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Elezaby A, Dexheimer R, Sallam K. Cardiovascular effects of immunosuppression agents. Front Cardiovasc Med 2022; 9:981838. [PMID: 36211586 PMCID: PMC9534182 DOI: 10.3389/fcvm.2022.981838] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 08/30/2022] [Indexed: 11/26/2022] Open
Abstract
Immunosuppressive medications are widely used to treat patients with neoplasms, autoimmune conditions and solid organ transplants. Key drug classes, namely calcineurin inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and purine synthesis inhibitors, have direct effects on the structure and function of the heart and vascular system. In the heart, immunosuppressive agents modulate cardiac hypertrophy, mitochondrial function, and arrhythmia risk, while in vasculature, they influence vessel remodeling, circulating lipids, and blood pressure. The aim of this review is to present the preclinical and clinical literature examining the cardiovascular effects of immunosuppressive agents, with a specific focus on cyclosporine, tacrolimus, sirolimus, everolimus, mycophenolate, and azathioprine.
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Affiliation(s)
- Aly Elezaby
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA, United States
| | - Ryan Dexheimer
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
| | - Karim Sallam
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA, United States
- *Correspondence: Karim Sallam
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Konda P, Golamari R, Eisen HJ. Novel Immunosuppression in Solid Organ Transplantation. Handb Exp Pharmacol 2022; 272:267-285. [PMID: 35318509 DOI: 10.1007/164_2021_569] [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] [Indexed: 06/14/2023]
Abstract
Solid organ transplantation and survival has improved tremendously in the last few decades, much of the success has been attributed to the advancements in immunosuppression. While steroids are being replaced and much of the immunosuppressive strategies focus on steroid free regimens, novel agents have introduced in the induction, maintenance, and treatment of acute rejection phase. MTOR inhibitors have helped with the renal sparing side effect from the calcineurin inhibitors, newer agents such as rituximab have decreased the incidence of donor-specific antibodies which led to decreased incidence of acute rejection reactions. In this chapter we discuss the newer therapies directed specifically for solid organ transplantation.
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Affiliation(s)
- Prasad Konda
- Heart and Vascular Institute, Pennsylvania State University/Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Reshma Golamari
- Department of Hospital Medicine, Pennsylvania State University/Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Howard J Eisen
- Heart and Vascular Institute, Pennsylvania State University/Milton S. Hershey Medical Center, Hershey, PA, USA.
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Hu YN, Lee NY, Roan JN, Hsu CH, Luo CY. High-dose calcineurin inhibitor-free everolimus as a maintenance regimen for heart transplantation may be a risk factor for Pneumocystis pneumonia. Transpl Infect Dis 2017; 19. [PMID: 28425200 DOI: 10.1111/tid.12709] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 12/21/2016] [Accepted: 01/15/2017] [Indexed: 11/28/2022]
Abstract
BACKGROUND Everolimus reduces the incidence of cardiac-allograft vasculopathy (CAV) and is less renally toxic than are calcineurin inhibitors (CNIs). We evaluated the safety of CNI-free everolimus for post-heart transplant (HTx) patients. METHODS We retrospectively reviewed the records of 36 consecutive patients who had undergone an HTx between January 2006 and December 2013 in National Cheng Kung University Hospital. All patients initially had been treated with the standard tacrolimus regimen. The Study group-12 patients with CAV, renal impairment, or a history of malignancy-were switched from tacrolimus to everolimus. The Control group consisted of 19 patients who remained on the standard regimen. The target everolimus trough concentration was 8-14 ng/mL. The primary outcome was survival, and the secondary outcomes were bacterial, viral, fungal, and other infections; Pneumocystis jirovecii pneumonia (PJP); and rejection (≥2R). RESULTS During a 53.3±25.6-month follow-up, the survival rate, rejection rate, and number of infections, except for PJP, were not significantly different between the two groups. In the Study group, 6 patients were diagnosed with PJP 33±18.2 months after switching. None of the Control group patients were diagnosed with PJP during follow-up. CONCLUSIONS A high-dose CNI-free everolimus maintenance regimen might yield a higher incidence of post-transplantation PJP.
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Affiliation(s)
- Yu-Ning Hu
- Division of Cardiovascular Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Nan-Yao Lee
- Division of Infection, Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Jun-Neng Roan
- Division of Cardiovascular Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Institute of Clinical Medicine, National Cheng Kung University Hospital and College of Medicine, Tainan, Taiwan
| | - Chi-Hsin Hsu
- Institute of Clinical Medicine, National Cheng Kung University Hospital and College of Medicine, Tainan, Taiwan.,Division of Critical Care Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chwan-Yau Luo
- Division of Cardiovascular Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan
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Qiu Y, Wang X, Fan J, Rao Z, Lu Y, Lin T. Conversion From Calcineurin Inhibitors to Mammalian Target-of-Rapamycin Inhibitors in Heart Transplant Recipients: A Meta-Analysis of Randomized Controlled Trials. Transplant Proc 2016; 47:2952-6. [PMID: 26707320 DOI: 10.1016/j.transproceed.2015.09.059] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 09/17/2015] [Indexed: 02/05/2023]
Abstract
OBJECTIVE Conversion from calcineurin inhibitors (CNIs) to mammalian target-of-rapamycin inhibitors (mTORi) was systematically evaluated in heart transplant recipients (HTRs) for the first time. METHODS MEDLINE (PUBMED), EMBASE, Cochrane Library, and clinical trial registries were searched comprehensively. After screening for eligibility, the randomized controlled trials (RCTs) comparing continuation of CNI with conversion to mTORi therapy underwent review, quality assessment, and data extraction. Outcomes analyzed including creatinine clearance, serum creatinine level, rejection, adverse effects, and triglyceride levels were expressed as mean differences (MDs) or as risk ratios (RRs) with 95% confidence intervals (CIs). RESULTS This is the first systematic review evaluating converting from CNI to mTORi therapy in HTRs. A total of 4 RCTs (231 HTRs, 117 vs 114) were included in our analysis. Patients converted to mTORi had a higher creatinine clearance (MD, 19.31; 95% CI [11.16, 27.46]; P < .00001) and lower serum creatinine levels (MD, -0.15; 95% CI [-0.25, -0.05]; P = .002). Patients converted to mTORi had a significantly higher occurrence of adverse effects, which included skin diseases, gastrointestinal side effects, bone marrow suppression, and infections. There was no significant difference between the 2 groups regarding graft rejection and triglyceride levels (RR, 2.61; 95% CI [0.08, 81.25]; P = .58; MD, 22.89; 95% CI [-21.86, 67.63]; P = .32). CONCLUSIONS Conversion from CNI to mTORi therapy may improve the renal function in HTRs, but the patients may suffer from a high incidence of mTORi-associated adverse events. Therefore, conversion to mTORi must be carefully assessed for the benefits and risks.
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Affiliation(s)
- Y Qiu
- 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
| | - X Wang
- 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
| | - J Fan
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Z Rao
- 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
| | - Y Lu
- 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
| | - T 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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Manito N, Delgado JF, Crespo-Leiro MG, Arizón JM, Segovia J, González-Vílchez F, Mirabet S, Lage E, Pascual-Figal D, Díaz B, Palomo J, Rábago G, Sanz M, Blasco T, Roig E. Twelve-month efficacy and safety of the conversion to everolimus in maintenance heart transplant recipients. World J Transplant 2015; 5:310-319. [PMID: 26722659 PMCID: PMC4689942 DOI: 10.5500/wjt.v5.i4.310] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 07/31/2015] [Accepted: 10/13/2015] [Indexed: 02/05/2023] Open
Abstract
AIM: To determine the clinical reasons for conversion to everolimus (EVL) and long-term outcomes in heart transplant (HT) recipients.
METHODS: A retrospective 12-mo study has been carried out in 14 Spanish centres to assess the efficacy and safety of conversion to EVL in maintenance HT recipients.
RESULTS: Two hundred and twenty-two patients were included (mean age: 53 ± 10.5 years; mean time from HT: 8.1 ± 4.5 years). The most common reasons for conversion were nephrotoxicity (30%), chronic allograft vasculopathy (20%) and neoplasms (17%). The doses and mean levels of EVL at baseline (conversion to EVL) and after one year were 1.3 ± 0.3 and 1.2 ± 0.6 mg/d and 6.4 ± 3.4 and 5.6 ± 2.5 ng/mL, respectively. The percentage of patients receiving calcineurin inhibitors (CNIs) at baseline and on the final visit was 95% and 65%, respectively. The doses and mean levels of CNIs decreased between baseline and month 12 from 142.2 ± 51.6 to 98.0 ± 39.4 mg/d (P < 0.001) and from 126.1 ± 50.9 to 89.2 ± 47.7 ng/mL (P < 0.001), respectively, for cyclosporine, and from 2.9 ± 1.8 to 2.6 ± 1.9 mg/d and from 8.3 ± 4.0 to 6.5 ± 2.7 ng/mL (P = 0.011) for tacrolimus. In the subgroup of patients converted because of nephrotoxicity, creatinine clearance increased from 34.9 ± 10.1 to 40.4 ± 14.4 mL/min (P < 0.001). There were 37 episodes of acute rejection in 24 patients (11%). The most frequent adverse events were oedemas (12%), infections (9%) and gastrointestinal problems (6%). EVL was suspended in 44 patients (20%). Since the database was closed at the end of the study, no further follow-up data is available.
CONCLUSION: Conversion to EVL in maintenance HT recipients allowed minimisation or suspension of the CNIs, with improved kidney function in the patients with nephrotoxicity, after 12 mo.
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Söderlund C, Rådegran G. Immunosuppressive therapies after heart transplantation — The balance between under- and over-immunosuppression. Transplant Rev (Orlando) 2015; 29:181-9. [DOI: 10.1016/j.trre.2015.02.005] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Revised: 01/16/2015] [Accepted: 02/22/2015] [Indexed: 01/06/2023]
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Chronic renal insufficiency in heart transplant recipients: risk factors and management options. Drugs 2015; 74:1481-94. [PMID: 25134671 DOI: 10.1007/s40265-014-0274-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Renal dysfunction after heart transplantation is a frequently observed complication, in some cases resulting in significant limitation of quality of life and reduced survival. Since the pathophysiology of renal failure (RF) is multifactorial, the current etiologic paradigm for chronic kidney disease after heart transplantation relies on the concept of calcineurin inhibitor (CNI)-related nephrotoxicity acting on a predisposed recipient. Until recently, the management of RF has been restricted to the minimization of CNI dosage and general avoidance of classic nephrotoxic risk factors, with somewhat limited success. The recent introduction of proliferation signal inhibitors (PSIs) (sirolimus and everolimus), a new class of immunosuppressive drugs lacking intrinsic nephrotoxicity, has provided a completely new alternative in this clinical setting. As clinical experience with these new drugs increases, new renal-sparing strategies are becoming available. PSIs can be used in combination with reduced doses of CNIs and even in complete CNI-free protocols. Different strategies have been devised, including de novo use to avoid acute renal toxicity in high-risk patients immediately after transplantation, or more delayed introduction in those patients developing chronic RF after prolonged CNI exposure. In this review, the main information on the clinical relevance and pathophysiology of RF after heart transplantation, as well as the currently available experience with renal-sparing immunosuppressive regimens, particularly focused on the use of PSIs, is reviewed and summarized, including the key practical points for their appropriate clinical usage.
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Ribezzo M, Boffini M, Ricci D, Barbero C, Bonato R, Attisani M, Pasero D, Rinaldi M. Incidence and Treatment of Lymphedema in Heart Transplant Patients Treated With Everolimus. Transplant Proc 2014; 46:2334-8. [DOI: 10.1016/j.transproceed.2014.07.036] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Prospective Study of Everolimus With Calcineurin Inhibitor-Free Immunosuppression After Heart Transplantation: Results at Four Years. Ann Thorac Surg 2014; 97:888-93. [DOI: 10.1016/j.athoracsur.2013.09.031] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2013] [Revised: 09/08/2013] [Accepted: 09/10/2013] [Indexed: 01/13/2023]
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Gonzalez-Vilchez F, Vazquez de Prada JA, Paniagua MJ, Gomez-Bueno M, Arizon JM, Almenar L, Roig E, Delgado J, Lambert JL, Perez-Villa F, Sanz-Julve ML, Crespo-Leiro M, Segovia J, Lopez-Granados A, Martinez-Dolz L, Mirabet S, Escribano P, Diaz-Molina B, Farrero M, Blasco T. Use of mTOR inhibitors in chronic heart transplant recipients with renal failure: calcineurin-inhibitors conversion or minimization? Int J Cardiol 2013; 171:15-23. [PMID: 24309084 DOI: 10.1016/j.ijcard.2013.11.036] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2013] [Revised: 11/08/2013] [Accepted: 11/17/2013] [Indexed: 01/13/2023]
Abstract
BACKGROUND In the last decade, mTOR inhibitors (mTOR-is) have become the cornerstone of the calcineurin inhibitor (CNI)-reduced/free regimens aimed to the preservation of post-transplant renal function. We compared utility and safety of the total replacement of calcineurin inhibitors with a mTOR-i with a strategy based on calcineurin inhibitor minimization and concomitant use of m-TOR-i. METHODS In a retrospective multi-center cohort of 394 maintenance cardiac recipients with renal failure (GFR<60 mL/min/1.73 m(2)), we compared 235 patients in whom CNI was replaced with a mTOR-i (sirolimus or everolimus) with 159 patients in whom mTOR-is were used to minimize CNIs. A propensity score analysis was carried out to balance between group differences. RESULTS Overall, after a median time of 2 years from mTOR-i initiation, between group differences for the evolution of renal function were not observed. In a multivariate adjusted model, improvement of renal function was limited to patients with mTOR-i usage within 5years after transplantation, particularly with the conversion strategy, and in those patients who could maintain mTOR-i therapy. Significant differences between strategies were not found for mortality, infection and mTOR-i withdrawal due to drug-related adverse events. However, conversion group tended to have a higher acute rejection incidence than the minimization group (p=0.07). CONCLUSION In terms of renal benefits, our results support an earlier use of mTOR-is, irrespective of the strategy. The selection of either a conversion or a CNI minimization protocol should be based on the clinical characteristics of the patients, particularly their rejection risk.
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Affiliation(s)
- F Gonzalez-Vilchez
- Heart Failure and Cardiac Transplantation Unit, Cardiology Service, University Hospital Marques de Valdecilla, Instituto de Formación e Investigación Marqués de Valdecilla (IFIMAV), Santander, Spain.
| | - J A Vazquez de Prada
- Heart Failure and Cardiac Transplantation Unit, Cardiology Service, University Hospital Marques de Valdecilla, Instituto de Formación e Investigación Marqués de Valdecilla (IFIMAV), Santander, Spain
| | - M J Paniagua
- Heart Failure and Cardiac Transplantation Unit, Cardiology Service, University Hospital de La Coruña, La Coruña, Spain
| | - M Gomez-Bueno
- Heart Failure and Cardiac Transplantation Unit, Cardiology Service, University Hospital Puerta de Hierro, Majadahonda, Madrid, Spain
| | - J M Arizon
- Heart Failure and Cardiac Transplantation Unit, Cardiology Service, University Hospital Reina Sofia, Cordoba, Spain
| | - L Almenar
- Heart Failure and Cardiac Transplantation Unit, Cardiology Service, University Hospital La Fe, Valencia, Spain
| | - E Roig
- Heart Failure and Cardiac Transplantation Unit, Cardiology Service, University Hospital Santa Creu i Sant Pau, Barcelona, Spain
| | - J Delgado
- Heart Failure and Cardiac Transplantation Unit, Cardiology Service, University Hospital 12 de Octubre, Madrid, Spain
| | - J L Lambert
- Heart Failure and Cardiac Transplantation Unit, Cardiology Service, University Hospital Central de Asturias, Oviedo, Spain
| | - F Perez-Villa
- Heart Failure and Cardiac Transplantation Unit, Cardiology Service, University Hospital Clinic de Barcelona, Barcelona, Spain
| | - M L Sanz-Julve
- Heart Failure and Cardiac Transplantation Unit, Cardiology Service, University Hospital Miguel Servet, Zaragoza, Spain
| | - M Crespo-Leiro
- Heart Failure and Cardiac Transplantation Unit, Cardiology Service, University Hospital de La Coruña, La Coruña, Spain
| | - J Segovia
- Heart Failure and Cardiac Transplantation Unit, Cardiology Service, University Hospital Puerta de Hierro, Majadahonda, Madrid, Spain
| | - A Lopez-Granados
- Heart Failure and Cardiac Transplantation Unit, Cardiology Service, University Hospital Reina Sofia, Cordoba, Spain
| | - L Martinez-Dolz
- Heart Failure and Cardiac Transplantation Unit, Cardiology Service, University Hospital La Fe, Valencia, Spain
| | - S Mirabet
- Heart Failure and Cardiac Transplantation Unit, Cardiology Service, University Hospital Santa Creu i Sant Pau, Barcelona, Spain
| | - P Escribano
- Heart Failure and Cardiac Transplantation Unit, Cardiology Service, University Hospital 12 de Octubre, Madrid, Spain
| | - B Diaz-Molina
- Heart Failure and Cardiac Transplantation Unit, Cardiology Service, University Hospital Central de Asturias, Oviedo, Spain
| | - M Farrero
- Heart Failure and Cardiac Transplantation Unit, Cardiology Service, University Hospital Clinic de Barcelona, Barcelona, Spain
| | - T Blasco
- Heart Failure and Cardiac Transplantation Unit, Cardiology Service, University Hospital Miguel Servet, Zaragoza, Spain
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González-Vílchez F, Vázquez de Prada JA, Paniagua MJ, Almenar L, Mirabet S, Gómez-Bueno M, Díaz-Molina B, Arizón JM, Delgado J, Pérez-Villa F, Crespo-Leiro MG, Martínez-Dolz L, Roig E, Segovia J, Lambert JL, Lopez-Granados A, Escribano P, Farrero M. Rejection after conversion to a proliferation signal inhibitor in chronic heart transplantation. Clin Transplant 2013; 27:E649-58. [PMID: 24025040 DOI: 10.1111/ctr.12241] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/06/2013] [Indexed: 01/10/2023]
Abstract
We sought to determine the incidence, risk factors, and consequences of acute rejection (AR) after conversion from a calcineurin inhibitor (CNI) to a proliferation signal inhibitor (PSI) in maintenance heart transplantation. Relevant clinical data were retrospectively obtained for 284 long-term heart transplant recipients from nine centers in whom CNIs were replaced with a PSI (sirolimus or everolimus) between October 2001 and March 2009. The rejection rate at one yr was 8.3%, stabilizing to 2% per year thereafter. The incidence rate after conversion (4.9 per 100 patient-years) was significantly higher than that observed on CNI therapy in the pre-conversion period (2.2 per 100 patient-years). By multivariate analysis, rejection risk was associated with a history of late AR prior to PSI conversion, early conversion (<5 yr) after transplantation and age <50 yr at the time of conversion. Use of mycophenolate mofetil was a protective factor. Post-conversion rejection did not significantly influence the evolution of left ventricular ejection fraction, renal function, or mortality during further follow-up. Conversion to a CNI-free immunosuppression based on a PSI results in an increased risk of AR. Awareness of the clinical determinants of post-conversion rejection could help to refine the current PSI conversion strategies.
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Affiliation(s)
- Francisco González-Vílchez
- Heart Failure and Cardiac Transplantation Unit, Cardiology Service, Instituto de Formación e Investigación Marqués de Valdecilla (IFIMAV), University Hospital Marques de Valdecilla, Santander, Spain
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Everolimus therapy is associated with reduced lipoprotein-associated phospholipase A2 (Lp-Pla2) activity and oxidative stress in heart transplant recipients. Atherosclerosis 2013; 230:164-70. [PMID: 23958269 DOI: 10.1016/j.atherosclerosis.2013.07.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2013] [Revised: 07/05/2013] [Accepted: 07/10/2013] [Indexed: 11/21/2022]
Abstract
BACKGROUND Several studies demonstrated decreased severity and incidence of cardiac allograft vasculopathy (CAV) in heart transplant recipients receiving immunosuppressive therapy with everolimus. However, data regarding the influence of everolimus on risk factors predisposing to CAV are hitherto limited. We here systematically evaluated cardiovascular risk factors in heart transplanted patients, who underwent conversion to everolimus or were maintained on conventional therapy with calcineurin inhibitors (CNI). METHODS 50 Patients receiving everolimus and 91 patients receiving CNI in addition to mycophenolate mofetil and low-dosed steroids were included in the study. CAV risk factors were determined in plasma or urine using standard enzymatic or immunochemical methods. RESULTS No significant differences were observed between both groups with regard to lipid (total, LDL- and HDL-cholesterol), metabolic (glucose, insulin), inflammatory (C-reactive protein, IL-6, myeloperoxidase) and cardiac (troponin I, NT-proBNP) risk factors. However, significantly lower activity of lipoprotein-associated phospholipase A2 (Lp-PLA2) and a negative correlation between the Lp-PLA2 activity and the everolimus concentration were observed in plasmas from everolimus-treated patients. Conversion to everolimus significantly lowered Lp-PLA2 activity in heart transplant recipients. Studies in vitro revealed reduced Lp-PLA2 expression in hepatocytes and macrophages pre-exposed to everolimus. In addition, reduced plasma markers of oxidative stress including oxidized LDL, 8-iso-prostaglandin F2α and protein carbonyls were noted in heart transplant recipients receiving everolimus therapy. CONCLUSION Our results suggest that everolimus specifically lowers plasma activity and cellular production of Lp-PLA2 and thereby dampens oxidative stress. These effects may additionally contribute to the reduced CAV incidence observed in heart transplant recipients receiving everolimus therapy.
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Current strategies and future trends in immunosuppression after heart transplantation. Curr Opin Organ Transplant 2013; 17:540-5. [PMID: 22941325 DOI: 10.1097/mot.0b013e328358000c] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW Current immunosuppressive drugs have provided excellent outcomes after heart transplantation. However, more patients suffer from long-term complications of these drugs. A series of prospective randomized trials has been conducted and has offered disparate results. This report reviews the challenges of immunosuppressive therapy during the past decade, describes recent reports and explores potential future trends in immunosuppressive protocols in heart transplantation. RECENT FINDINGS The traditional combination of cyclosporine, azathioprine and steroids has been changed to tacrolimus (Tac) or cyclosporine in combination with mycophenolate mofetil (MMF) and steroids due to the results of several trials. The use of mammalian target of rapamycin inhibitors in combination with Tac or cyclosporine A has not shown a clear benefit compared with MMF. All different combinations have shown some positive effects counteracted by side-effects and negative synergism of combinations. Future protocols need to be adapted according to individual patient's needs and risks. SUMMARY The changing population of heart transplantation patients has become older and sicker. Immunosuppression strategies should be developed for each patient based on their risk for rejection and their risk for developing important complications of immunosuppressive therapy.
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Efficacy and safety of low-dose everolimus as maintenance immunosuppression in cardiac transplant recipients. J Transplant 2012; 2012:976921. [PMID: 22577516 PMCID: PMC3345239 DOI: 10.1155/2012/976921] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2011] [Accepted: 02/14/2012] [Indexed: 01/14/2023] Open
Abstract
For cardiac transplant (CTx) recipients, the recommended everolimus (EVL) dose is 0.75 mg bid or 1.5 mg bid and the target trough blood level is 3–8 μg/L. We studied a cohort of 56 CTx patients with chronic kidney disease receiving 0.75 mg bid EVL to maintain blood levels of 5–8 ug/L (designated RD group) and a cohort of 51 CTx patients with chronic kidney disease receiving 0.5 mg bid to maintain blood levels of 3–5 ug/L (designated LD group). The primary endpoint was a composite of death, rejection and premature EVL discontinuation up to 1 year after introduction of EVL. The primary endpoint was reached by 32% of patients in the LD group and by 41.1% of patients in the RD group (P = 0.361). Biochemical safety parameters were comparable in both groups. Our results indicate that low-dose EVL may be as effective and safe as regular dose EVL.
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Gonzalez-Vilchez F, Vazquez de Prada JA, Almenar L, Arizon del Prado JM, Mirabet S, Diaz-Molina B, Delgado JF, Gomez-Bueno M, Paniagua MJ, Perez-Villa F, Roig E, Martínez-Dolz L, Brossa V, Lambert JL, Segovia J, Crespo-Leiro MG, Ruiz-Cano MJ. Withdrawal of proliferation signal inhibitors due to adverse events in the maintenance phase of heart transplantation. J Heart Lung Transplant 2012; 31:288-95. [DOI: 10.1016/j.healun.2011.10.011] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2011] [Revised: 10/14/2011] [Accepted: 10/19/2011] [Indexed: 01/09/2023] Open
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