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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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Chimerism and tolerance: past, present and future strategies to prolong renal allograft survival. Curr Opin Nephrol Hypertens 2021; 30:63-74. [PMID: 33186221 DOI: 10.1097/mnh.0000000000000666] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
PURPOSE OF REVIEW Immunological factors are a major cause of kidney allograft loss. Calcineurin inhibitors (CNIs) have improved short-term kidney allograft survival; however, they in turn contribute to long-term kidney allograft loss from chronic CNI nephrotoxicity. Tolerance induction in transplantation can avoid the long-term adverse effects of immunosuppressive medications. This review aims to critically discuss recent efforts in inducing transplantation tolerance. RECENT FINDINGS Tolerance induction mediated by chimerism has shown some promise in minimizing or even complete withdrawal of immunosuppressive treatments in kidney allograft recipients. There has been a number of approaches as varied as the number of centres conducting these trials. However, they can be grouped into those mediated by transient microchimerism and those facilitated by more stable macro or full donor chimerism. The success rates in terms of long-term drug-free graft survival has been limited in microchimerism-mediated tolerance induction approaches. Mixed macrochimerism of less than 50% donor may be unstable with mostly the recipient's native immune system overpowering the donor chimeric status.Tolerance induction leading to chimerism has been limited to living donor kidney transplantation and additional long-term outcomes are required. Furthermore, immune monitoring after tolerance induction has faced a limitation in studying due to a lack of sufficient study participants and appropriate study controls. SUMMARY Tolerance induction is one of several strategies used to prolong kidney allograft survival, but it has not been routinely utilized in clinical practice. However, future applications from the trials to clinical practice remain limited to living donor kidney transplantation. Once further data regarding tolerance inductions exist and practicality becomes widely accepted, tolerance induction may shift the paradigm in the field of kidney transplantation to achieve the best possible outcome of 'One Organ for Life'.
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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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Préterre J, Visentin J, Saint Cricq M, Kaminski H, Del Bello A, Prezelin-Reydit M, Merville P, Kamar N, Couzi L. Comparison of two strategies based on mammalian target of rapamycin inhibitors in secondary prevention of non-melanoma skin cancer after kidney transplantation, a pilot study. Clin Transplant 2021; 35:e14207. [PMID: 33369772 DOI: 10.1111/ctr.14207] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 12/10/2020] [Accepted: 12/16/2020] [Indexed: 01/05/2023]
Abstract
After kidney transplantation, withdrawal of calcineurin inhibitors (CNI) and conversion to sirolimus (SRL) may reduce the occurrence of new non-melanoma skin cancer (NMSC). Conversely, a reduced CNI exposure with everolimus (EVR) is an alternative strategy that has not been thoroughly evaluated. We retrospectively compared the occurrence of newly diagnosed NMSCs in two cohorts of kidney transplant recipients (KTR) with at least one NMSC: 35 patients were converted to EVR with reduced CNI exposure (CNI/EVR group), whereas 46 patients were converted to SRL in association with mycophenolic acid (MPA) (SRL/MPA group). Two years after conversion, survival free of new NMSC was similar between the two cohorts (p = .37), with 19 KTR (54.3%) in the CNI/EVR group and 22 (47.8%) in the SRL/MPA group being diagnosed of at least one new NMSC. Half of the KTR from both groups showed adverse events, leading to mTORi discontinuation for 37.1% of KTR in the CNI/EVR group and 21.7% in the SRL/MPA group (p = .09). The incidence of rejections was similar between the two groups. In a retrospective cohort of KTR with at least one post-transplant NMSC, the outcome of the patients converted to a CNI/EVR regimen was not different from those converted to a SRL/MPA regimen.
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Affiliation(s)
- Julie Préterre
- CHU de Bordeaux, Service de Néphrologie-Transplantation-Dialyse-Aphérèse, Hôpital Pellegrin, Bordeaux, France
| | - Jonathan Visentin
- CHU de Bordeaux, Service d'Immunologie et Immunogénétique, Hôpital Pellegrin, Bordeaux, France.,Université de Bordeaux, CNRS "ImmunoConcEpT" UMR 5164, Bordeaux, France
| | - Morgane Saint Cricq
- Department of Nephrology, Dialysis and Organ Transplantation, Hôpital Rangueil, CHU de Toulouse, Toulouse, France
| | - Hannah Kaminski
- CHU de Bordeaux, Service de Néphrologie-Transplantation-Dialyse-Aphérèse, Hôpital Pellegrin, Bordeaux, France.,Université de Bordeaux, CNRS "ImmunoConcEpT" UMR 5164, Bordeaux, France
| | - Arnaud Del Bello
- Department of Nephrology, Dialysis and Organ Transplantation, Hôpital Rangueil, CHU de Toulouse, Toulouse, France.,Centre de Physiopathologie Toulouse Purpan, University Paul Sabatier, INSERM U1043, Toulouse, France
| | - Mathilde Prezelin-Reydit
- CHU de Bordeaux, Service de Néphrologie-Transplantation-Dialyse-Aphérèse, Hôpital Pellegrin, Bordeaux, France
| | - Pierre Merville
- CHU de Bordeaux, Service de Néphrologie-Transplantation-Dialyse-Aphérèse, Hôpital Pellegrin, Bordeaux, France.,Université de Bordeaux, CNRS "ImmunoConcEpT" UMR 5164, Bordeaux, France
| | - Nassim Kamar
- Department of Nephrology, Dialysis and Organ Transplantation, Hôpital Rangueil, CHU de Toulouse, Toulouse, France.,Centre de Physiopathologie Toulouse Purpan, University Paul Sabatier, INSERM U1043, Toulouse, France
| | - Lionel Couzi
- CHU de Bordeaux, Service de Néphrologie-Transplantation-Dialyse-Aphérèse, Hôpital Pellegrin, Bordeaux, France.,Université de Bordeaux, CNRS "ImmunoConcEpT" UMR 5164, Bordeaux, France
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Yin S, Song T, Li X, Xu H, Zhang X, Jiang Y, Lin T. Non-linear Relationship between Tacrolimus Blood Concentration and Acute Rejection After Kidney Transplantation: A Systematic Review and Dose-Response Meta-Analysis of Cohort Studies. Curr Pharm Des 2020; 25:2394-2403. [PMID: 31333109 DOI: 10.2174/1381612825666190717101941] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Accepted: 06/28/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Maintaining the exposure of tacrolimus (Tac) after kidney transplantation (KT) must be necessary to prevent acute rejection (AR) and improve graft survival，but there is still no clear consensus on the optimal Tac target blood concentration and concentration-effect relationship is poorly defined. METHODS We conducted a dose-response meta-analysis to quantitatively assess the association between Tac blood concentration and (AR) or adverse effects after KT. A comprehensive search of PubMed, Embase and Cochrane library databases was conducted to find eligible studies up to 10th September 2018. Unpublished data from patients receiving KT in West China Hospital (Sichuan University, China) were also collected. Both twostage dose-response and one-stage dose-response meta-analysis models were used to improve the statistical power. RESULTS A total of 4967 individuals from 10 original studies and 1453 individuals from West China Hospital were eligible for the ultimate analysis. In the two-stage dose-response meta-analysis model, we observed a significant non-linear relationship between Tac blood concentration and AR (P < 0.001) with moderate heterogeneity (I2 = 46.0%, P = 0.08). Tac blood concentration at 8ng/ml was associated with the lowest risk of AR (RR: 0.26, 95%CI: 0.13 - 0.54) by reference to 2ng/ml. Tac concentration at 7.0 - 11.0 ng/ml reduced the risk of AR by at least 70%, 5-14 ng/ml by at least 60%, and 4.5 - 14 ng/ml at least 50%. In the one-stage dose-response model, we also found a strong non-linear relationship between Tac and AR (P < 0.001) with moderate heterogeneity (I2 = 41.2%, P = 0.10). Tac concentration of 7.5 ng/ml was associated with the lowest risk of AR (RR: 0.35, 95%CI: 0.16 - 0.77). The blood concentration at 5.5 - 9.5 ng/ml was associated with the reduced AR by at least 60% and 4.5 - 10.5 ng/ml by at least 50% by reference to 2 ng/ml. CONCLUSION Maintaining Tac blood concentration at 5 - 9.5 ng/ml within the first year may prevent AR most effectively.
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Affiliation(s)
- Saifu Yin
- Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,Organ transplantation Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Turun Song
- Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,Organ transplantation Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xingxing Li
- West China Hospital/West China school of Medicine, Sichuan University, Chengdu, Sichuan, China
| | - Hanyue Xu
- West China Hospital/West China school of Medicine, Sichuan University, Chengdu, Sichuan, China
| | - Xueling Zhang
- West China Hospital/West China school of Medicine, Sichuan University, Chengdu, Sichuan, China
| | - Yamei Jiang
- Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,Organ transplantation Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Tao Lin
- Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,Organ transplantation Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Traitanon O, Mathew JM, Shetty A, Bontha SV, Maluf DG, El Kassis Y, Park SH, Han J, Ansari MJ, Leventhal JR, Mas V, Gallon L. Mechanistic analyses in kidney transplant recipients prospectively randomized to two steroid free regimen-Low dose Tacrolimus with Everolimus versus standard dose Tacrolimus with Mycophenolate Mofetil. PLoS One 2019; 14:e0216300. [PMID: 31136582 PMCID: PMC6538151 DOI: 10.1371/journal.pone.0216300] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 04/17/2019] [Indexed: 01/05/2023] Open
Abstract
Calcineurin inhibitors (CNI), the cornerstone of immunosuppression after transplantation are implicated in nephrotoxicity and allograft dysfunction. We hypothesized that combined low doses of CNI and Everolimus (EVR) may result in better graft outcomes and greater tolerogenic milieu. Forty adult renal transplant recipients were prospectively randomized to (steroid free) low dose Tacrolimus (TAC) and EVR or standard dose TAC and Mycophenolate (MMF) after Alemtuzumab induction. Baseline characteristics were statistically similar. EVR levels were maintained at 3-8 ng/ml. TAC levels were 4.5±1.9 and 6.4±1.5 ng/ml in the TAC+EVR and TAC+MMF group respectively. Follow up was 14±4 and 17±5 months respectively and included protocol kidney biopsies at 3 and 12 months post-transplantation. Rejection-rate was lower in the TAC+EVR group. However patient and overall graft survival, eGFR and incidence of adverse events were similar. TAC+EVR induced expansion of CD4+CD25hiFoxp3+ regulatory T cells as early as 3 months and expansion of IFN-γ+CD4+CD25hiFoxp3+ regulatory T cells at 12 months post-transplant. Gene expression profile showed a trend toward decreased inflammation, angiogenesis and connective tissue growth in the TAC+EVR Group. Thus, greater tolerogenic mechanisms were found to be operating in patients with low dose TAC+EVR and this might be responsible for the lower rejection-rate than in patients on standard dose TAC+MMF. However, further studies with longer follow up and evaluating impact on T regulatory cells are warranted.
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Affiliation(s)
- Opas Traitanon
- Department of Medicine-Nephrology, Northwestern University, Chicago, IL, United States of America
- Department of Medicine-Nephrology, Thammasart University Hospital, Pathumthani, Thailand
| | - James M. Mathew
- Department of Surgery, Northwestern University, Chicago, IL, United States of America
- Comprehensive Transplant Center, Northwestern University, Chicago, IL, United States of America
- Department of Microbiology-Immunology, Northwestern University, Chicago, IL, United States of America
- * E-mail: (LG); (JMM)
| | - Aneesha Shetty
- Department of Medicine-Nephrology, Northwestern University, Chicago, IL, United States of America
| | - Sai Vineela Bontha
- Methodist University Transplant Institute; University of Tennessee Health Science Center; Memphis, TN, United States of America
| | - Daniel G. Maluf
- Methodist University Transplant Institute; University of Tennessee Health Science Center; Memphis, TN, United States of America
| | - Yvonne El Kassis
- Department of Medicine-Nephrology, Northwestern University, Chicago, IL, United States of America
| | - Sook H. Park
- Department of Medicine-Nephrology, Northwestern University, Chicago, IL, United States of America
| | - Jing Han
- Comprehensive Transplant Center, Northwestern University, Chicago, IL, United States of America
| | - M. Javeed Ansari
- Department of Medicine-Nephrology, Northwestern University, Chicago, IL, United States of America
- Comprehensive Transplant Center, Northwestern University, Chicago, IL, United States of America
| | - Joseph R. Leventhal
- Department of Surgery, Northwestern University, Chicago, IL, United States of America
- Comprehensive Transplant Center, Northwestern University, Chicago, IL, United States of America
| | - Valeria Mas
- Methodist University Transplant Institute; University of Tennessee Health Science Center; Memphis, TN, United States of America
| | - Lorenzo Gallon
- Department of Medicine-Nephrology, Northwestern University, Chicago, IL, United States of America
- Comprehensive Transplant Center, Northwestern University, Chicago, IL, United States of America
- * E-mail: (LG); (JMM)
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Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immunosuppressive cells of the myeloid lineage upregulated by mediators of inflammation, such as IL-2, granulocyte colony-stimulating factor, and S100A8/A9. These cells have been studied extensively by tumor biologists. Because of their robust immunosuppressive potential, MDSCs have stirred recent interest among transplant immunologists as well. MDSCs inhibit T-cell responses through, among other mechanisms, the activity of arginase-1 and inducible nitric oxide synthase, and the expansion of T regulatory cells. In the context of transplantation, MDSCs have been studied in several animal models, and to a lesser degree in humans. Here, we will review the immunosuppressive qualities of this important cell type and discuss the relevant studies of MDSCs in transplantation. It may be possible to exploit the immunosuppressive capacity of MDSCs for the benefit of transplant patients.
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Jones-Hughes T, Snowsill T, Haasova M, Coelho H, Crathorne L, Cooper C, Mujica-Mota R, Peters J, Varley-Campbell J, Huxley N, Moore J, Allwood M, Lowe J, Hyde C, Hoyle M, Bond M, Anderson R. Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model. Health Technol Assess 2018; 20:1-594. [PMID: 27578428 DOI: 10.3310/hta20620] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND End-stage renal disease is a long-term irreversible decline in kidney function requiring renal replacement therapy: kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation, followed by immunosuppressive therapy (induction and maintenance therapy) to reduce the risk of kidney rejection and prolong graft survival. OBJECTIVES To review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect(®), Novartis Pharmaceuticals UK Ltd) and rabbit anti-human thymocyte immunoglobulin (rATG) (Thymoglobulin(®), Sanofi) as induction therapy, and immediate-release tacrolimus (TAC) (Adoport(®), Sandoz; Capexion(®), Mylan; Modigraf(®), Astellas Pharma; Perixis(®), Accord Healthcare; Prograf(®), Astellas Pharma; Tacni(®), Teva; Vivadex(®), Dexcel Pharma), prolonged-release tacrolimus (Advagraf(®) Astellas Pharma), belatacept (BEL) (Nulojix(®), Bristol-Myers Squibb), mycophenolate mofetil (MMF) (Arzip(®), Zentiva; CellCept(®), Roche Products; Myfenax(®), Teva), mycophenolate sodium (MPS) (Myfortic(®), Novartis Pharmaceuticals UK Ltd), sirolimus (SRL) (Rapamune(®), Pfizer) and everolimus (EVL) (Certican(®), Novartis) as maintenance therapy in adult renal transplantation. METHODS Clinical effectiveness searches were conducted until 18 November 2014 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science (via ISI), Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted until 18 November 2014 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Database (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and the American Economic Association's electronic bibliography (via EconLit, EBSCOhost). Included studies were selected according to predefined methods and criteria. A random-effects model was used to analyse clinical effectiveness data (odds ratios for binary data and mean differences for continuous data). Network meta-analyses were undertaken within a Bayesian framework. A new discrete time-state transition economic model (semi-Markov) was developed, with acute rejection, graft function (GRF) and new-onset diabetes mellitus used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death. RESULTS Eighty-nine randomised controlled trials (RCTs), of variable quality, were included. For induction therapy, no treatment appeared more effective than another in reducing graft loss or mortality. Compared with placebo/no induction, rATG and BAS appeared more effective in reducing biopsy-proven acute rejection (BPAR) and BAS appeared more effective at improving GRF. For maintenance therapy, no treatment was better for all outcomes and no treatment appeared most effective at reducing graft loss. BEL + MMF appeared more effective than TAC + MMF and SRL + MMF at reducing mortality. MMF + CSA (ciclosporin), TAC + MMF, SRL + TAC, TAC + AZA (azathioprine) and EVL + CSA appeared more effective than CSA + AZA and EVL + MPS at reducing BPAR. SRL + AZA, TAC + AZA, TAC + MMF and BEL + MMF appeared to improve GRF compared with CSA + AZA and MMF + CSA. In the base-case deterministic and probabilistic analyses, BAS, MMF and TAC were predicted to be cost-effective at £20,000 and £30,000 per quality-adjusted life-year (QALY). When comparing all regimens, only BAS + TAC + MMF was cost-effective at £20,000 and £30,000 per QALY. LIMITATIONS For included trials, there was substantial methodological heterogeneity, few trials reported follow-up beyond 1 year, and there were insufficient data to perform subgroup analysis. Treatment discontinuation and switching were not modelled. FUTURE WORK High-quality, better-reported, longer-term RCTs are needed. Ideally, these would be sufficiently powered for subgroup analysis and include health-related quality of life as an outcome. CONCLUSION Only a regimen of BAS induction followed by maintenance with TAC and MMF is likely to be cost-effective at £20,000-30,000 per QALY. STUDY REGISTRATION This study is registered as PROSPERO CRD42014013189. FUNDING The National Institute for Health Research Health Technology Assessment programme.
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Affiliation(s)
- Tracey Jones-Hughes
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Tristan Snowsill
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Marcela Haasova
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Helen Coelho
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Louise Crathorne
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Chris Cooper
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Ruben Mujica-Mota
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Jaime Peters
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Jo Varley-Campbell
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Nicola Huxley
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Jason Moore
- Exeter Kidney Unit, Royal Devon and Exeter Foundation Trust Hospital, Exeter, UK
| | - Matt Allwood
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Jenny Lowe
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Chris Hyde
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Martin Hoyle
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Mary Bond
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Rob Anderson
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
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9
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Mallat SG, Tanios BY, Itani HS, Lotfi T, McMullan C, Gabardi S, Akl EA, Azzi JR. CMV and BKPyV Infections in Renal Transplant Recipients Receiving an mTOR Inhibitor-Based Regimen Versus a CNI-Based Regimen: A Systematic Review and Meta-Analysis of Randomized, Controlled Trials. Clin J Am Soc Nephrol 2017; 12:1321-1336. [PMID: 28576905 PMCID: PMC5544521 DOI: 10.2215/cjn.13221216] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2016] [Accepted: 04/24/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND OBJECTIVES The objective of this meta-analysis is to compare the incidences of cytomegalovirus and BK polyoma virus infections in renal transplant recipients receiving a mammalian target of rapamycin inhibitor (mTOR)-based regimen compared with a calcineurin inhibitor-based regimen. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We conducted a comprehensive search for randomized, controlled trials up to January of 2016 addressing our objective. Other outcomes included acute rejection, graft loss, serious adverse events, proteinuria, wound-healing complications, and eGFR. Two review authors selected eligible studies, abstracted data, and assessed risk of bias. We assessed quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation methodology. RESULTS We included 28 randomized, controlled trials with 6211 participants classified into comparison 1: mTOR inhibitor versus calcineurin inhibitor and comparison 2: mTOR inhibitor plus reduced dose of calcineurin inhibitor versus regular dose of calcineurin inhibitor. Results showed decreased incidence of cytomegalovirus infection in mTOR inhibitor-based group in both comparison 1 (risk ratio, 0.54; 95% confidence interval, 0.41 to 0.72), with high quality of evidence, and comparison 2 (risk ratio, 0.43; 95% confidence interval, 0.24 to 0.80), with moderate quality of evidence. The available evidence neither confirmed nor ruled out a reduction of BK polyoma virus infection in mTOR inhibitor-based group in both comparisons. Secondary outcomes revealed more serious adverse events and acute rejections in mTOR inhibitor-based group in comparison 1 and no difference in comparison 2. There was no difference in graft loss in both comparisons. eGFR was higher in the mTOR inhibitor-based group in comparison 1 (mean difference =4.07 ml/min per 1.73 m2; 95% confidence interval, 1.34 to 6.80) and similar to the calcineurin inhibitor-based group in comparison 2. More proteinuria and wound-healing complications occurred in the mTOR inhibitor-based groups. CONCLUSIONS We found moderate- to high-quality evidence of reduced risk of cytomegalovirus infection in renal transplant recipients in the mTOR inhibitor-based compared with the calcineurin inhibitor-based regimen. Our review also suggested that a combination of a mTOR inhibitor and a reduced dose of calcineurin inhibitor may be associated with similar eGFR and rates of acute rejections and serious adverse events compared with a standard calcineurin inhibitor-based regimen at the expense of higher incidence of proteinuria and wound-healing complications.
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Affiliation(s)
| | | | - Houssam S. Itani
- Division of Nephrology, Department of Internal Medicine, Makassed General Hospital, Beirut, Lebanon
| | | | - Ciaran McMullan
- Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; and
| | - Steven Gabardi
- Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; and
| | - Elie A. Akl
- Department of Internal Medicine, American University of Beirut, Beirut, Lebanon
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Jamil R. Azzi
- Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; and
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10
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Karpe KM, Talaulikar GS, Walters GD, Cochrane Kidney and Transplant Group. Calcineurin inhibitor withdrawal or tapering for kidney transplant recipients. Cochrane Database Syst Rev 2017; 7:CD006750. [PMID: 28730648 PMCID: PMC6483545 DOI: 10.1002/14651858.cd006750.pub2] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Calcineurin inhibitors (CNI) can reduce acute transplant rejection and immediate graft loss but are associated with significant adverse effects such as hypertension and nephrotoxicity which may contribute to chronic rejection. CNI toxicity has led to numerous studies investigating CNI withdrawal and tapering strategies. Despite this, uncertainty remains about minimisation or withdrawal of CNI. OBJECTIVES This review aimed to look at the benefits and harms of CNI tapering or withdrawal in terms of graft function and loss, incidence of acute rejection episodes, treatment-related side effects (hypertension, hyperlipidaemia) and death. SEARCH METHODS We searched the Cochrane Kidney and Transplant Specialised Register to 11 October 2016 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA All randomised controlled trials (RCTs) where drug regimens containing CNI were compared to alternative drug regimens (CNI withdrawal, tapering or low dose) in the post-transplant period were included, without age or dosage restriction. DATA COLLECTION AND ANALYSIS Two authors independently assessed studies for eligibility, risk of bias, and extracted data. Results were expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). MAIN RESULTS We included 83 studies that involved 16,156 participants. Most were open-label studies; less than 30% of studies reported randomisation method and allocation concealment. Studies were analysed as intent-to-treat in 60% and all pre-specified outcomes were reported in 54 studies. The attrition and reporting bias were unclear in the remainder of the studies as factors used to judge bias were reported inconsistently. We also noted that 50% (47 studies) of studies were funded by the pharmaceutical industry.We classified studies into four groups: CNI withdrawal or avoidance with or without substitution with mammalian target of rapamycin inhibitors (mTOR-I); and low dose CNI with or without mTOR-I. The withdrawal groups were further stratified as avoidance and withdrawal subgroups for major outcomes.CNI withdrawal may lead to rejection (RR 2.54, 95% CI 1.56 to 4.12; moderate certainty evidence), may make little or no difference to death (RR 1.09, 95% CI 0.96 to 1.24; moderate certainty), and probably slightly reduces graft loss (RR 0.85, 95% CI 0.74 to 0.98; low quality evidence). Hypertension was probably reduced in the CNI withdrawal group (RR 0.82, 95% CI 0.71 to 0.95; low certainty), while CNI withdrawal may make little or no difference to malignancy (RR 1.10, 95% CI 0.93 to 1.30; low certainty), and probably makes little or no difference to cytomegalovirus (CMV) (RR 0.87, 95% CI 0.52 to 1.45; low certainty)CNI avoidance may result in increased acute rejection (RR 2.16, 95% CI 0.85 to 5.49; low certainty) but little or no difference in graft loss (RR 0.96, 95% CI 0.79 to 1.16; low certainty). Late CNI withdrawal increased acute rejection (RR 3.21, 95% CI 1.59 to 6.48; moderate certainty) but probably reduced graft loss (RR 0.84, 95% CI 0.72 to 0.97, low certainty).Results were similar when CNI avoidance or withdrawal was combined with the introduction of mTOR-I; acute rejection was probably increased (RR 1.43; 95% CI 1.15 to 1.78; moderate certainty) and there was probably little or no difference in death (RR 0.96; 95% CI 0.69 to 1.36, moderate certainty). mTOR-I substitution may make little or no difference to graft loss (RR 0.94, 95% CI 0.75 to 1.19; low certainty), probably makes little of no difference to hypertension (RR 0.86, 95% CI 0.64 to 1.15; moderate), and probably reduced the risk of cytomegalovirus (CMV) (RR 0.60, 95% CI 0.44 to 0.82; moderate certainty) and malignancy (RR 0.69, 95% CI 0.47 to 1.00; low certainty). Lymphoceles were increased with mTOR-I substitution (RR 1.45, 95% CI 0.95 to 2.21; low certainty).Low dose CNI combined with mTOR-I probably increased glomerular filtration rate (GFR) (MD 6.24 mL/min, 95% CI 3.28 to 9.119; moderate certainty), reduced graft loss (RR 0.75, 95% CI 0.55 to 1.02; moderate certainty), and made little or no difference to acute rejection (RR 1.13 ; 95% CI 0.91 to 1.40; moderate certainty). Hypertension was decreased (RR 0.98, 95% CI 0.80 to 1.20; low certainty) as was CMV (RR 0.41, 95% CI 0.16 to 1.06; low certainty). Low dose CNI plus mTOR-I makes probably makes little of no difference to malignancy (RR 1.22, 95% CI 0.42 to 3.53; low certainty) and may make little of no difference to death (RR 1.16, 95% CI 0.71 to 1.90; moderate certainty). AUTHORS' CONCLUSIONS CNI avoidance increased acute rejection and CNI withdrawal increases acute rejection but reduced graft loss at least over the short-term. Low dose CNI with induction regimens reduced acute rejection and graft loss with no major adverse events, also in the short-term. The use of mTOR-I reduced CMV infections but increased the risk of acute rejection. These conclusions must be tempered by the lack of long-term data in most of the studies, particularly with regards to chronic antibody-mediated rejection, and the suboptimal methodological quality of the included studies.
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Affiliation(s)
- Krishna M Karpe
- Canberra HospitalRenal ServicesYamba DriveGarranACTAustralia2605
- Australian National University Medical SchoolActonACTAustralia2601
| | - Girish S Talaulikar
- Canberra HospitalRenal ServicesYamba DriveGarranACTAustralia2605
- Australian National University Medical SchoolActonACTAustralia2601
| | - Giles D Walters
- Canberra HospitalRenal ServicesYamba DriveGarranACTAustralia2605
- Australian National University Medical SchoolActonACTAustralia2601
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11
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Kälble F, Seckinger J, Schaier M, Morath C, Schwenger V, Zeier M, Sommerer C. Switch to an everolimus-facilitated cyclosporine A sparing immunosuppression improves glycemic control in selected kidney transplant recipients. Clin Transplant 2017; 31. [PMID: 28581202 DOI: 10.1111/ctr.13024] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/27/2017] [Indexed: 12/21/2022]
Abstract
BACKGROUND Mammalian target of rapamycin inhibitors (mToRi) allow calcineurin inhibitor (CNI) sparing therapy in renal transplant recipients with possible beneficial effects on the long-term allograft function and cardiovascular risk. The influence of mToRi on glucose metabolism is still under discussion. METHODS In a retrospective analysis, renal allograft recipients switched from a cyclosporine A (CsA) to an everolimus (EVR)-based immunosuppression in the first year after transplantation were compared with patients on continued CsA treatment. At 6-month intervals, the prevalence of impaired fasting glucose (IFG) and new onset of diabetes after transplantation (NODAT) were assessed. RESULTS A total of 146 renal transplant recipients were included. The cumulative prevalence of IFG and NODAT 30-months post-transplantation was significantly lower in patients switched to an immunosuppression with EVR compared to patients on continued CsA treatment (10% vs 22%, P=.049). However, patients switched to EVR showed a higher incidence of acute cellular rejections in the first 12 months (23% vs 11%, P=.048). CONCLUSION EVR-based immunosuppression was associated with a similar or even improved glycemic control and improved renal function. However, due to higher rejection rates, patients switched to EVR should be carefully selected as rejection therapy with steroids counteracts the benefit in glycemic control.
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Affiliation(s)
- Florian Kälble
- Nephrology Unit, University Hospital Heidelberg, Heidelberg, Germany
| | - Jörg Seckinger
- Nephrology Unit, University Hospital Heidelberg, Heidelberg, Germany.,Department of Internal Medicine, Division of Nephrology, Zug Cantonal Hospital, Baar, Switzerland
| | - Matthias Schaier
- Nephrology Unit, University Hospital Heidelberg, Heidelberg, Germany
| | - Christian Morath
- Nephrology Unit, University Hospital Heidelberg, Heidelberg, Germany
| | - Vedat Schwenger
- Nephrology Unit, University Hospital Heidelberg, Heidelberg, Germany.,Department of Nephrology, Katharinenhospital Stuttgart, Stuttgart, Germany
| | - Martin Zeier
- Nephrology Unit, University Hospital Heidelberg, Heidelberg, Germany
| | - Claudia Sommerer
- Nephrology Unit, University Hospital Heidelberg, Heidelberg, Germany
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12
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Qazi Y, Shaffer D, Kaplan B, Kim DY, Luan FL, Peddi VR, Shihab F, Tomlanovich S, Yilmaz S, McCague K, Patel D, Mulgaonkar S. Efficacy and Safety of Everolimus Plus Low-Dose Tacrolimus Versus Mycophenolate Mofetil Plus Standard-Dose Tacrolimus in De Novo Renal Transplant Recipients: 12-Month Data. Am J Transplant 2017; 17:1358-1369. [PMID: 27775865 DOI: 10.1111/ajt.14090] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Revised: 09/11/2016] [Accepted: 10/07/2016] [Indexed: 01/25/2023]
Abstract
In this 12-month, multicenter, randomized, open-label, noninferiority study, de novo renal transplant recipients (RTxRs) were randomized (1:1) to receive everolimus plus low-dose tacrolimus (EVR+LTac) or mycophenolate mofetil plus standard-dose Tac (MMF+STac) with induction therapy (basiliximab or rabbit anti-thymocyte globulin). Noninferiority of composite efficacy failure rate (treated biopsy-proven acute rejection [tBPAR]/graft loss/death/loss to follow-up) in EVR+LTac versus MMF+STac was missed by 1.4%, considering the noninferiority margin of 10% (24.6% vs. 20.4%; 4.2% [-3.0, 11.4]). Incidence of tBPAR (19.1% vs. 11.2%; p < 0.05) was significantly higher, while graft loss (1.3% vs. 3.9%; p < 0.05) and composite of graft loss/death/lost to follow-up (6.1% vs. 10.5%, p = 0.05) were significantly lower in EVR+LTac versus MMF+STac groups, respectively. Mean estimated glomerular filtration rate was similar between EVR+LTac and MMF+STac groups (63.1 [22.0] vs. 63.1 [19.5] mL/min/1.73 m2 ) and safety was comparable. In conclusion, EVR+LTac missed noninferiority versus MMF+STac based on the 10% noninferiority margin. Further studies evaluating optimal immunosuppression for improved efficacy will guide appropriate dosing and target levels of EVR and LTac in RTxRs.
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Affiliation(s)
- Y Qazi
- University of Southern California, Los Angeles, CA
| | - D Shaffer
- Division of Kidney and Pancreas Transplantation, Vanderbilt University Medical Center, Nashville, TN
| | - B Kaplan
- Department of Medicine, Mayo Clinic Arizona, Phoenix, AZ
| | - D Y Kim
- Henry Ford Hospital, Detroit, MI
| | - F L Luan
- Universtiy of Michigan, Ann Arbor, MI.,Barnabas Health, Livingston, NJ
| | - V R Peddi
- California Pacific Medical Center, San Francisco, CA
| | - F Shihab
- University of Utah School of Medicine, Salt Lake City, UT
| | | | - S Yilmaz
- University Calgary, Calgary, Alberta, Canada
| | - K McCague
- Novartis Pharmaceuticals Corporation, East Hanover, NJ
| | - D Patel
- Novartis Pharmaceuticals Corporation, East Hanover, NJ
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13
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Bemelman FJ, de Fijter JW, Kers J, Meyer C, Peters-Sengers H, de Maar EF, van der Pant KAMI, de Vries APJ, Sanders JS, Zwinderman A, Idu MM, Berger S, Reinders MEJ, Krikke C, Bajema IM, van Dijk MC, Ten Berge IJM, Ringers J, Lardy J, Roelen D, Moes DJ, Florquin S, Homan van der Heide JJ. Early Conversion to Prednisolone/Everolimus as an Alternative Weaning Regimen Associates With Beneficial Renal Transplant Histology and Function: The Randomized-Controlled MECANO Trial. Am J Transplant 2017; 17:1020-1030. [PMID: 27639190 DOI: 10.1111/ajt.14048] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Revised: 08/20/2016] [Accepted: 09/07/2016] [Indexed: 01/25/2023]
Abstract
In renal transplantation, use of calcineurin inhibitors (CNIs) is associated with nephrotoxicity and immunosuppression with malignancies and infections. This trial aimed to minimize CNI exposure and total immunosuppression while maintaining efficacy. We performed a randomized controlled, open-label multicenter trial with early cyclosporine A (CsA) elimination. Patients started with basiliximab, prednisolone (P), mycophenolate sodium (MPS), and CsA. At 6 months, immunosuppression was tapered to P/CsA, P/MPS, or P/everolimus (EVL). Primary outcomes were renal fibrosis and inflammation. Secondary outcomes were estimated glomerular filtration rate (eGFR) and incidence of rejection at 24 months. The P/MPS arm was prematurely halted. The trial continued with P/CsA (N = 89) and P/EVL (N = 96). Interstitial fibrosis and inflammation were significantly decreased and the eGFR was significantly higher in the P/EVL arm. Cumulative rejection rates were 13% (P/EVL) and 19% (P/CsA), (p = 0.08). A post hoc analysis of HLA and donor-specific antibodies at 1 year after transplantation revealed no differences. An individualized immunosuppressive strategy of early CNI elimination to dual therapy with everolimus was associated with decreased allograft fibrosis, preserved allograft function, and good efficacy, but also with more serious adverse events and discontinuation. This can be a valuable alternative regimen in patients suffering from CNI toxicity.
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Affiliation(s)
- F J Bemelman
- Renal Transplant Unit, Amsterdam, the Netherlands
| | - J W de Fijter
- Renal Transplant Unit, Department of Nephrology, Leiden University Medical Centre, Leiden, the Netherlands
| | - J Kers
- Department of Pathology, Academic Medical Centre, Amsterdam, the Netherlands
| | - C Meyer
- University of Amsterdam, Amsterdam, the Netherlands
| | | | - E F de Maar
- Department of Nephrology, Groningen University Hospital, Groningen, the Netherlands
| | | | - A P J de Vries
- Renal Transplant Unit, Department of Nephrology, Leiden University Medical Centre, Leiden, the Netherlands
| | - J-S Sanders
- Department of Nephrology, Groningen University Hospital, Groningen, the Netherlands
| | - A Zwinderman
- Department of Epidemiology and Biostatistics, Academic Medical Centre, Amsterdam, the Netherlands
| | - M M Idu
- Department of Surgery, Academic Medical Centre, Amsterdam, the Netherlands
| | - S Berger
- Department of Nephrology, Groningen University Hospital, Groningen, the Netherlands
| | - M E J Reinders
- Renal Transplant Unit, Department of Nephrology, Leiden University Medical Centre, Leiden, the Netherlands
| | - C Krikke
- Department of Surgery, Groningen University Hospital, Groningen, the Netherlands
| | - I M Bajema
- Department of Pathology, Leiden University Medical Centre, Leiden, the Netherlands
| | - M C van Dijk
- Department of Pathology, Groningen University Hospital, Groningen, the Netherlands
| | | | - J Ringers
- Department of Surgery, Leiden University Medical Centre, Leiden, the Netherlands
| | - J Lardy
- Sanquin Diagnostic Services, Amsterdam, the Netherlands
| | - D Roelen
- Department of Immunogenetics and Transplantation Immunology, Leiden University Medical Centre, Leiden, the Netherlands
| | - D-J Moes
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, the Netherlands
| | - S Florquin
- Department of Pathology, Academic Medical Centre, Amsterdam, the Netherlands
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14
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Fernandes-Silva G, Ivani de Paula M, Rangel ÉB. mTOR inhibitors in pancreas transplant: adverse effects and drug-drug interactions. Expert Opin Drug Metab Toxicol 2016; 13:367-385. [DOI: 10.1080/17425255.2017.1239708] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Gabriel Fernandes-Silva
- Universidade Federal de São Paulo/Hospital do Rim e Hipertensão, Nephrology Department, São Paulo, SP, Brazil
| | - Mayara Ivani de Paula
- Universidade Federal de São Paulo/Hospital do Rim e Hipertensão, Nephrology Department, São Paulo, SP, Brazil
| | - Érika B. Rangel
- Universidade Federal de São Paulo/Hospital do Rim e Hipertensão, Nephrology Department, São Paulo, SP, Brazil
- Hospital Israelita Albert Einstein, Instituto Israelita de Ensino e Pesquisa, São Paulo, SP, Brazil
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15
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Sawinski D, Trofe-Clark J, Leas B, Uhl S, Tuteja S, Kaczmarek JL, French B, Umscheid CA. Calcineurin Inhibitor Minimization, Conversion, Withdrawal, and Avoidance Strategies in Renal Transplantation: A Systematic Review and Meta-Analysis. Am J Transplant 2016; 16:2117-38. [PMID: 26990455 DOI: 10.1111/ajt.13710] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 12/28/2015] [Accepted: 01/07/2016] [Indexed: 01/25/2023]
Abstract
Despite their clinical efficacy, concerns about calcineurin inhibitor (CNI) toxicity make alternative regimens that reduce CNI exposure attractive for renal transplant recipients. In this systematic review and meta-analysis, we assessed four CNI immunosuppression strategies (minimization, conversion, withdrawal, and avoidance) designed to reduce CNI exposure and assessed the impact of each on patient and allograft survival, acute rejection and renal function. We evaluated 92 comparisons from 88 randomized controlled trials and found moderate- to high-strength evidence suggesting that minimization strategies result in better clinical outcomes compared with standard-dose regimens; moderate-strength evidence indicating that conversion to a mammalian target of rapamycin inhibitor or belatacept was associated with improved renal function but increased rejection risk; and moderate- to high-strength evidence suggesting planned CNI withdrawal could result in improved renal function despite an association with increased rejection risk. The evidence base for avoidance studies was insufficient to draw meaningful conclusions. The applicability of the review is limited by the large number of studies examining cyclosporine-based strategies and low-risk populations. Additional research is needed with tacrolimus-based regimens and higher risk populations. Moreover, research is necessary to clarify the effect of induction and adjunctive agents in alternative immunosuppression strategies and should include more comprehensive and consistent reporting of patient-centered outcomes.
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Affiliation(s)
- D Sawinski
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | - J Trofe-Clark
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.,Department of Pharmacy Services, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - B Leas
- Center for Evidence-based Practice, University of Pennsylvania Health System, Philadelphia, PA
| | - S Uhl
- ECRI Institute, Plymouth Meeting, PA
| | - S Tuteja
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | | | - B French
- Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | - C A Umscheid
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.,Center for Evidence-based Practice, University of Pennsylvania Health System, Philadelphia, PA.,Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
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16
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Soliman K, Mogadam E, Laftavi M, Patel S, Feng L, Said M, Pankewycz O. Long-term outcomes following sirolimus conversion after renal transplantation. Immunol Invest 2015; 43:819-28. [PMID: 25296236 DOI: 10.3109/08820139.2014.947033] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Long-term outcomes following renal transplantation remain limited due to chronic progressive injury partly as a result of calcineurin inhibitor (CNI) toxicity. Thus, patients have been converted to non-CNI immunosuppressives despite the lack of evidence of long-term benefits from CNI free therapy. We now report our 10-year experience converting patients with well functioning transplants from CNI to sirolimus. We retrospectively analyzed outcomes of patients receiving continuous CNI based therapy (CNI, n = 309) or who were switched to sirolimus within the first year of post-transplantation (CONV, n = 54). The groups were similar for most recipient, graft and donor characteristics, however, diabetes was more common in the CNI group and statin use was more frequent in the CONV group. The average time to conversion was 7.2 months and the creatinine level at the time of switching was 1.4 mg/dl. Ten year graft and patient survival rates were equivalent in both groups. There were no differences in the causes of death or graft loss in both groups. Renal function was available for 5 years posttransplant and was no different between groups. Thus, there is no evidence that routinely switching patients with well functioning renal allografts to sirolimus from CNI based immunosuppression provides long-term benefit.
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Affiliation(s)
- Karim Soliman
- Department of Surgery, Division of Transplantation, State University of New York (SUNY) at Buffalo , Buffalo, NY , USA and
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17
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Yanik EL, Siddiqui K, Engels EA. Sirolimus effects on cancer incidence after kidney transplantation: a meta-analysis. Cancer Med 2015; 4:1448-59. [PMID: 26108799 PMCID: PMC4567030 DOI: 10.1002/cam4.487] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 05/21/2015] [Accepted: 05/27/2015] [Indexed: 12/21/2022] Open
Abstract
Sirolimus, an immunosuppressant option for kidney transplant recipients, may reduce cancer risk by interrupting the mammalian target of rapamycin pathway. However, studies of sirolimus and cancer incidence in kidney recipients have not been definitive, and have had limited ability to examine specific cancer types. The literature was systematically reviewed to identify randomized controlled trials (RCTs) and observational studies of kidney recipients that compared sirolimus users to sirolimus nonusers. Meta-analytic methods were used to obtain pooled estimates of the association between sirolimus use and incidence of total cancer and specific cancer types. Estimates were stratified by study type (RCT vs. observational) and use of cyclosporine (an immunosuppressant that affects DNA repair). Twenty RCTs and two observational studies were eligible for meta-analysis, including 39,039 kidney recipients overall. Sirolimus use was associated with lower overall cancer incidence (incidence rate ratio [IRR] = 0.71, 95% CI = 0.56-0.90), driven by a reduction in incidence of nonmelanoma skin cancer (NMSC, IRR = 0.49, 95% CI = 0.32-0.76). The protective effect of sirolimus on NMSC risk was most notable in studies comparing sirolimus against cyclosporine (IRR = 0.19, 95% CI = 0.04-0.84). After excluding NMSCs, there was no overall association between sirolimus and incidence of other cancers (IRR = 1.06, 95% CI = 0.69-1.63). However, sirolimus use had associations with lower kidney cancer incidence (IRR = 0.40, 95% CI = 0.20-0.81), and higher prostate cancer incidence (IRR = 1.85, 95% CI = 1.17-2.91). Among kidney recipients, sirolimus users have lower NMSC risk, which may be partly due to removal of cyclosporine. Sirolimus may also reduce kidney cancer risk but did not appear protective for other cancers, and it may actually increase prostate cancer risk.
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Affiliation(s)
- Elizabeth L Yanik
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Kulsoom Siddiqui
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.,Brown School of Social Work, Washington University in St. Louis, St. Louis, Missouri
| | - Eric A Engels
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
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Recent trials in immunosuppression and their consequences for current therapy. Curr Opin Organ Transplant 2015; 19:387-94. [PMID: 24905020 DOI: 10.1097/mot.0000000000000093] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
PURPOSE OF REVIEW Although the scarcity of clinical trials with de-novo immunosuppression has been typical over the last 2 years, several attempts have been made in drug conversion, dosing optimization, and bioequivalence. On the basis of recent clinical and animal studies, future directions of management and treatment are outlined. RECENT FINDINGS Studies with new tacrolimus formulations showed better bioavailability and lower doses, which might translate into less toxicity. The long-term results of studies with costimulation blockade confirmed their safety and efficacy. Calcineurin inhibitor (CNI)-free regimens based on mTOR inhibitors were shown to be associated with increased risk of the humoral response. Therefore, ongoing trials are predominantly designed to minimize calcineurin inhibitor dose only. Biologics, such as B-cell-specific agents (bortezomib and rituximab) and complement inhibitors (eculizumab) used to treat antibody-mediated rejection, recurrence of glomerulonephritis, are shifted to more preventive applications. The pretransplant quantification of alloreactive memory/effector T cell response may help to better stratify a patient's immunologic risk and allow for drug minimization. SUMMARY Despite clinical trials with innovative protocols with already established agents, tacrolimus-based and induction-based protocols have been shown to be the mainstay of immunosuppressive regimens. In the future, research aims to focus on biomarker-driven immunosuppression and cell therapy approaches.
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Donor-Specific Antibodies, C4d and Their Relationship With the Prognosis of Transplant Glomerulopathy. Transplantation 2015; 99:69-76. [DOI: 10.1097/tp.0000000000000310] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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20
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Affiliation(s)
- Dirk R J Kuypers
- Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven B-3000, Belgium.
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21
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Gallon L, Traitanon O, Sustento-Reodica N, Leventhal J, Ansari MJ, Gehrau RC, Ariyamuthu V, De Serres SA, Alvarado A, Chhabra D, Mathew JM, Najafian N, Mas V. Cellular and molecular immune profiles in renal transplant recipients after conversion from tacrolimus to sirolimus. Kidney Int 2014; 87:828-38. [PMID: 25354238 PMCID: PMC4382402 DOI: 10.1038/ki.2014.350] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Revised: 08/26/2014] [Accepted: 08/28/2014] [Indexed: 02/01/2023]
Abstract
Tacrolimus and Sirolimus are commonly used maintenance immunesuppressants in kidney transplantation. Since their effects on immune cells and allograft molecular profiles have not been elucidated, we characterized the effects of Tacrolimus to Sirolimus conversion on frequency and function of T cells, and on graft molecular profiles. Samples from renal transplant patients in a randomized trial of 18 patients with late Sirolimus conversion and 12 on Tacrolimus maintenance were utilized. Peripheral blood was collected at 0, 6, 12 and 24-months post-randomization with T cell subpopulations analyzed by flow cytometry and T cell alloreactivity tested by IFN-γ ELISPOT. Graft biopsy samples obtained 24-months post-randomization were used for gene expression analysis. Sirolimus conversion led to an increase in CD4+25+++Foxp3+ regulatory T cells. While Tacrolimus-maintained patients showed a decrease in indirect alloreactivity over time post-transplant, Sirolimus conversion increased indirect alloreactive T cell frequencies compared to Tacrolimus-maintained patients. No histological differences were found in graft biopsies, but molecular profiles showed activation of the antigen presentation, IL-12 signaling, oxidative stress, macrophage-derived production pathways, and increased inflammatory and immune response in Sirolimus-converted patients. Thus, chronic immune alterations are induced after Sirolimus conversion. Despite the molecular profile being favorable to calcineurin inhibitor-based regimen, there was no impact in renal function over 30 months of follow-up.
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Affiliation(s)
- Lorenzo Gallon
- 1] Comprehensive Transplant Center, Northwestern University, Chicago, Illinois, USA [2] Department of Medicine-Nephrology, Northwestern University, Chicago, Illinois, USA
| | - Opas Traitanon
- 1] Department of Medicine-Nephrology, Northwestern University, Chicago, Illinois, USA [2] Department of Medicine-Nephrology, Thammasart University Hospital, Pathumthani, Thailand
| | | | - Joseph Leventhal
- Comprehensive Transplant Center, Northwestern University, Chicago, Illinois, USA
| | - M Javeed Ansari
- 1] Comprehensive Transplant Center, Northwestern University, Chicago, Illinois, USA [2] Department of Medicine-Nephrology, Northwestern University, Chicago, Illinois, USA
| | - Ricardo C Gehrau
- University of Virginia, Department of Surgery, Charlottesville, Virginia, USA
| | - Venkatesh Ariyamuthu
- Department of Medicine-Nephrology, Northwestern University, Chicago, Illinois, USA
| | - Sacha A De Serres
- 1] Transplantation Research Center, Division of Nephrology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Department of Nephrology, Cleveland Clinic Florida, Cleveland, Florida, USA
| | - Antonio Alvarado
- 1] Comprehensive Transplant Center, Northwestern University, Chicago, Illinois, USA [2] Department of Medicine-Nephrology, Northwestern University, Chicago, Illinois, USA
| | - Darshika Chhabra
- Advocate Christ Medical Center, Kidney Transplant, Oak Lawn, Illinois, USA
| | - James M Mathew
- Comprehensive Transplant Center, Northwestern University, Chicago, Illinois, USA
| | - Nader Najafian
- 1] Transplantation Research Center, Division of Nephrology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Department of Nephrology, Cleveland Clinic Florida, Cleveland, Florida, USA
| | - Valeria Mas
- University of Virginia, Department of Surgery, Charlottesville, Virginia, USA
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Murakami N, Riella LV, Funakoshi T. Risk of metabolic complications in kidney transplantation after conversion to mTOR inhibitor: a systematic review and meta-analysis. Am J Transplant 2014; 14:2317-27. [PMID: 25146383 DOI: 10.1111/ajt.12852] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Revised: 05/14/2014] [Accepted: 05/28/2014] [Indexed: 01/25/2023]
Abstract
Mammalian target of rapamycin (mTOR) inhibitors have been used in transplantation with the hope of minimizing calcineurin inhibitor (CNI)-induced nephrotoxicity. However, mTOR inhibitors are also associated with a range of side effects, including metabolic complications. We aimed to determine the risks of metabolic complications after the conversion from CNI to mTOR inhibitor postkidney transplant. A systematic search in PubMed up to September 2013 identified nine relevant trials (a total of 2323 patients). The primary end points were the relative risks (RRs) of new-onset diabetes after transplant (NODAT) and hypercholesterolemia. The overall RRs of NODAT and hypercholesterolemia associated with mTOR inhibitors were 1.32 (95% confidence interval [CI] 0.92-1.87) and 2.15 (95% CI 1.35-3.41), respectively, compared with CNI-based regimen. Subgroup analyses revealed no differences in the incidence of NODAT or hypercholesterolemia between sirolimus- versus everolimus-based regimen, or between early versus late conversion. Analyses of secondary outcomes revealed a higher risk of acute rejection, proteinuria and anemia, but no difference in the risk of opportunistic infections after mTOR inhibitor conversion. In conclusion, the conversion from CNI to mTOR inhibitor in low-to-moderate risk kidney transplant recipients was associated with nonsignificant trend toward increased risk of NODAT and significant increase in hypercholesterolemia, acute rejection, proteinuria and anemia.
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Affiliation(s)
- N Murakami
- Department of Medicine, Beth Israel Medical Center, New York, NY
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Mjörnstedt L, Schwartz Sørensen S, von Zur Mühlen B, Jespersen B, Hansen JM, Bistrup C, Andersson H, Gustafsson B, Solbu D, Holdaas H. Renal function three years after early conversion from a calcineurin inhibitor to everolimus: results from a randomized trial in kidney transplantation. Transpl Int 2014; 28:42-51. [PMID: 25176389 DOI: 10.1111/tri.12437] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Revised: 04/14/2014] [Accepted: 08/25/2014] [Indexed: 11/29/2022]
Abstract
In a 36-month, open-label, multicenter trial, 202 kidney transplant recipients were randomized at week 7 post-transplant to convert to everolimus or remain on cyclosporine: 182 were analyzed to month 36 (92 everolimus, 90 controls). Mean (SD) change in measured GFR (mGFR) from randomization to month 36 was 1.3 (14.0) ml/min with everolimus versus -1.7 (15.4) ml/min in controls (P = 0.210). In patients who remained on treatment, mean mGFR improved from randomization to month 36 by 7.9 (11.5) ml/min with everolimus (n = 37) but decreased by 1.4 (14.7) ml/min in controls (n = 62) (P = 0.001). During months 12-36, death-censored graft survival was 100%, patient survival was 98.9% and 96.7% in the everolimus and control groups, respectively, and 13.0% and 11.1% of everolimus and control patients, respectively, experienced mild biopsy-proven acute rejection (BPAR). Protocol biopsies in a limited number of on-treatment patients showed similar interstitial fibrosis progression. Donor-specific antibodies were present at month 36 in 6.3% (2/32) and 18.0% (9/50) of on-treatment everolimus and control patients with available data (P = 0.281). During months 12-36, adverse events were comparable, but discontinuation was more frequent with everolimus (33.7% vs. 10.0%). Conversion from cyclosporine to everolimus at 7 weeks post-transplant was associated with a significant benefit in renal function at 3 years when everolimus was continued.
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Affiliation(s)
- Lars Mjörnstedt
- Transplant Institute, Sahlgrenska University Hospital, University of Göteborg, Göteborg, Sweden
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Placental, Lipid, and Glucidic Effects of Mammalian Target of Rapamycin Inhibitors: Impact on Fetal Growth and Metabolic Disorders During Pregnancy After Solid Organ Transplantation. Transplant Proc 2014; 46:2254-8. [DOI: 10.1016/j.transproceed.2014.07.047] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Mathis AS, Egloff G, Ghin HL. Calcineurin inhibitor sparing strategies in renal transplantation, part one: Late sparing strategies. World J Transplant 2014; 4:57-80. [PMID: 25032096 PMCID: PMC4094953 DOI: 10.5500/wjt.v4.i2.57] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2014] [Revised: 03/25/2014] [Accepted: 05/14/2014] [Indexed: 02/05/2023] Open
Abstract
Kidney transplantation improves quality of life and reduces the risk of mortality. A majority of the success of kidney transplantation is attributable to the calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, and their ability to reduce acute rejection rates. However, long-term graft survival rates have not improved over time, and although controversial, evidence does suggest a role of chronic CNI toxicity in this failure to improve outcomes. Consequently, there is interest in reducing or removing CNIs from immunosuppressive regimens in an attempt to improve outcomes. Several strategies exist to spare calcineurin inhibitors, including use of agents such as mycophenolate mofetil (MMF), mycophenolate sodium (MPS), sirolimus, everolimus or belatacept to facilitate late calcineurin inhibitor withdrawal, beyond 6 mo post-transplant; or using these agents to plan early withdrawal within 6 mo; or to avoid the CNIs all together using CNI-free regimens. Although numerous reviews have been written on this topic, practice varies significantly between centers. This review organizes the data based on patient characteristics (i.e., the baseline immunosuppressive regimen) as a means to aid the practicing clinician in caring for their patients, by matching up their situation with the relevant literature. The current review, the first in a series of two, examines the potential of immunosuppressive agents to facilitate late CNI withdrawal beyond 6 mo post-transplant, and has demonstrated that the strongest evidence resides with MMF/MPS. MMF or MPS can be successfully introduced/maintained to facilitate late CNI withdrawal and improve renal function in the setting of graft deterioration, albeit with an increased risk of acute rejection and infection. Additional benefits may include improved blood pressure, lipid profile and serum glucose. Sirolimus has less data directly comparing CNI withdrawal to an active CNI-containing regimen, but modest improvement in short-term renal function is possible, with an increased risk of proteinuria, especially in the setting of baseline renal dysfunction and/or proteinuria. Renal outcomes may be improved when sirolimus is used in combination with MMF. Although data with everolimus is less robust, results appear similar to those observed with sirolimus.
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