital at WestmeadDepartment of NephrologyLocked Bag 4001WestmeadNSWAustralia2145
| | - Elisabeth M Hodson
- The Children's Hospital at WestmeadCochrane Kidney and Transplant, Centre for Kidney ResearchLocked Bag 4001WestmeadNSWAustralia2145
| | - Lorraine A Hamiwka
- University of Calgary/Alberta Children's HospitalDepartment of Medicine/Pediatrics2888 Shaganappi Trail NW Children's HospitalCalgaryAlbertaCanadaT3B 6A8
| | - Vincent WS Lee
- Westmead & Blacktown HospitalsDepartment of Renal MedicineDarcy RdWestmeadNSWAustralia2145
- The University of Sydney at WestmeadCentre for Transplant and Renal Research, Westmead Millennium InstituteWestmeadAustralia
| | - Jeremy R Chapman
- Westmead Millennium Institute, The University of Sydney at WestmeadCentre for Transplant and Renal ResearchDarcy RdWestmeadNSWAustralia2145
| | - Jonathan C Craig
- The Children's Hospital at WestmeadCochrane Kidney and Transplant, Centre for Kidney ResearchLocked Bag 4001WestmeadNSWAustralia2145
- Flinders UniversityCollege of Medicine and Public HealthAdelaideSAAustralia5001
| | - Angela C Webster
- The University of Sydney at WestmeadCentre for Transplant and Renal Research, Westmead Millennium InstituteWestmeadAustralia
- The University of SydneySydney School of Public HealthEdward Ford Building A27SydneyNSWAustralia2006
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Masaki N, Iwadoh K, Tonsho M, Koyama I, Nakajima I, Fuchinoue S. Trough Level of Mycophenolic Acid Did Not Affect De Novo DSA Development in Kidney Transplantation. Transplant Proc 2019; 51:2624-2628. [DOI: 10.1016/j.transproceed.2019.03.078] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 03/05/2019] [Accepted: 03/23/2019] [Indexed: 11/28/2022]
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19
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Mammalian Target of Rapamycin Inhibitors Combined With Calcineurin Inhibitors as Initial Immunosuppression in Renal Transplantation: A Meta-analysis. Transplantation 2019; 103:2031-2056. [DOI: 10.1097/tp.0000000000002769] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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20
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Ciancio G, Gaynor JJ, Guerra G, Sageshima J, Roth D, Chen L, Kupin W, Mattiazzi A, Tueros L, Ruiz P, Vianna R, Burke GW. Antibody-mediated rejection implies a poor prognosis in kidney transplantation: Results from a single center. Clin Transplant 2018; 32:e13392. [PMID: 30152116 DOI: 10.1111/ctr.13392] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 07/09/2018] [Accepted: 08/22/2018] [Indexed: 11/28/2022]
Abstract
Two major barriers to achieving long-term graft survival include patient nonadherence in taking the prescribed immunosuppression and antibody-mediated rejection(AMR). We were therefore interested in determining the prognostic impact of developing an AMR component to rejection in a prospective randomized trial of 200 kidney transplant recipients who received dual induction therapy (rATG combined with either daclizumab or alemtuzumab) and planned early corticosteroid withdrawal. With a median follow-up of 96 months post-transplant, 40/200 developed a first BPAR; 9/200 developed a second BPAR. An AMR component to rejection was observed in 70% (28/40) of cases. Percentages having C4d deposition, histopathologic evidence of acute AMR, and presence of DSAs/non-DSAs at the time of first developing the AMR component were 64.3% (18/28), 60.7% (17/28), and 53.6% (15/28), respectively. Development of an AMR component was associated with a significantly higher death-censored graft failure rate following rejection in comparison with the patient state of experiencing BPAR but without developing an AMR component (estimated hazard ratio: 4.52, P = 0.01). The observed percentage developing graft failure following development of an AMR component was 53.6% (15/28) vs only 20.0%(3/15) if it was not observed. Actuarial death-censored graft survival at 60 months following development of an AMR component was 28.3 ± 11.9%. In summary, it appears that more effective AMR prevention/treatment strategies are warranted.
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Affiliation(s)
- Gaetano Ciancio
- The Lillian Jean Kaplan Renal Transplant Center, Miami Transplant Institute, Miami, Florida.,Department of Surgery, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, Florida
| | - Jeffrey J Gaynor
- The Lillian Jean Kaplan Renal Transplant Center, Miami Transplant Institute, Miami, Florida.,Department of Surgery, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, Florida
| | - Giselle Guerra
- The Lillian Jean Kaplan Renal Transplant Center, Miami Transplant Institute, Miami, Florida.,Division of Nephrology, Department of Medicine, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, Florida
| | - Junichiro Sageshima
- The Lillian Jean Kaplan Renal Transplant Center, Miami Transplant Institute, Miami, Florida.,Department of Surgery, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, Florida
| | - David Roth
- The Lillian Jean Kaplan Renal Transplant Center, Miami Transplant Institute, Miami, Florida.,Division of Nephrology, Department of Medicine, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, Florida
| | - Linda Chen
- The Lillian Jean Kaplan Renal Transplant Center, Miami Transplant Institute, Miami, Florida.,Department of Surgery, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, Florida
| | - Warren Kupin
- The Lillian Jean Kaplan Renal Transplant Center, Miami Transplant Institute, Miami, Florida.,Division of Nephrology, Department of Medicine, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, Florida
| | - Adela Mattiazzi
- The Lillian Jean Kaplan Renal Transplant Center, Miami Transplant Institute, Miami, Florida.,Division of Nephrology, Department of Medicine, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, Florida
| | - Lissett Tueros
- The Lillian Jean Kaplan Renal Transplant Center, Miami Transplant Institute, Miami, Florida.,Department of Surgery, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, Florida
| | - Phillip Ruiz
- The Lillian Jean Kaplan Renal Transplant Center, Miami Transplant Institute, Miami, Florida.,Department of Surgery, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, Florida
| | - Rodrigo Vianna
- The Lillian Jean Kaplan Renal Transplant Center, Miami Transplant Institute, Miami, Florida.,Department of Surgery, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, Florida
| | - George W Burke
- The Lillian Jean Kaplan Renal Transplant Center, Miami Transplant Institute, Miami, Florida.,Department of Surgery, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, Florida
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21
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Bajpai NK, Bajpayee A, Charan J, Pareek P, Elhence P, Kirubakaran R. Interventions for treating antibody-mediated acute rejection in kidney transplant recipients. Hippokratia 2018. [DOI: 10.1002/14651858.cd013033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Nitin K Bajpai
- All India Institute of Medical Sciences (AIIMS); Department of Nephrology; Jodhpur Rajasthan India 342005
| | - Archana Bajpayee
- All India Institute of Medical Sciences (AIIMS); Department of Transfusion Medicine & Blood Bank; Basni Phase II Jodhpur Rajasthan India 342005
| | - Jaykaran Charan
- All India Institute of Medical Sciences (AIIMS); Department of Pharmacology; Basni Phase II Jodhpur Rajasthan India 342005
| | - Puneet Pareek
- All India Institute of Medical Sciences (AIIMS); Department of Radiation Oncology; Basni Phase II Jodhpur Rajasthan India 342005
| | - Poonam Elhence
- All India Institute of Medical Sciences (AIIMS); Department of Pathology; Basni Phase II Jodhpur Rajasthan India 342005
| | - Richard Kirubakaran
- Christian Medical College; Cochrane South Asia, Prof. BV Moses Centre for Evidence-Informed Health Care and Health Policy; Carman Block II Floor CMC Campus, Bagayam Vellore India 632002
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22
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Early Steroid Withdrawal Compared With Standard Immunosuppression in Kidney Transplantation - Interim Analysis of the Amsterdam-Leiden-Groningen Randomized Controlled Trial. Transplant Direct 2018; 4:e354. [PMID: 30123827 PMCID: PMC6089519 DOI: 10.1097/txd.0000000000000794] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 02/02/2018] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND The optimal immunosuppressive regimen in kidney transplant recipients, delivering maximum efficacy with minimal toxicity, is unknown. METHODS The Amsterdam, LEiden, GROningen trial is a randomized, multicenter, investigator-driven, noninferiority, open-label trial in 305 kidney transplant recipients, in which 2 immunosuppression minimization strategies—one consisting of early steroid withdrawal, the other of tacrolimus minimization 6 months after transplantation—were compared with standard immunosuppression with basiliximab, corticosteroids, tacrolimus, and mycophenolic acid. The primary endpoint was kidney function. Secondary endpoints included death, primary nonfunction, graft failure, rejection, discontinuation of study medication, and a combined endpoint of treatment failure. An interim analysis was scheduled at 6 months, that is, just before tacrolimus minimization. RESULTS This interim analysis revealed no significant differences in Modification of Diet in Renal Disease between the early steroid withdrawal group and the standard immunosuppression groups (43.2 mL/min per 1.73 m2 vs 45.0 mL/min per 1.73 m2, P = 0.408). There were also no significant differences in the secondary endpoints of death (1.0% vs 1.5%; P = 0.737), primary nonfunction (4.1% vs 1.5%, P = 0.159), graft failure (3.1% vs 1.5%, P = 0.370), rejection (18.6% vs 13.6%, P = 0.289), and discontinuation of study medication (19.6% vs 12.6%, P = 0.348). Treatment failure, defined as a composite endpoint of these individual secondary endpoints, was more common in the early steroid withdrawal group (P = 0.027), but this group had fewer serious adverse events and a more favorable cardiovascular risk profile. CONCLUSIONS Based on these interim results, early steroid withdrawal is a safe short-term immunosuppressive strategy. Long-term outcomes, including a comparison with tacrolimus minimization after 6 months, will be reported in the final 2-year analysis.
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Kojima CA, Nga HS, Takase HM, Bravin AM, Martinez Garcia MDFF, Garcia PD, Contti MM, de Andrade LGM. Sirolimus Associated with Tacrolimus at Low Doses in Elderly Kidney Transplant Patients: A Prospective Randomized Controlled Trial. EXP CLIN TRANSPLANT 2017; 16:301-306. [PMID: 28836934 DOI: 10.6002/ect.2016.0335] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES There is no consensus on the best immunosuppressive regimen for elderly renal transplant recipients. The objective of this study was to assess cytomegalovirus infection incidence and kidney transplant outcomes in elderly recipients treated with mammalian target of rapamycin inhibitors sirolimus/ tacrolimus at low doses compared with those receiving tacrolimus/mycophenolate sodium. MATERIALS AND METHODS In this single-center prospective randomized study (Trial Registration No. NCT02683291), kidney transplant recipients over 60 years of age were randomly allocated into 2 groups: tacrolimus-sirolimus (21 patients) and tacrolimus-mycophenolate (23 patients). Cytomegalovirus infection rate and patient survival, biopsy-proven acute rejection, and renal function at 12 months were assessed. RESULTS Cytomegalovirus infection rate was higher in the mycophenolate group (60.9%) than in the sirolimus group (16.7%; P = .004). The rates of biopsy-proven acute rejection, patient survival, graft survival, and estimated glomerular filtration rate over 12 months did not significantly differ between groups. CONCLUSIONS The incidence of cytomegalovirus infection was significantly lower in the sirolimus group. The use of tacrolimus combined with sirolimus in elderly kidney transplant recipients is safe.
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24
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Huh KH, Lee JG, Ha J, Oh CK, Ju MK, Kim CD, Cho HR, Jung CW, Lim BJ, Kim YS. De novo low-dose sirolimus versus mycophenolate mofetil in combination with extended-release tacrolimus in kidney transplant recipients: a multicentre, open-label, randomized, controlled, non-inferiority trial. Nephrol Dial Transplant 2017; 32:1415-1424. [DOI: 10.1093/ndt/gfx093] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 04/07/2017] [Indexed: 12/20/2022] Open
Affiliation(s)
- Kyu Ha Huh
- Department of Transplantation Surgery, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae Geun Lee
- Department of Transplantation Surgery, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Jongwon Ha
- Department of Surgery, Seoul National University Hospital, Seoul, Republic of Korea
| | - Chang-Kwon Oh
- Department of Surgery, Ajou University Hospital, Suwon, Republic of Korea
| | - Man Ki Ju
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
- Department of Surgery, Gangnam Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Chan-Duck Kim
- Department of Internal Medicine (Nephrology), Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Hong Rae Cho
- Department of Surgery, Ulsan University Hospital, Ulsan, Republic of Korea
| | - Cheol Woong Jung
- Department of Surgery, Korea University Anam Hospital, Seoul, Republic of Korea
| | - Beom Jin Lim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yu Seun Kim
- Department of Transplantation Surgery, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
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25
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Wong TC, Lo CM, Fung JY. Emerging drugs for prevention of T-cell mediated rejection in liver and kidney transplantation. Expert Opin Emerg Drugs 2017; 22:123-136. [PMID: 28503959 DOI: 10.1080/14728214.2017.1330884] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Acute and chronic graft rejection continues to be an important problem after solid organ transplantation. With the introduction of potent immunosuppressive agents such as calcineurin inhibitors, the risk of rejection has been significantly reduced. However, the adverse effects of life-long immunosuppression remain a concern, and there exist a fine balance between over-immunosuppression and risk of rejection. Areas covered: In this review, the current standard of care in immunosuppressive therapy, including the use of steroids, calcineurin inhibitors, mycophenolate prodrugs and mammalian target of rapamycin inhibitors, will be discussed. Newer immunosuppressive agents showing promising early data after liver and kidney transplantation will also be explored. Expert Opinion: Currently, calcineurin inhibitors continue to be a vital component of immunosuppressive therapy after solid organ transplantation. Although minimization and avoidance strategies have been developed, the ultimate goal of inducing tolerance remains elusive. Newer emerging agents should have potent and specific immunosuppressive activity, with minimal associated side effects. An individualized approach should be adopted to tailor immunosuppression according to the different needs of recipients.
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Affiliation(s)
- Tiffany Cl Wong
- a Department of Surgery, Department of Medicine , Queen Mary Hospital, The University of Hong Kong , Hong Kong , Hong Kong S.A.R
| | - Chung-Mau Lo
- a Department of Surgery, Department of Medicine , Queen Mary Hospital, The University of Hong Kong , Hong Kong , Hong Kong S.A.R
| | - James Yy Fung
- a Department of Surgery, Department of Medicine , Queen Mary Hospital, The University of Hong Kong , Hong Kong , Hong Kong S.A.R
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26
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Filler G, Medeiros M. Improving long-term outcomes after pediatric renal transplantation by addressing dyslipidemia. Pediatr Transplant 2017; 21. [PMID: 28370889 DOI: 10.1111/petr.12880] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/14/2016] [Indexed: 01/06/2023]
Affiliation(s)
- Guido Filler
- Department of Paediatrics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.,Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.,Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
| | - Mara Medeiros
- Laboratorio de Investigacion en Nefrologia, Hospital Infantil de Mexico Federico Gomez, Mexico City, México.,Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, México City, México
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27
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Maier M, Takano T, Sapir-Pichhadze R. Changing Paradigms in the Management of Rejection in Kidney Transplantation: Evolving From Protocol-Based Care to the Era of P4 Medicine. Can J Kidney Health Dis 2017; 4:2054358116688227. [PMID: 28270929 PMCID: PMC5308536 DOI: 10.1177/2054358116688227] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 11/17/2016] [Indexed: 12/30/2022] Open
Abstract
PURPOSE OF REVIEW P4 medicine denotes an evolving field of medicine encompassing predictive, preventive, personalized, and participatory medicine. Using the example of kidney allograft rejection because of donor-recipient incompatibility in human leukocyte antigens, this review outlines P4 medicine's relevance to the various stages of the kidney transplant cycle. SOURCES OF INFORMATION A search for English articles was conducted in Medline via OvidSP (up to August 18, 2016) using a combination of subject headings (MeSH) and free text in titles, abstracts, and author keywords for the concepts kidney transplantation and P4 medicine. The electronic database search was expanded further on particular subject headings. FINDINGS Available histocompatibility methods exemplify current applications of the predictive and preventive domains of P4 medicine in kidney transplant recipients' care. Pharmacogenomics are discussed as means to facilitate personalized immunosuppression regimens and promotion of active patient participation as a means to improve adherence. LIMITATIONS For simplicity, this review focuses on rejection. P4 medicine, however, should more broadly address health concerns in kidney transplant recipients, including competing outcomes such as infections, malignancies, and cardiovascular disease. This review highlights how biomarkers to evaluate these competing outcomes warrant validation and standardization prior to their incorporation into clinical practice. IMPLICATIONS Consideration of all 4 domains of the P4 medicine framework when caring for and/or studying kidney transplant recipients has the potential of increasing therapeutic efficiency, minimizing adverse effects, decreasing health care costs, and maximizing wellness. Technologies to gauge immune competency, immunosuppression requirements, and early/reversible immune-mediated injuries are required to optimize kidney transplant care.
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Affiliation(s)
- Mirela Maier
- Division of Nephrology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
- Metabolic Disorders and Complications, Research Institute of McGill University Health Centre, Montreal, Quebec, Canada
| | - Tomoko Takano
- Division of Nephrology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
- Metabolic Disorders and Complications, Research Institute of McGill University Health Centre, Montreal, Quebec, Canada
| | - Ruth Sapir-Pichhadze
- Division of Nephrology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
- Metabolic Disorders and Complications, Research Institute of McGill University Health Centre, Montreal, Quebec, Canada
- Multi-Organ Transplant Program, Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec, Canada
- Centre for Outcomes Research and Evaluation, McGill University Health Centre, Montreal, Quebec, Canada
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28
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Lee J, Song SH, Lee JG, Kim BS, Huh KH, Kim YS. Sirolimus Combination with Tacrolimus in Kidney Transplant Recipients at High Immunological Risk: Observational Results 3 Years after Transplantation. KOREAN JOURNAL OF TRANSPLANTATION 2016. [DOI: 10.4285/jkstn.2016.30.4.165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- Juhan Lee
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Seung Hwan Song
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Jae Geun Lee
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Beom Seok Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Kyu Ha Huh
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Yu Seun Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
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29
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Shrestha BM. Two Decades of Tacrolimus in Renal Transplant: Basic Science and Clinical Evidences. EXP CLIN TRANSPLANT 2016; 15:1-9. [PMID: 27938316 DOI: 10.6002/ect.2016.0157] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Tacrolimus, a calcineurin inhibitor, has been the cornerstone of immunosuppressive regimens in renal transplant over 2 decades. This has significantly improved the outcomes of renal transplant, including reduction of acute rejection episodes, improvement of renal function and graft survival, and reduction of some of the adverse effects associated with cyclosporine. However, use of tacrolimus is associated with a number of undesirable effects, such as nephrotoxicity, posttransplant diabetes mellitus, neurotoxicity, and cosmetic and electrolyte disturbances. To alleviate these effects, several strategies have been adopted to minimize or eliminate tacrolimus from maintenance regimens of immunosuppression, with some success. This review focuses on advancements in the understanding of the basic science related to tacrolimus and the clinical evidences that have examined the efficacy and safety of tacrolimus in renal transplant over the past 2 decades and highlights the future directions.
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Affiliation(s)
- Badri Man Shrestha
- From the Sheffield Kidney Institute, Sheffield Teaching Hospitals NHS Trust, Sheffield, United Kingdom
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30
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Ikeda M, Tsukada N, Chikai H, Tasaki M, Saito K, Nakagawa Y, Takahashi K, Suzuki K. Successful Second Allogeneic Stem Cell Transplantation From a Sibling Donor for Relapse of Myelodysplastic Syndrome in a Recipient of a Renal Transplant From His Mother: Case Report. Transplant Proc 2016; 48:3085-3087. [PMID: 27932152 DOI: 10.1016/j.transproceed.2016.03.033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Revised: 02/26/2016] [Accepted: 03/23/2016] [Indexed: 01/30/2023]
Abstract
There have been few reports on allogeneic stem cell transplantation in patients who have previously undergone solid organ transplantation. The clinical course of such patients is not yet well recognized. Therefore, appropriate immunosuppressive prophylaxis for the rejection of a solid organ graft or for graft-versus-host disease has not yet been established. We present the case of a successful allogeneic stem cell transplantation in a patient who relapsed after a first allogeneic stem cell transplantation for myelodysplastic syndrome and who had previously undergone renal transplantation. The prophylaxis in this case for graft-versus-host disease and rejection of the transplanted kidney was mycophenolate mofetil and tacrolimus. No hyperacute rejection of the transplanted kidney was observed. However, the patient's renal function deteriorated after the cessation of the mycophenolate mofetil and the reduction of the tacrolimus. This deterioration seemed to be due to rejection with humoral immunity of donor lymphocytes, and we were able to control it by resuming the mycophenolate mofetil and local graft irradiation.
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Affiliation(s)
- M Ikeda
- Division of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan
| | - N Tsukada
- Division of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan.
| | - H Chikai
- Division of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan
| | - M Tasaki
- Division of Urology, Department of Regenerative and Transplant Medicine, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - K Saito
- Division of Urology, Department of Regenerative and Transplant Medicine, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Y Nakagawa
- Division of Urology, Department of Regenerative and Transplant Medicine, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - K Takahashi
- Niigata Organ Transplant Foundation, Tokyo, Japan
| | - K Suzuki
- Division of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan
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31
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Kumar J, Bridson JM, Sharma A, Halawa A. Systematic Review on Role of Mammalian Target of Rapamycin Inhibitors as an Alternative to Calcineurin Inhibitors in Renal Transplant: Challenges and Window to Excel. EXP CLIN TRANSPLANT 2016; 15:241-252. [PMID: 27915965 DOI: 10.6002/ect.2016.0270] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
OBJECTIVES This review focuses on the current limited evidence of graft function and graft survival in various immunosuppressive regimens involving mammalian target of rapamycin inhibitors with or without calcineurin inhibitors. MATERIALS AND METHODS We evaluated the current literature for describing the role of mammalian target of rapamycin inhibitors as an alternative to calcineurin inhibitors by searching the PubMed, EMBASE, Cochrane, Crossref, and Scopus databases using medical subject heading terms. RESULTS Our detailed analyses of all relevant literature showed use of mammalian target of rapamycin inhibitor-based de novo regimens, early calcineurin inhibitor withdrawal with subsequent introduction of mammalian target of rapamycin inhibitor-based regimens, and late conversion from a calcineurin inhibitor-based regimen to mammalian target of rapamycin inhibitor-based regimens. Notably, early calcineurin inhibitor withdrawal with subsequent introduction of mammalian target of rapamycin inhibitor-based regimen seemed to be a more practical and realistic approach toward immunosuppressive treatment of renal transplant recipients. However, in view of the high rejection rate observed in these studies, it is advisable not to offer these regimens to patients with moderate to high immunologic risk. CONCLUSIONS The present evidences suggest that treatment with mammalian target of rapamycin inhibitors allows early and substantial calcineurin inhibitor minimization. The mammalian target of rapamycin inhibitors everolimus and sirolimus are preferred due to their complementary mechanisms of action and favorable nephrotoxicity profile, which have opened the way for calcineurin inhibitor reduction/withdrawal in the early posttransplant period.
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Affiliation(s)
- Jayant Kumar
- From the Department of Hepato-Pancreato-Biliary Surgery, Hammersmith Hospital, Imperial College, London, United Kingdom; and the Faculty of Health and Sciences, Institute of Learning and Teaching, University of Liverpool, United Kingdom
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32
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Wang X, Wang H, Shen B, Overholser BR, Cooper BR, Lu Y, Tang H, Zhou C, Sun X, Zhong L, Favus MJ, Decker BS, Liu W, Peng Z. 1-Alpha, 25-dihydroxyvitamin D3 alters the pharmacokinetics of mycophenolic acid in renal transplant recipients by regulating two extrahepatic UDP-glucuronosyltransferases 1A8 and 1A10. Transl Res 2016; 178:54-62.e6. [PMID: 27496319 DOI: 10.1016/j.trsl.2016.07.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Revised: 05/31/2016] [Accepted: 07/07/2016] [Indexed: 11/18/2022]
Abstract
Mycophenolic acid (MPA) is an important immunosuppressant broadly used in renal transplantation. However, the large inter-patient variability in mycophenolic acid (MPA) pharmacokinetics (PK) limits its use. We hypothesize that extrahepatic metabolism of MPA may have significant impact on MPA PK variability. Two intestinal UDP-glucuronosyltransferases 1A8 and 1A10 plays critical role in MPA metabolism. Both in silico and previous genome-wide analyses suggested that vitamin D (VD) may regulate intestinal UGT1A expression. We validated the VD response elements (VDREs) across the UGT1A locus with chromatin immunoprecipitation (ChIP) and luciferase reporter assays. The impact of 1-alpha,25-dihydroxyvitamin D3 (D3) on UGT1A8 and UGT1A10 transcription and on MPA glucuronidation was tested in human intestinal cell lines LS180, Caco-2 and HCT-116. The correlation between transcription levels of VD receptor (VDR) and the two UGT genes were examined in human normal colorectal tissue samples (n = 73). PK alterations of MPA following the parent drug, mycophenolate mofetil (MMF), and D3 treatment was assessed among renal transplant recipients (n = 10). Our ChIP assay validate three VDREs which were further demonstrated as transcriptional enhancers with the luciferase assays. D3 treatment significantly increased transcription of both UGT genes as well as MPA glucuronidation in cells. The VDR mRNA level was highly correlated with that of both UGT1A8 and UGT1A10 in human colorectal tissue. D3 treatment in patients led to about 40% reduction in both AUC0-12 and Cmax while over 70% elevation of total clearance of MPA. Our study suggested a significant regulatory role of VD on MPA metabolism and PK via modulating extrahepatic UGT activity.
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Affiliation(s)
- Xiaoliang Wang
- Department of General Surgery, Shanghai First People's Hospital, Medical College, Shanghai Jiaotong University, Shanghai, P. R. China; Department of Medicinal Chemistry & Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Ind, USA
| | - Hongwei Wang
- Section of Endocrinology, Department of Medicine, The University of Chicago, Chicago, Ill, USA
| | - Bing Shen
- Department of Urology, Shanghai First People's Hospital, Medical College, Shanghai Jiaotong University, Shanghai, P. R. China
| | - Brian R Overholser
- Department of Pharmacy Practice, College of Pharmacy, Purdue University, West Lafayette, Ind, USA
| | - Bruce R Cooper
- Bindley Bioscience Center, Metabolite Profiling Facility, Purdue University, West Lafayette, Ind, USA
| | - Yinghao Lu
- Department of Hematology, Affiliated Hospital of Guiyang Medical College, The Hematopoietic Stem Cell Transplant Center of Guizhou Province, Guiyang, P. R. China
| | - Huamei Tang
- Department of Pathology, Shanghai First People's Hospital, Medical College, Shanghai Jiaotong University, Shanghai, P. R. China
| | - Chongzhi Zhou
- Department of General Surgery, Shanghai First People's Hospital, Medical College, Shanghai Jiaotong University, Shanghai, P. R. China
| | - Xing Sun
- Department of General Surgery, Shanghai First People's Hospital, Medical College, Shanghai Jiaotong University, Shanghai, P. R. China
| | - Lin Zhong
- Department of General Surgery, Shanghai First People's Hospital, Medical College, Shanghai Jiaotong University, Shanghai, P. R. China
| | - Murray J Favus
- Section of Endocrinology, Department of Medicine, The University of Chicago, Chicago, Ill, USA
| | - Brian S Decker
- Division of Nephrology, School of Medicine, Indiana University, Indianapolis, Ind, USA; Department of Medicine, School of Medicine, Indiana University, Indianapolis, Ind, USA
| | - Wanqing Liu
- Department of Medicinal Chemistry & Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Ind, USA.
| | - Zhihai Peng
- Department of General Surgery, Shanghai First People's Hospital, Medical College, Shanghai Jiaotong University, Shanghai, P. R. China.
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Ciancio G, Gaynor JJ, Guerra G, Sageshima J, Roth D, Chen L, Kupin W, Mattiazzi A, Tueros L, Flores S, Hanson L, Ruiz P, Vianna R, Burke GW. Randomized trial of rATg/Daclizumab vs. rATg/Alemtuzumab as dual induction therapy in renal transplantation: Results at 8years of follow-up. Transpl Immunol 2016; 40:42-50. [PMID: 27888093 DOI: 10.1016/j.trim.2016.11.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 11/16/2016] [Accepted: 11/17/2016] [Indexed: 01/28/2023]
Abstract
Our goal in using dual induction therapy is to bring the kidney transplant recipient closer (through more effectively timed lymphodepletion) to an optimally immunosuppressed state. Here, we report long-term results of a prospective randomized trial comparing (Group I,N=100) rATG/Dac (3 rATG, 2 Dac doses) vs. (Group II,N=100) rATG/Alemtuzumab(C1H) (1 dose each), using reduced tacrolimus dosing, EC-MPS, and early corticosteroid withdrawal. Lower EC-MPS dosing was targeted in Group II to avoid severe leukopenia. Median follow-up was 96mo post-transplant. There were no differences in 1st BPAR (including borderline) rates: 10/100 vs. 9/100 in Groups I and II during the first 12mo(P=0.54), and 20/100 vs. 20/100 throughout the study(P=0.90). Equally favorable renal function was maintained in both treatment arms(N.S.). While not significant, more patients in Group II experienced graft loss, 25/100 vs. 18/100 in Group I(P=0.23). Actuarial patient/graft survival at 96mo was 92%/83% vs. 85%/73% in Groups I and II(N.S.). DWFG-due-to-infection(N.S.), EC-MPS withholding-due-to-leukopenia during the first 2mo(P=0.03), and incidence of viral infections(P=0.09) were higher in Group II, whereas EC-MPS withholding-due-to-GI symptoms was higher in Group I(P=0.009). No other adverse event differences were observed. While long-term anti-rejection and renal function efficacy were demonstrated in both treatment arms, slight over-immunosuppression of Group II patients occurred.
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Affiliation(s)
- Gaetano Ciancio
- The Lillian Jean Kaplan Renal Transplant Center and the Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Jeffrey J Gaynor
- The Lillian Jean Kaplan Renal Transplant Center and the Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Giselle Guerra
- Division of Nephrology of the Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Junichiro Sageshima
- The Lillian Jean Kaplan Renal Transplant Center and the Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - David Roth
- Division of Nephrology of the Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Linda Chen
- The Lillian Jean Kaplan Renal Transplant Center and the Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Warren Kupin
- Division of Nephrology of the Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Adela Mattiazzi
- Division of Nephrology of the Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Lissett Tueros
- The Lillian Jean Kaplan Renal Transplant Center and the Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Sandra Flores
- The Lillian Jean Kaplan Renal Transplant Center and the Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Lois Hanson
- The Lillian Jean Kaplan Renal Transplant Center and the Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Phillip Ruiz
- The Lillian Jean Kaplan Renal Transplant Center and the Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Rodrigo Vianna
- The Lillian Jean Kaplan Renal Transplant Center and the Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - George W Burke
- The Lillian Jean Kaplan Renal Transplant Center and the Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
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Ciancio G, Tryphonopoulos P, Gaynor J, Guerra G, Sageshima J, Roth D, Chen L, Kupin W, Mattiazzi A, Tueros L, Flores S, Hanson L, Powell R, Ruiz P, Vianna R, Burke G. Pilot Randomized Trial of Tacrolimus/Everolimus vs Tacrolimus/Enteric-Coated Mycophenolate Sodium in Adult, Primary Kidney Transplant Recipients at a Single Center. Transplant Proc 2016; 48:2006-10. [DOI: 10.1016/j.transproceed.2016.03.048] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Revised: 02/19/2016] [Accepted: 03/01/2016] [Indexed: 10/21/2022]
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Cunningham KC, Hager DR, Fischer J, D'Alessandro AM, Leverson GE, Kaufman DB, Djamali A. Single-Dose Basiliximab Induction in Low-Risk Renal Transplant Recipients. Pharmacotherapy 2016; 36:823-9. [DOI: 10.1002/phar.1774] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
| | - David R. Hager
- Department of Pharmacy; University of Wisconsin; Madison Wisconsin
| | - Jessica Fischer
- Department of Pharmacy; University of Wisconsin; Madison Wisconsin
| | | | - Glen E. Leverson
- Department of Surgery; University of Wisconsin; Madison Wisconsin
| | - Dixon B. Kaufman
- Department of Surgery; University of Wisconsin; Madison Wisconsin
| | - Arjang Djamali
- Department of Medicine; University of Wisconsin; Madison Wisconsin
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Chand S, McKnight AJ, Shabir S, Chan W, McCaughan JA, Maxwell AP, Harper L, Borrows R. Analysis of single nucleotide polymorphisms implicate mTOR signalling in the development of new-onset diabetes after transplantation. BBA CLINICAL 2016; 5:41-5. [PMID: 27051588 PMCID: PMC4802392 DOI: 10.1016/j.bbacli.2015.12.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Revised: 12/07/2015] [Accepted: 12/17/2015] [Indexed: 12/13/2022]
Abstract
Introduction Despite excellent first year outcomes in kidney transplantation, there remain significant long-term complications related to new-onset diabetes after transplantation (NODAT). The purpose of this study was to validate the findings of previous investigations of candidate gene variants in patients undergoing a protocolised, contemporary immunosuppression regimen, using detailed serial biochemical testing to identify NODAT development. Methods One hundred twelve live and deceased donor renal transplant recipients were prospectively followed-up for NODAT onset, biochemical testing at days 7, 90, and 365 after transplantation. Sixty-eight patients were included after exclusion for non-white ethnicity and pre-transplant diabetes. Literature review to identify candidate gene variants was undertaken as described previously. Results Over 25% of patients developed NODAT. In an adjusted model for age, sex, BMI, and BMI change over 12 months, five out of the studied 37 single nucleotide polymorphisms (SNPs) were significantly associated with NODAT: rs16936667:PRDM14 OR 10.57;95% CI 1.8–63.0;p = 0.01, rs1801282:PPARG OR 8.5; 95% CI 1.4–52.7; p = 0.02, rs8192678:PPARGC1A OR 0.26; 95% CI 0.08–0.91; p = 0.03, rs2144908:HNF4A OR 7.0; 95% CI 1.1–45.0;p = 0.04 and rs2340721:ATF6 OR 0.21; 95%CI 0.04–1.0; p = 0.05. Conclusion This study represents a replication study of candidate SNPs associated with developing NODAT and implicates mTOR as the central regulator via altered insulin sensitivity, pancreatic β cell, and mitochondrial survival and dysfunction as evidenced by the five SNPs. General significance
Highlights the importance of careful biochemical phenotyping with oral glucose tolerance tests to diagnose NODAT in reducing time to diagnosis and missed cases. This alters potential genotype:phenotype association. The replication study generates the hypothesis that mTOR signalling pathway may be involved in NODAT development.
Oral glucose tolerance tests reduce time to NODAT diagnosis and missed cases Biochemical testing changes genotype:phenotype association mTOR signalling pathway may be involved in NODAT development
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Key Words
- ATF6, Activated transcription factor
- BMI, Body mass index
- GWAS, Genome-wide association study
- HLA, Human leucocyte antigen
- HNF4, Hepatocyte nuclear factor 4
- NODAT, New-onset diabetes after transplantation
- New-onset diabetes after transplantation
- PI3, Phospho-inositide 3-kinase
- PPARGC1α, Peroxisome proliferator-activated receptor gamma co-activator 1 alpha
- PPARy, Peroxisome proliferator-activated receptor gamma
- PRDM14, PR domain zinc protein 14
- SNP, Single nucleotide polymorphism
- mTOR
- mTOR, Mammalian target of rapamycin
- single nucleotide polymorphisms
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Affiliation(s)
- S Chand
- Department of Nephrology and Kidney Transplantation, Queen Elizabeth Hospital, Birmingham B15 2WB, United Kingdom; Centre for Translational Inflammation Research, University of Birmingham, Birmingham B15 2WB, United Kingdom
| | - A J McKnight
- Regional Nephrology Unit, Belfast City Hospital, Belfast BT9 7AB, Northern Ireland
| | - S Shabir
- Department of Nephrology and Kidney Transplantation, Queen Elizabeth Hospital, Birmingham B15 2WB, United Kingdom; Centre for Translational Inflammation Research, University of Birmingham, Birmingham B15 2WB, United Kingdom
| | - W Chan
- Department of Nephrology and Kidney Transplantation, Queen Elizabeth Hospital, Birmingham B15 2WB, United Kingdom
| | - J A McCaughan
- Regional Nephrology Unit, Belfast City Hospital, Belfast BT9 7AB, Northern Ireland
| | - A P Maxwell
- Regional Nephrology Unit, Belfast City Hospital, Belfast BT9 7AB, Northern Ireland
| | - L Harper
- Department of Nephrology and Kidney Transplantation, Queen Elizabeth Hospital, Birmingham B15 2WB, United Kingdom; Centre for Translational Inflammation Research, University of Birmingham, Birmingham B15 2WB, United Kingdom
| | - R Borrows
- Department of Nephrology and Kidney Transplantation, Queen Elizabeth Hospital, Birmingham B15 2WB, United Kingdom; Centre for Translational Inflammation Research, University of Birmingham, Birmingham B15 2WB, United Kingdom
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Trolinger M. Kidney Transplant for the Twenty-First Century. PHYSICIAN ASSISTANT CLINICS 2016. [DOI: 10.1016/j.cpha.2015.09.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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González F, Valjalo R. Combining cytochrome P-450 3A4 modulators and cyclosporine or everolimus in transplantation is successful. World J Transplant 2015; 5:338-347. [PMID: 26722662 PMCID: PMC4689945 DOI: 10.5500/wjt.v5.i4.338] [Citation(s) in RCA: 5] [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: 07/01/2015] [Revised: 08/10/2015] [Accepted: 09/18/2015] [Indexed: 02/05/2023] Open
Abstract
AIM: To describe the long term follow-up of kidney allograft recipients receiving ketoconazole with calcineurin inhibitors (CNI) alone or combined with everolimus.
METHODS: This is an open-label, prospective observational clinical trial in low immunologic risk patients who, after signing an Institutional Review Board approved consent form, were included in one of two groups. The first one (n = 59) received everolimus (target blood level, 3-8 ng/mL) and the other (n = 114) azathioprine 2 mg/kg per day or mycophenolate mofetyl (MMF) 2 g/d. Both groups also received tapering steroids, the cytochrome P-450 3A4 (CYP3A4) modulator, ketoconazole 50-100 mg/d, and cyclosporine with C0 targets in the everolimus group of 200-250 ng/mL in 1 mo, 100-125 ng/mL in 2 mo, and 50-65 ng/mL thereafter, and in the azathioprine or MMF group of 250-300 ng/mL in 1 mo, 200-250 ng/mL in 2 mo, 180-200 ng/mL until 3-6 mo, and 100-125 ng/mL thereafter. Clinical visits were performed monthly the first year and quarterly thereafter by treating physicians and all data was extracted by the investigators.
RESULTS: The clinical characteristics of these two cohorts were similar. During the follow up (66 + 31 mo), both groups showed comparable clinical courses, but the biopsy proven acute rejection rate during the full follow-up period seemed to be lower in the everolimus group (20% vs 36%; P = 0.04). The everolimus group did not show a higher surgical complication rate than the other group. By the end of the follow-up period, the everolimus group tended to show a higher glomerular filtration rate. Nevertheless, we found no evidence of a consistent negative slope of the temporal allograft function estimated by the modification of the diet in renal disease formula in any of both groups. At 6 years of follow-up, the uncensored and death-censored graft survivals were 91% and 93%, and 91% and 83% in the everolimus plus cyclosporine, and cyclosporine alone groups, respectively. The addition of ketoconazole saved 80% of cyclosporine and 56% of everolimus doses.
CONCLUSION: Combining CYP3A4 modulators with CNI or mammalian target of rapamycin inhibitor, in low immunological risk kidney transplant recipients is feasible, effective, safe and affordable even in the long term.
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Naik AS, Dharnidharka VR, Schnitzler MA, Brennan DC, Segev DL, Axelrod D, Xiao H, Kucirka L, Chen J, Lentine KL. Clinical and economic consequences of first-year urinary tract infections, sepsis, and pneumonia in contemporary kidney transplantation practice. Transpl Int 2015; 29:241-52. [PMID: 26563524 DOI: 10.1111/tri.12711] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Revised: 08/10/2015] [Accepted: 10/30/2015] [Indexed: 12/15/2022]
Abstract
We examined United States Renal Data System registry records for Medicare-insured kidney transplant recipients in 2000-2011 to study the clinical and cost impacts of urinary tract infections (UTI), pneumonia, and sepsis in the first year post-transplant among a contemporary, national cohort. Infections were identified by billing diagnostic codes. Among 60 702 recipients, 45% experienced at least one study infection in the first year post-transplant, including UTI in 32%, pneumonia in 13%, and sepsis in 12%. Older recipient age, female sex, diabetic kidney failure, nonstandard criteria organs, sirolimus-based immunosuppression, and steroids at discharge were associated with increased risk of first-year infections. By time-varying, multivariate Cox regression, all study infections predicted increased first-year mortality, ranging from 41% (aHR 1.41, 95% CI 1.25-1.56) for UTI alone, 6- to 12-fold risk for pneumonia or sepsis alone, to 34-fold risk (aHR 34.38, 95% CI 30.35-38.95) for those with all three infections. Infections also significantly increased first-year costs, from $17 691 (standard error (SE) $591) marginal cost increase for UTI alone, to approximately $40 000-$50 000 (SE $1054-1238) for pneumonia or sepsis alone, to $134 773 (SE $1876) for those with UTI, pneumonia, and sepsis. Clinical and economic impacts persisted in years 2-3 post-transplant. Early infections reflect important targets for management protocols to improve post-transplant outcomes and reduce costs of care.
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Affiliation(s)
- Abhijit S Naik
- Division of Nephrology, University of Michigan, Ann Arbor, MI, USA
| | - Vikas R Dharnidharka
- Division of Nephrology, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
| | - Mark A Schnitzler
- Saint Louis University Center for Transplant Research, Saint Louis University Hospital, St. Louis, MO, USA
| | - Daniel C Brennan
- Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Dorry L Segev
- Division of Abdominal Transplantation, Department of Surgery, Johns Hopkins University, Baltimore, MD, USA
| | - David Axelrod
- Division of Abdominal Transplantation, Department of Surgery, Dartmouth Hitchcock Medical Center, Hanover, NH, USA
| | - Huiling Xiao
- Saint Louis University Center for Transplant Research, Saint Louis University Hospital, St. Louis, MO, USA
| | - Lauren Kucirka
- Division of Abdominal Transplantation, Department of Surgery, Johns Hopkins University, Baltimore, MD, USA
| | - Jiajing Chen
- Center for Outcomes Research, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - Krista L Lentine
- Saint Louis University Center for Transplant Research, Saint Louis University Hospital, St. Louis, MO, USA
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Gaynor JJ, Ciancio G, Guerra G, Sageshima J, Roth D, Goldstein MJ, Chen L, Kupin W, Mattiazzi A, Tueros L, Flores S, Hanson L, Ruiz P, Vianna R, Burke GW. Lower tacrolimus trough levels are associated with subsequently higher acute rejection risk during the first 12 months after kidney transplantation. Transpl Int 2015; 29:216-26. [DOI: 10.1111/tri.12699] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Revised: 08/03/2015] [Accepted: 09/29/2015] [Indexed: 11/29/2022]
Affiliation(s)
- Jeffrey J. Gaynor
- Miami Transplant Institute; Department of Surgery; University of Miami Miller School of Medicine; Miami FL USA
| | - Gaetano Ciancio
- Miami Transplant Institute; Department of Surgery; University of Miami Miller School of Medicine; Miami FL USA
| | - Giselle Guerra
- Miami Transplant Institute; Department of Medicine; University of Miami Miller School of Medicine; Miami FL USA
| | - Junichiro Sageshima
- Miami Transplant Institute; Department of Surgery; University of Miami Miller School of Medicine; Miami FL USA
| | - David Roth
- Miami Transplant Institute; Department of Medicine; University of Miami Miller School of Medicine; Miami FL USA
| | - Michael J. Goldstein
- Miami Transplant Institute; Department of Surgery; University of Miami Miller School of Medicine; Miami FL USA
| | - Linda Chen
- Miami Transplant Institute; Department of Surgery; University of Miami Miller School of Medicine; Miami FL USA
| | - Warren Kupin
- Miami Transplant Institute; Department of Medicine; University of Miami Miller School of Medicine; Miami FL USA
| | - Adela Mattiazzi
- Miami Transplant Institute; Department of Medicine; University of Miami Miller School of Medicine; Miami FL USA
| | - Lissett Tueros
- Miami Transplant Institute; Department of Surgery; University of Miami Miller School of Medicine; Miami FL USA
| | - Sandra Flores
- Miami Transplant Institute; Department of Surgery; University of Miami Miller School of Medicine; Miami FL USA
| | - Lois Hanson
- Miami Transplant Institute; Department of Surgery; University of Miami Miller School of Medicine; Miami FL USA
| | - Phillip Ruiz
- Miami Transplant Institute; Department of Surgery; University of Miami Miller School of Medicine; Miami FL USA
| | - Rodrigo Vianna
- Miami Transplant Institute; Department of Surgery; University of Miami Miller School of Medicine; Miami FL USA
| | - George W. Burke
- Miami Transplant Institute; Department of Surgery; University of Miami Miller School of Medicine; Miami FL USA
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Langsford D, Dwyer K. Dysglycemia after renal transplantation: Definition, pathogenesis, outcomes and implications for management. World J Diabetes 2015; 6:1132-51. [PMID: 26322159 PMCID: PMC4549664 DOI: 10.4239/wjd.v6.i10.1132] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2014] [Revised: 07/06/2015] [Accepted: 08/16/2015] [Indexed: 02/05/2023] Open
Abstract
New-onset diabetes after transplantation (NODAT) is major complication following renal transplantation. It commonly develops within 3-6 mo post-transplantation. The development of NODAT is associated with significant increase in risk of major cardiovascular events and cardiovascular death. Other dysglycemic states, such as impaired glucose tolerance are also associated with increasing risk of cardiovascular events. The pathogenesis of these dysglycemic states is complex. Older recipient age is a consistent major risk factor and the impact of calcineurin inhibitors and glucocorticoids has been well described. Glucocorticoids likely cause insulin resistance and calcineurin inhibitors likely cause β-cell toxicity. The impact of transplantation in incretin hormones remains to be clarified. The oral glucose tolerance test remains the best diagnostic test but other tests may be validated as screening tests. Possibly, NODAT can be prevented by administering insulin early in patients identified as high risk for NODAT. Once NODAT has been diagnosed altering immunosuppression may be acceptable, but creates the difficulty of balancing immunological with metabolic risk. With regard to hypoglycemic use, metformin may be the best option. Further research is needed to better understand the pathogenesis, identify high risk patients and to improve management options given the significant increased risk of major cardiovascular events and death.
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Xie X, Jiang Y, Lai X, Xiang S, Shou Z, Chen J. mTOR inhibitor versus mycophenolic acid as the primary immunosuppression regime combined with calcineurin inhibitor for kidney transplant recipients: a meta-analysis. BMC Nephrol 2015; 16:91. [PMID: 26126806 PMCID: PMC4486141 DOI: 10.1186/s12882-015-0078-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2014] [Accepted: 05/21/2015] [Indexed: 01/01/2023] Open
Abstract
Background A number of studies have provided information regarding the risks and benefits of mammalian target of rapamycin inhibitors (mTOR-I) combined with calcineurin inhibitors (CNI) versus mycophenolic acid (MPA). Methods Medline, Embase and the Cochrane Central Register of Controlled Trials were searched. Randomized controlled trials comparing mTOR-I to MPA as the primary immunosuppressive regimen in combination with CNI were selected and meta-analyzed. Results Eleven randomized controlled trials consisting of 4930 patients in total were included. No significant difference was observed in the risk of biopsy-proven acute rejection and patient death between the two groups. However, an increased risk of graft loss (relative risk (RR) = 1.20) and inferior graft function (creatinine clearance, weighted mean difference (WMD) = −2.41 μmol/L) were demonstrated in mTOR-I-treated patients. Patients treated with mTOR-I had a higher risk of new-onset diabetes mellitus (RR = 1.32), dyslipidemia, proteinuria (RR = 1.79), peripheral edema (RR = 1.34), thrombocytopenia (RR = 1.97) and lymphocoele (RR = 1.80), but a lower risk of cytomegalovirus infection (RR = 0.40), malignancy (RR = 0.64) and leucopenia (RR = 0.43). There was no difference in diarrhea, anemia, urinary tract infection, polyoma virus infection and impaired wound healing when mTOR-I was compared with MPA. Conclusions mTOR-I showed no particular superiority to MPA. Notably, mTOR-I had an increased risk of graft loss when combined with CNI, even when combined with a reduced dose of CNI. Therefore, the optimal dosage strategies for mTOR-I and CNI need to be further explored. Electronic supplementary material The online version of this article (doi:10.1186/s12882-015-0078-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xishao Xie
- Kidney Disease Center, The First Affiliated Hospital, Medical School of Zhejiang University, Qingchun Rd, Hangzhou, Zhejiang, China.
| | - Yan Jiang
- Kidney Disease Center, The First Affiliated Hospital, Medical School of Zhejiang University, Qingchun Rd, Hangzhou, Zhejiang, China.
| | - Xiuxiu Lai
- Kidney Disease Center, The First Affiliated Hospital, Medical School of Zhejiang University, Qingchun Rd, Hangzhou, Zhejiang, China.
| | - Shilong Xiang
- Kidney Disease Center, The First Affiliated Hospital, Medical School of Zhejiang University, Qingchun Rd, Hangzhou, Zhejiang, China.
| | - Zhangfei Shou
- Kidney Disease Center, The First Affiliated Hospital, Medical School of Zhejiang University, Qingchun Rd, Hangzhou, Zhejiang, China.
| | - Jianghua Chen
- Kidney Disease Center, The First Affiliated Hospital, Medical School of Zhejiang University, Qingchun Rd, Hangzhou, Zhejiang, China.
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Ortega F, Díaz-Corte C, Valdés C. Adherence to immunosuppressor medication in renal transplanted patients. World J Clin Urol 2015; 4:27-37. [DOI: 10.5410/wjcu.v4.i1.27] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Revised: 05/27/2014] [Accepted: 12/17/2014] [Indexed: 02/06/2023] Open
Abstract
Non-adherence is a priority public health concern. Non-adherence means not taking medications, missing medications, taking too much, not taking enough, wrong timing, wrong dose and/or wrong pill, but may also refer to missing appointments, not booking appointments, not doing blood work, not returning calls and/or refusal to follow the treatment regimen. In renal transplantation, adherence to immunosuppressive medication is a fundamental requisite in order to preserve graft function, since non-adherence is one of the main causes for late acute rejection, incomplete recovery after rejection treatment, chronic graft dysfunction, graft loss, and death. Transplantation failure due to treatment non-adherence is economically, socially, ethically and morally unjustifiable. This is a very prevalent issue: in some studies, its incidence is as high as 70% of patients. The self-reported nonadherence levels found in certain studies, including those performed immediately after transplantation show the need for early and continued intervention after kidney transplantation in order to maximise adherence and consequently clinical outcomes. There is not a single method to assess non adherence, thus combining several measures increases diagnostic accuracy. Electronic monitoring with a microdevice that records each time a pill bottle is opened is considered the “gold standard” for measuring adherence, but self-report at a confidential interview was the best measure of adherence. Thus non-adherence risk can be effectively assessed using clinically available assessment tools. Medication Adherence Scale, Brief Medical Questionnaire, Immunosuppressant Therapy Adherence Scale, Immunosuppressant Therapy Barrier Scale, Long-Term Medication Behavior Self-Efficacy Scale and Simplified Medication Adherence Questionnaire are some of the self-reported questionnaires. There are multiple factors associated with non-adherence in immunosuppressant therapy: Younger patients (adolescent, especially), poor health coverage, poor social support, unmarried, no family, non-Caucasian, immigrant, lower income, lower socioeconomic class, greater parental distress and lower family cohesion; complex medical regimens, higher number of drugs, longer time after transplant, toxicity, side effects, poor tolerance to medication, higher number of physicians involved, poor provider-patient rapport; psychological (dependency, high levels of anxiety and hostility, poorer behavioral functioning and greater distress in children) and psychiatric (depression) illnesses, low self-efficacy with medicine intake, perception of immunosuppressive therapy as not been necessary to preserve kidney function, forgetfulness, rebelliousness, poor perception of health, poor satisfaction, low Health-related Quality of life, addictions, lack of coping strategies and avoidance behavior; patient morbidity: comorbidity, receiving a transplant from a live donor, retransplantation, and non-insulin-dependent diabetes. The most frequent strategies to promote medication-taking must focus on modifiable risk factors. Reasons for non-adherence are complex and diverse and any successful intervention aimed at improving adherence must be multidimensional. Although effective intervention strategies are needed to improve immunosuppressant therapy adherence, few intervention studies have been conducted in the adult renal transplant population. In this study, we perform an exhaustive review of the different strategies reported in the literature. A number of key reasons for non-adherence are also provided.
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Gaynor JJ, Ciancio G, Guerra G, Sageshima J, Hanson L, Roth D, Goldstein MJ, Chen L, Kupin W, Mattiazzi A, Tueros L, Flores S, Barba LJ, Lopez A, Rivas J, Ruiz P, Vianna R, Burke GW. Multivariable risk of developing new onset diabetes after transplant-results from a single-center study of 481 adult, primary kidney transplant recipients. Clin Transplant 2015; 29:301-10. [PMID: 25581205 DOI: 10.1111/ctr.12510] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/04/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND Understanding the relative contributions of baseline demographics and immunosuppressive therapy on NODAT risk may help in developing preventive strategies. METHODS Using our prospectively followed cohort of 481 adult, primary kidney transplant recipients without pre-transplant diabetes, we determined the significant baseline predictors for the hazard rate of developing NODAT via Cox stepwise regression. The multivariable influence of first BPAR (defined as a time-dependent covariate) was also tested. RESULTS Median follow-up was 57 mo post-transplant; the overall percentage who developed NODAT was 22.5% (108/481). Four baseline predictors of a greater NODAT hazard rate were found (by order of selection): higher BMI (p < 0.000001), planned maintenance with SRL (p = 0.0003), non-white recipient (p = 0.0004), and older recipient age (p = 0.0004). Approximately one-half of the 106 patients in the highest demographic risk category (BMI ≥25 kg/m(2) , non-white race, and age at transplant ≥40 yr) developed NODAT; actuarial NODAT risk ranged from 10% to 30% in the lower demographic risk categories. First BPAR was also associated with significantly higher NODAT in multivariable analysis (p = 0.02)-the highly elevated NODAT rate observed during the first few months post-transplant and following first BPAR appears to demonstrate the diabetogenic effect of using high-dose (intravenous) corticosteroids. CONCLUSIONS The disturbingly high NODAT rate found among patients having multiple demographic risk factors is still an important problem that awaits a better solution.
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Affiliation(s)
- Jeffrey J Gaynor
- Department of Surgery, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL, USA
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Gaynor JJ, Ciancio G, Guerra G, Sageshima J, Hanson L, Roth D, Goldstein MJ, Chen L, Kupin W, Mattiazzi A, Tueros L, Flores S, Barba LJ, Lopez A, Rivas J, Ruiz P, Vianna R, Burke GW. Single-centre study of 628 adult, primary kidney transplant recipients showing no unfavourable effect of new-onset diabetes after transplant. Diabetologia 2015; 58:334-45. [PMID: 25361829 DOI: 10.1007/s00125-014-3428-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Accepted: 10/01/2014] [Indexed: 01/28/2023]
Abstract
AIMS/HYPOTHESIS To better understand the implications of new-onset diabetes after transplant (NODAT), we used our prospectively followed cohort of 628 adult primary kidney transplant recipients to determine the prognostic impact of pretransplant diabetes and NODAT. METHODS The study cohort consisted of all participants in four randomised immunosuppression trials performed at our centre since May 2000. For each cause-specific hazard analysed, Cox stepwise regression was used to determine a multivariable model of significant baseline predictors; the multivariable influence of having pretransplant diabetes and NODAT (t) (the latter defined as a zero-one, time-dependent covariate) was subsequently tested. Similar analyses of estimated glomerular filtration rate (eGFR) at 36 and 60 months post transplant were performed using stepwise linear regression. Finally, a repeated measures analysis of mean HbA1c as a function of diabetes category (pretransplant diabetes vs NODAT) and randomised trial (first to fourth) was performed. RESULTS Median follow-up was 56 months post transplant. Patients with pretransplant diabetes comprised 23.4% (147/628), and 22.5% (108/481) of the remaining patients developed NODAT. Pretransplant diabetes had no prognostic influence on first biopsy-proven acute rejection and death-censored graft failure hazard rates, nor on eGFR, but was associated with significantly higher rates of death with a functioning graft (DWFG) (p = 0.003), DWFG due to a cardiovascular event (p = 0.005) and infection that required hospitalisation (p = 0.03). NODAT (t) had no unfavourable impact on any of these hazard rates nor on eGFR, with actuarial freedom from DWFG remaining at over 90% among patients in pre- and post-NODAT states at 72 months post transplant/NODAT. Mean HbA1c for patients in the first to fourth randomised trials, averaged across diabetes category, decreased by trial (7.28%, 6.92%, 6.87% and 6.64% [56.1, 52.1, 51.6 and 49.1 mmol/mol], respectively; p = 0.02). CONCLUSIONS/INTERPRETATION Less-than-expected post-NODAT risk for graft loss and death may exist in the current climate of tighter glucose monitoring post transplant.
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Affiliation(s)
- Jeffrey J Gaynor
- Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Highland Professional Building, 1801 NW 9th Avenue, Miami, FL, 33136, USA,
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Barnieh L, Yilmaz S, McLaughlin K, Hemmelgarn BR, Klarenbach S, Manns BJ. The Cost of Kidney Transplant over Time. Prog Transplant 2014; 24:257-62. [DOI: 10.7182/pit2014710] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Background Kidney transplant improves quality of life and survival compared with dialysis. Despite advances in immunosuppressant regimens and the prevention and treatment of acute rejection, graft survival rates have not improved significantly in the past decade. Although the clinical effectiveness of these regimens has been studied, the impact of changes over time on cost has not. Methods Costs of kidney transplant were compared between 2 periods demarcated by a programmatic change from cyclosporine (early) to tacrolimus (late) and from nonroutine induction (early) to routine induction (late) therapy in adult patients receiving a first kidney-only transplant in Calgary, Alberta, Canada, in an 8-year period. Results Complete costs for 3 years after transplant was available for 344 patients, including 161 adult recipients in the early period (April 1, 1998-December 31, 2001) and 183 adult recipients in the late period (January 1, 2002-March 31, 2006). The mean total 3-year cost of transplant for recipients was Can$100 034 in the early period and Can$144 712 in the late period largely attributed to increases in the cost of immunosuppressants ( P < .001). Conclusions Given that the cost of transplant has increased significantly over time, the cost-effectiveness of these and other immunosuppressive regimens should be evaluated carefully.
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Affiliation(s)
- Lianne Barnieh
- University of Calgary (LB, SY, KM, BRH, BJM), University of Alberta (SK), Canada
| | - Serdar Yilmaz
- University of Calgary (LB, SY, KM, BRH, BJM), University of Alberta (SK), Canada
| | - Kevin McLaughlin
- University of Calgary (LB, SY, KM, BRH, BJM), University of Alberta (SK), Canada
| | - Brenda R. Hemmelgarn
- University of Calgary (LB, SY, KM, BRH, BJM), University of Alberta (SK), Canada
| | - Scott Klarenbach
- University of Calgary (LB, SY, KM, BRH, BJM), University of Alberta (SK), Canada
| | - Braden J. Manns
- University of Calgary (LB, SY, KM, BRH, BJM), University of Alberta (SK), Canada
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Fu L, Huang Z, Song T, He S, Zeng D, Rao Z, Xie L, Song Y, Wang L, Lin T. Short-term therapeutic drug monitoring of mycophenolic acid reduces infection: a prospective, single-center cohort study in Chinese living-related kidney transplantation. Transpl Infect Dis 2014; 16:760-6. [PMID: 25092411 DOI: 10.1111/tid.12275] [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] [Received: 10/20/2013] [Revised: 03/16/2014] [Accepted: 05/16/2014] [Indexed: 02/05/2023]
Abstract
BACKGROUND The role of therapeutic drug monitoring (TDM) of mycophenolic acid (MPA) in kidney transplant recipients (KTRs) is not clear. We performed a prospective cohort study to evaluate the efficiency of MPA TDM in the Chinese population. METHODS A total of 183 living-related KTRs were studied; 101 KTRs received controlled-dose mycophenolate mofetil (MMF) (the CD group), and 82 patients received fixed-dose MMF (the FD group). MPA exposure was measured at days 3, 7, 14, and 30 in the CD group, and at day 30 in the FD group. The primary endpoint was treatment failure (a composite of acute rejection, graft loss, death, or MMF discontinuation) at 12 months post transplantation. RESULTS In the CD group, with a starting MMF dose of 2 g/day, approximately 35% of patients had high MPA levels, which were >60 mg × h/L, and mean MPA levels were 59.17 mg × h/L and 61.38 mg × h/L for the CD and FD groups, respectively (P = 0.588). After adjusting MMF dose, MPA exposures in the CD group at day 30 were lower than those in the FD group at day 30 (54.06 vs. 61.38, P = 0.004). At month 12, the CD group had fewer infections (16.8% vs. 31.7%, P = 0.018) with no difference in treatment failure, acute rejection, diarrhea, or anemia. CONCLUSIONS KTRs can benefit from short-term TDM of MPA in reducing infection, without increasing acute rejection.
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Affiliation(s)
- L Fu
- Department of Urology, West China Hospital, Sichuan University, Sichuan, People's Republic of China
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Graft failure due to noncompliance among 628 kidney transplant recipients with long-term follow-up: a single-center observational study. Transplantation 2014; 97:925-33. [PMID: 24445926 DOI: 10.1097/01.tp.0000438199.76531.4a] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND In adult kidney transplantation, there is no clear consensus on the incidence of graft failure-due-to noncompliance (GFNC), with some reporting it as relatively uncommon and others as a major cause of late graft failure. We suspected that GFNC was a major cause of late graft loss at our center but did not know the extent of this problem. METHODS In our prospectively followed cohort of 628 adult, primary kidney-alone transplant recipients with long-term follow-up, GFNC and other graft loss causes were determined from our ongoing clinical evaluations. Using competing risks methodology, we determined the overall percentage of patients developing GFNC and the significant prognostic factors for its hazard rate and cumulative incidence (via Cox regression). RESULTS Cumulative incidence estimates (± standard error) of GFNC (n=29), GF-with-compliance (n=46), receiving a never-functioning graft (n=7), and death-with-a-functioning-graft (n=53) at 101 months after transplant (last-observed-graft loss) were as follows: 9.8%± 2.4%, 10.9%± 1.7%, 1.1%± 0.4%, and 13.0%± 1.9%, respectively. Only three patients experienced GFNC during the first 24 months; GFNC represented 48.1% (26/54) of death-censored GFs beyond 24 months. Two baseline variables were jointly associated with a significantly higher GFNC hazard and cumulative incidence: younger recipient age (P<0.000001 each) and non-white recipient (P=0.004 and P=0.02). Estimated percentages of ever developing GFNC were 28.4%± 6.5% among 79 non-whites younger than 35 years versus 0.0% (0/144) among whites 50 years or older. Among 302 recipients younger than 50 years, 18.1%± 4.1% developed GFNC, representing 67.6% (25/37) of its death-censored graft failures observed beyond 24 months after transplant. CONCLUSIONS GFNC is a major cause of late GF at our center, with younger and non-white recipients at a significantly greater GFNC risk. Interventional approaches to eliminate GFNC could dramatically improve long-term kidney graft survival.
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Focus on mTOR inhibitors and tacrolimus in renal transplantation: Pharmacokinetics, exposure–response relationships, and clinical outcomes. Transpl Immunol 2014; 31:22-32. [DOI: 10.1016/j.trim.2014.05.002] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Revised: 05/09/2014] [Accepted: 05/15/2014] [Indexed: 01/05/2023]
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