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Mohamed ME, Saqr A, Staley C, Onyeaghala G, Teigen L, Dorr CR, Remmel RP, Guan W, Oetting WS, Matas AJ, Israni AK, Jacobson PA. Pharmacomicrobiomics: Immunosuppressive Drugs and Microbiome Interactions in Transplantation. Transplantation 2024; 108:1895-1910. [PMID: 38361239 PMCID: PMC11327386 DOI: 10.1097/tp.0000000000004926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
The human microbiome is associated with human health and disease. Exogenous compounds, including pharmaceutical products, are also known to be affected by the microbiome, and this discovery has led to the field of pharmacomicobiomics. The microbiome can also alter drug pharmacokinetics and pharmacodynamics, possibly resulting in side effects, toxicities, and unanticipated disease response. Microbiome-mediated effects are referred to as drug-microbiome interactions (DMI). Rapid advances in the field of pharmacomicrobiomics have been driven by the availability of efficient bacterial genome sequencing methods and new computational and bioinformatics tools. The success of fecal microbiota transplantation for recurrent Clostridioides difficile has fueled enthusiasm and research in the field. This review focuses on the pharmacomicrobiome in transplantation. Alterations in the microbiome in transplant recipients are well documented, largely because of prophylactic antibiotic use, and the potential for DMI is high. There is evidence that the gut microbiome may alter the pharmacokinetic disposition of tacrolimus and result in microbiome-specific tacrolimus metabolites. The gut microbiome also impacts the enterohepatic recirculation of mycophenolate, resulting in substantial changes in pharmacokinetic disposition and systemic exposure. The mechanisms of these DMI and the specific bacteria or communities of bacteria are under investigation. There are little or no human DMI data for cyclosporine A, corticosteroids, and sirolimus. The available evidence in transplantation is limited and driven by small studies of heterogeneous designs. Larger clinical studies are needed, but the potential for future clinical application of the pharmacomicrobiome in avoiding poor outcomes is high.
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Affiliation(s)
- Moataz E Mohamed
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN
| | - Abdelrahman Saqr
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN
| | | | - Guillaume Onyeaghala
- Hennepin Healthcare Research Institute, Minneapolis, MN
- Department of Medicine, University of Minnesota, Minneapolis, MN
| | - Levi Teigen
- Department of Food Science and Nutrition, University of Minnesota, St Paul, MN
| | - Casey R Dorr
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN
- Hennepin Healthcare Research Institute, Minneapolis, MN
- Department of Medicine, University of Minnesota, Minneapolis, MN
- Department of Medicine, Hennepin Healthcare, Minneapolis, MN
| | - Rory P Remmel
- Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN
| | - Weihua Guan
- Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN
| | - William S Oetting
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN
| | - Arthur J Matas
- Department of Surgery, University of Minnesota, Minneapolis, MN
| | - Ajay K Israni
- Hennepin Healthcare Research Institute, Minneapolis, MN
- Department of Medicine, Hennepin Healthcare, Minneapolis, MN
- Department of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN
| | - Pamala A Jacobson
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN
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Zhang D, Lv W, Xu Y, Zhang Z, Zeng S, Zhang W, Gong L, Shao L, Zhang M, He T, Liu Y, Wang Y, Liu L, Hu X. Microbial bile acid metabolite ameliorates mycophenolate mofetil-induced gastrointestinal toxicity through vitamin D3 receptor. Am J Transplant 2024; 24:1132-1145. [PMID: 38452932 DOI: 10.1016/j.ajt.2024.02.029] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/24/2024] [Accepted: 02/26/2024] [Indexed: 03/09/2024]
Abstract
Mycophenolate mofetil (MMF) is one of the most used immunosuppressive drugs in organ transplantation, but frequent gastrointestinal (GI) side effects through unknown mechanisms limit its clinical use. Gut microbiota and its metabolites were recently reported to play a vital role in MMF-induced GI toxicity, but the specific mechanism of how they interact with the human body is still unclear. Here, we found that secondary bile acids (BAs), as bacterial metabolites, were significantly reduced by MMF administration in the gut of mice. Microbiome data and fecal microbiota transfer model supported a microbiota-dependent effect on the reduction of secondary BAs. Supplementation of the secondary BA lithocholic acid alleviated MMF-induced weight loss, colonic inflammation, and oxidative phosphorylation damage. Genetic deletion of the vitamin D3 receptor (VDR), which serves as a primary colonic BA receptor, in colonic epithelial cells (VDRΔIEC) abolished the therapeutic effect of lithocholic acid on MMF-induced GI toxicity. Impressively, we discovered that paricalcitol, a Food and Drug Administration-approved VDR agonist that has been used in clinics for years, could effectively alleviate MMF-induced GI toxicity. Our study reveals a previously unrecognized mechanism of gut microbiota, BAs, and VDR signaling in MMF-induced GI side effects, offering potential therapeutic strategies for clinics.
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Affiliation(s)
- Di Zhang
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; Institute of Urology, Capital Medical University, Beijing, China
| | - Wei Lv
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yue Xu
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; Institute of Urology, Capital Medical University, Beijing, China
| | - Zijian Zhang
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; Institute of Urology, Capital Medical University, Beijing, China
| | - Song Zeng
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; Institute of Urology, Capital Medical University, Beijing, China
| | - Weixun Zhang
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; Institute of Urology, Capital Medical University, Beijing, China
| | - Lian Gong
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; Institute of Urology, Capital Medical University, Beijing, China
| | - Limei Shao
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Min Zhang
- Department of Research Ward, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Tian He
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yingying Liu
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yuxuan Wang
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; Institute of Urology, Capital Medical University, Beijing, China
| | - Ling Liu
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
| | - Xiaopeng Hu
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; Institute of Urology, Capital Medical University, Beijing, China.
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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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Clinical Correlates and Outcomes of Dual Basiliximab and Antithymocyte Globulin Induction in Kidney Transplant Recipients: A National Study. Transplant Direct 2021; 7:e736. [PMID: 35836670 PMCID: PMC9276156 DOI: 10.1097/txd.0000000000001190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 05/19/2021] [Indexed: 11/26/2022] Open
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Farag A, Gaynor JJ, Serena G, Ciancio G. Evidence to support a drain-free strategy in kidney transplantation using a retrospective comparison of 500 consecutively transplanted cases at a single center. BMC Surg 2021; 21:74. [PMID: 33541328 PMCID: PMC7863357 DOI: 10.1186/s12893-021-01081-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 01/13/2021] [Indexed: 11/30/2022] Open
Abstract
Introduction Routine placement of surgical drains at the time of kidney transplant has been debated in terms of its prognostic value. Objectives To determine whether the placement of a surgical drain affects the incidence rate of developing wound complications and other clinical outcomes, particularly after controlling for other prognostic factors. Methods Retrospective analysis of 500 consecutive renal transplant cases who did not (Drain-free, DF) vs. did (Drain, D) receive a drain at the time of transplant was performed. The primary outcome was the development of any wound complication (superficial or deep) during the first 12 months post-transplant. Secondary outcomes included the development of superficial wound complications, deep wound complications, DGF, and graft loss during the first 12 months post-transplant. Results 388 and 112 recipients had DF/D, respectively. DF-recipients were significantly more likely to be younger, not have pre-transplant diabetes, receive a living donor kidney, receive a kidney-alone transplant, have a shorter duration of dialysis, shorter mean cold-ischemia-time, and greater pre-transplant use of anticoagulants/antiplatelets. Wound complications were 4.6% (18/388) vs. 5.4% (6/112) in DF vs. D groups, respectively (P = 0.75). Superficial wound complications were observed in 0.8% (3/388) vs. 0.0% (0/112) in DF vs. D groups, respectively (P = 0.35). Deep wound complications were observed in 4.1% (16/388) vs. 5.4% ((6/112) in DF vs. D groups, respectively (P = 0.57). Higher recipient body mass index and ≥ 1 year of pre-transplant dialysis were associated in multivariable analysis with an increased incidence of wound complications. Once the prognostic influence of these 2 factors were controlled, there was still no notable effect of drain use (yes/no). The lack of prognostic effect of drain use was similarly observed for the other clinical outcomes. Conclusions In a relatively large cohort of renal transplant recipients, routine surgical drain use appears to offer no distinct prognostic advantage.
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Affiliation(s)
- Ahmed Farag
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.,Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Surgery, Zagazig University School of Medicine, Zagazig, Egypt
| | - Jeffrey J Gaynor
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.,Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Giuseppe Serena
- Department of Surgery, Nassau University Medical Center, East Meadow, NY, USA
| | - Gaetano Ciancio
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA. .,Department of Urology, University of Miami Miller School of Medicine, Miami, FL, USA. .,Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL, USA. .,Department of Surgery and Urology, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL, USA. .,Miami Transplant Institute, 1801 NW 9th Ave, 7th Floor, Miami, FL, 33136, USA.
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Association of Intrapatient Variability of Tacrolimus Concentration With Early Deterioration of Chronic Histologic Lesions in Kidney Transplantation. Transplant Direct 2019; 5:e455. [PMID: 31321291 PMCID: PMC6553623 DOI: 10.1097/txd.0000000000000899] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 04/04/2019] [Accepted: 04/06/2019] [Indexed: 12/22/2022] Open
Abstract
Supplemental Digital Content is available in the text. High intrapatient variability (IPV) of tacrolimus (Tac) is increasingly recognized as a risk factor for poor graft outcomes in kidney transplantation. The timing of onset of its impact on kidney histologic lesions has not been investigated.
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Thomas IA, Gaynor JJ, Joseph T, De La Cruz-Munoz N, Sageshima J, Kupin W, Chen LJ, Ciancio G, Burke GW, Mattiazzi AD, Roth D, Guerra G. Roux-en-Y gastric bypass is an effective bridge to kidney transplantation: Results from a single center. Clin Transplant 2018; 32:e13232. [PMID: 29488657 DOI: 10.1111/ctr.13232] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/21/2018] [Indexed: 12/23/2022]
Abstract
Body mass index (BMI) > 35-40 kg/m2 is often a contraindication, while Roux-en-Y gastric bypass (RYGB) is performed to enable kidney transplantation. This single-center retrospective study evaluated pre- and post-transplant outcomes of 31 morbidly obese patients with end-stage renal disease having RYGB before kidney transplantation between July 2009 and June 2014. Fourteen RYGB patients were subsequently transplanted. Nineteen recipients not having GB with a BMI ≥ 36 kg/m2 at transplantation were used as historical controls. Mean BMI (±SE) before RYGB was 43.5 ± 0.7 kg/m2 (range: 35.4-50.5 kg/m2 ); 87.1% (27/31) achieved a BMI < 35 kg/m2 . The percentage having improved diabetes/hypertension control was 29.0% (9/31); 25.8% (8/31) had complications (mostly minor) after RYGB. Among transplanted patients, blacks/Hispanics comprised 78.6% (11/14) and 84.2% (16/19) of RYGB and controls; 57.1% (8/14) and 63.2% (12/19) had a (mostly long-standing) pretransplant history of diabetes. While biopsy-proven acute rejection (BPAR) occurred significantly higher among RYGB vs control patients (6/14 vs 3/19, P = .03), patients developing T-cell BPAR were also significantly more likely to have a tacrolimus (TAC) trough level < 4.0 ng/mL within 3 weeks of T-cell BPAR (P = .0007). In Cox's model, the impact of having a TAC level < 4.0 ng/mg remained significant (P = .007) while the effect of RYGB was no longer significant (P = .13). Infections, graft, and patient survival were not significantly different. Despite obvious effectiveness in achieving weight loss, RYGB will need more careful post-transplant monitoring given the observed higher BPAR rate.
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Affiliation(s)
- Ian A Thomas
- Department of Medicine, University of Miami/Jackson Memorial Hospital, Miami, FL, USA
| | - Jeffrey J Gaynor
- Department of Surgery, University of Miami/Jackson Memorial Hospital, Miami, FL, USA
| | - Tameka Joseph
- Department of Medicine, University of Miami/Jackson Memorial Hospital, Miami, FL, USA
| | | | | | - Warren Kupin
- Department of Medicine, University of Miami/Jackson Memorial Hospital, Miami, FL, USA
| | - Linda J Chen
- Department of Surgery, University of Miami/Jackson Memorial Hospital, Miami, FL, USA
| | - Gaetano Ciancio
- Department of Surgery, University of Miami/Jackson Memorial Hospital, Miami, FL, USA
| | - George W Burke
- Department of Surgery, University of Miami/Jackson Memorial Hospital, Miami, FL, USA
| | - Adela D Mattiazzi
- Department of Medicine, University of Miami/Jackson Memorial Hospital, Miami, FL, USA
| | - David Roth
- Department of Medicine, University of Miami/Jackson Memorial Hospital, Miami, FL, USA
| | - Giselle Guerra
- Department of Medicine, University of Miami/Jackson Memorial Hospital, Miami, FL, USA
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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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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 2016; 20:1-594. [PMID: 27578428 PMCID: PMC5018688 DOI: 10.3310/hta20620] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [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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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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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: 48] [Impact Index Per Article: 4.8] [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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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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15
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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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Sageshima J, Ciancio G, Chen L, Dohi T, El-Hinnawi A, Paloyo S, Misawa R, Ekwenna O, Yatawatta A, Burke GW. Everolimus with low-dose tacrolimus in simultaneous pancreas and kidney transplantation. Clin Transplant 2014; 28:797-801. [PMID: 24779669 DOI: 10.1111/ctr.12381] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/25/2014] [Indexed: 02/06/2023]
Abstract
The efficacy and safety of everolimus (EVR) in simultaneous pancreas and kidney transplantation (SPKT) is unclear. We retrospectively evaluated 25 consecutive SPKT recipients at our center from November 2011 to March 2013. All patients received dual induction (Thymoglobulin/basiliximab) and low-dose tacrolimus plus corticosteroids. Nine patients who received EVR were compared with 14 patients who received enteric-coated mycophenolate sodium (EC-MPS); two patients who received sirolimus were excluded from the analysis. With a median follow-up of 14 months, the pancreas graft survival rate was 100% in both groups, and the kidney graft survival rate was 100% and 93% in EVR and EC-MPS patients, respectively. One EC-MPS patient lost her kidney graft from proteinuric kidney disease. Another EC-MPS patient received treatment for clinically diagnosed pancreas and kidney graft rejection. No rejection was observed in EVR patients. Serum creatinine and HbA1c levels were similar between the groups. There was no significant difference of surgical or medical complications. In conclusion, EVR seems to provide comparable short-term outcome to EC-MPS when combined with low-dose tacrolimus/steroids and dual induction therapy. A larger study with a longer follow-up is required to further assess this combination.
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Affiliation(s)
- Junichiro Sageshima
- Division of Kidney and Pancreas Transplantation, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA; Miami Transplant Institute at the Jackson Memorial Hospital and University of Miami, Miami, FL, USA
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Gaynor JJ, Ciancio G, Guerra G, Sageshima J, Roth D, Chen L, Kupin W, Mattiazzi A, Tueros L, Flores S, Hanson L, Vianna R, Burke GW. Predictors of reduced tacrolimus dose and trough level through 36 months post-transplant among 578 adult primary kidney transplant recipients. Clin Transplant 2014. [DOI: 10.1111/ctr.12340] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Affiliation(s)
- Jeffrey J. Gaynor
- Department of Surgery; Miami Transplant Institute; University of Miami Miller School of Medicine; Miami FL USA
| | - Gaetano Ciancio
- Department of Surgery; Miami Transplant Institute; University of Miami Miller School of Medicine; Miami FL USA
| | - Giselle Guerra
- Department of Medicine; Miami Transplant Institute; University of Miami Miller School of Medicine; Miami FL USA
| | - Junichiro Sageshima
- Department of Surgery; Miami Transplant Institute; University of Miami Miller School of Medicine; Miami FL USA
| | - David Roth
- Department of Medicine; Miami Transplant Institute; University of Miami Miller School of Medicine; Miami FL USA
| | - Linda Chen
- Department of Surgery; Miami Transplant Institute; University of Miami Miller School of Medicine; Miami FL USA
| | - Warren Kupin
- Department of Medicine; Miami Transplant Institute; University of Miami Miller School of Medicine; Miami FL USA
| | - Adela Mattiazzi
- Department of Medicine; Miami Transplant Institute; University of Miami Miller School of Medicine; Miami FL USA
| | - Lissett Tueros
- Department of Surgery; Miami Transplant Institute; University of Miami Miller School of Medicine; Miami FL USA
| | - Sandra Flores
- Department of Surgery; Miami Transplant Institute; University of Miami Miller School of Medicine; Miami FL USA
| | - Lois Hanson
- Department of Surgery; Miami Transplant Institute; University of Miami Miller School of Medicine; Miami FL USA
| | - Rodrigo Vianna
- Department of Surgery; Miami Transplant Institute; University of Miami Miller School of Medicine; Miami FL USA
| | - George W. Burke
- Department of Surgery; Miami Transplant Institute; University of Miami Miller School of Medicine; Miami FL USA
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Sageshima J, Ciancio G, Chen L, Dohi T, El-Hinnawi A, Paloyo S, Gaynor JJ, Mattiazzi A, Guerra G, Kupin W, Roth D, Ruiz P, Burke GW. Lack of clinical association and effect of peripheral WBC counts on immune cell function test in kidney transplant recipients with T-cell depleting induction and steroid-sparing maintenance therapy. Transpl Immunol 2014; 30:88-92. [PMID: 24518158 DOI: 10.1016/j.trim.2014.01.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2013] [Revised: 01/21/2014] [Accepted: 01/28/2014] [Indexed: 02/07/2023]
Abstract
The Cylex ImmuKnow assay measures the amount of stimulated ATP production by CD4+ T-cells, and has been used clinically, trying to predict rejection and infection episodes. However, predictive values of this assay after induction therapy with steroid-sparing maintenance protocols are unclear. In this single-center cohort study, we analyzed renal transplant recipients who received T-cell depleting+/-anti-IL2 receptor antibodies and tacrolimus/mycophenolate maintenance without steroids. A total of 4224 ImmuKnow levels in 306 patients were available for analysis. ImmuKnow levels (Mean ± SE) changed over time after induction therapy with a paradoxical initial increase: 419 ± 23, 461 ± 32, 519 ± 14, 411 ± 10, 344 ± 6, and 405 ± 3 for pre-transplant, 0-1 wk, 1 wk-1 mo, 1-3 mos, 3 mos-1 yr, and thereafter. This change was parallel to the evolution of peripheral WBC counts and ImmuKnow levels had weak but significant correlation with WBC counts (R(2)=0.264, P<0.0001). The levels for biopsy-proven rejection (389 ± 56) and borderline/clinical rejection (254 ± 41) were not significantly higher than the levels of quiescent patients. The levels for opportunistic infection (349 ± 48) and other infections (345 ± 27) were not significantly lower than the levels of quiescent patients. The longitudinal changes in ImmuKnow levels were not predictive of rejection or infection. In conclusion, ImmuKnow levels can vary after T-cell depleting induction therapies at various time points, even without significant clinical events. Since ImmuKnow levels seem to be affected by WBC counts, ImmuKnow results need to be interpreted with caution. The effects of leukocytosis or leukopenia caused by immunosuppressive medication on the ImmuKnow assay need further investigation.
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Affiliation(s)
- Junichiro Sageshima
- Division of Kidney and Pancreas Transplantation, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA; Miami Transplant Institute at the Jackson Memorial Hospital and University of Miami, Miami, FL, USA.
| | - Gaetano Ciancio
- Division of Kidney and Pancreas Transplantation, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA; Miami Transplant Institute at the Jackson Memorial Hospital and University of Miami, Miami, FL, USA
| | - Linda Chen
- Division of Kidney and Pancreas Transplantation, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA; Miami Transplant Institute at the Jackson Memorial Hospital and University of Miami, Miami, FL, USA
| | - Takehiko Dohi
- Miami Transplant Institute at the Jackson Memorial Hospital and University of Miami, Miami, FL, USA
| | - Ashraf El-Hinnawi
- Miami Transplant Institute at the Jackson Memorial Hospital and University of Miami, Miami, FL, USA
| | - Siegfredo Paloyo
- Miami Transplant Institute at the Jackson Memorial Hospital and University of Miami, Miami, FL, USA
| | - Jeffrey J Gaynor
- Division of Kidney and Pancreas Transplantation, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA; Miami Transplant Institute at the Jackson Memorial Hospital and University of Miami, Miami, FL, USA
| | - Adela Mattiazzi
- Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA; Miami Transplant Institute at the Jackson Memorial Hospital and University of Miami, Miami, FL, USA
| | - Giselle Guerra
- Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA; Miami Transplant Institute at the Jackson Memorial Hospital and University of Miami, Miami, FL, USA
| | - Warren Kupin
- Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA; Miami Transplant Institute at the Jackson Memorial Hospital and University of Miami, Miami, FL, USA
| | - David Roth
- Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA; Miami Transplant Institute at the Jackson Memorial Hospital and University of Miami, Miami, FL, USA
| | - Phillip Ruiz
- Division of Kidney and Pancreas Transplantation, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA; Miami Transplant Institute at the Jackson Memorial Hospital and University of Miami, Miami, FL, USA
| | - George W Burke
- Division of Kidney and Pancreas Transplantation, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA; Miami Transplant Institute at the Jackson Memorial Hospital and University of Miami, Miami, FL, USA
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Connor A, Prowse A, Newell P, Rowe PA. A single-centre comparison of the clinical outcomes at 6 months of renal transplant recipients administered Adoport ® or Prograf ® preparations of tacrolimus. Clin Kidney J 2012; 6:21-28. [PMID: 27818747 PMCID: PMC5094386 DOI: 10.1093/ckj/sfs154] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2012] [Accepted: 10/03/2012] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND The use of generic formulations of immunosuppressive drugs in place of brand name drugs offers considerable cost savings. Brand name tacrolimus (Prograf®) came off patent in April 2008. However, published evidence supporting therapeutic equivalence of generic formulations of tacrolimus in solid organ transplantation is lacking. The South West Transplant Centre switched from administering Prograf® to a generic formulation (Adoport®) for de novo transplant recipients in November 2010. This study sought to compare the clinical outcomes of renal transplant recipients administered Prograf® with those receiving Adoport®. METHODS Data regarding patient characteristics and clinical outcomes were collected retrospectively for all patients undergoing renal transplantation at the South West Transplant Centre between 8 November 2009 and 8 November 2011 to whom tacrolimus was prescribed. RESULTS A total of 48 patients received Prograf® and 51 received Adoport®. At 6 months, no statistically significant differences were identified in the rates of patient survival, graft survival, acute allograft rejection, delayed graft function, calcineurin inhibitor toxicity or cytomegalovirus infection occurring within the two groups. CONCLUSIONS This is the first study to compare the clinical outcomes of patients receiving Adoport® with those receiving brand name tacrolimus. We report comparable clinical outcomes at 6 months in patients receiving either Prograf® or Adoport® from the time of renal transplantation. These early outcome data therefore support the use of Adoport® in place of Prograf® as a potential cost-saving measure.
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Affiliation(s)
- Andrew Connor
- South West Transplant Centre , Derriford Hospital , Plymouth , UK
| | - Andrew Prowse
- South West Transplant Centre , Derriford Hospital , Plymouth , UK
| | - Paul Newell
- Centre for Health & Environmental Statistics , Plymouth University , Plymouth , UK
| | - Peter A Rowe
- South West Transplant Centre , Derriford Hospital , Plymouth , UK
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Ciancio G, Gaynor JJ, Sageshima J, Guerra G, Zarak A, Roth D, Brown R, Kupin W, Chen L, Hanson L, Tueros L, Ruiz P, Livingstone AS, Burke GW. Randomized Trial of Dual Antibody Induction Therapy With Steroid Avoidance in Renal Transplantation. Transplantation 2011; 92:1348-57. [DOI: 10.1097/tp.0b013e3182384b21] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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