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Inglis SS, Abbas M, Asleh R, Garmany A, Smith BH, Kushwaha S, Pereira N, Clavell AL, Villavicencio MA, Spencer PJ, Daly RC, Behfar A, Rosenbaum AN. Incidence and risk factors for rejection after conversion from calcineurin inhibitor to sirolimus-based immunosuppression in orthotopic heart transplant recipients. J Heart Lung Transplant 2024:S1053-2498(24)02027-8. [PMID: 39743050 DOI: 10.1016/j.healun.2024.12.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 12/11/2024] [Accepted: 12/14/2024] [Indexed: 01/04/2025] Open
Abstract
BACKGROUND Although recommended in International Society for Heart and Lung Transplantation (ISHLT) guidelines, transition to mammalian targets of rapamycin (mTOR) inhibitors in heart transplant recipients is not routinely performed, in part due to perceived risk of rejection. This study sought to evaluate the incidence and risk factors for biopsy-proven, clinically relevant rejection following conversion from calcineurin inhibitor (CNI) to sirolimus (SRL) immunosuppression. METHODS A single center retrospective study was conducted of all consecutive adult patients who underwent orthotopic heart transplantation (OHT) and CNI-free SRL conversion from January 1999 to January 2023. All post-OHT biopsy data were obtained and graded per ISHLT criteria (antibody-mediated rejection [pAMR] or acute cellular rejection [ACR]). The primary endpoint was early rejection, defined as grade 2R ACR, pAMR 1, or greater, within 6 months after conversion. RESULTS 317 patients (72% male, mean age 51.5 ± 12.6 years) were included. Median time to SRL conversion following OHT was 0.76 years (IQR 0.49, 1.42). Median time from conversion to rejection was 0.51 years (IQR 0.31, 1.05). 38 patients (12%) experienced early rejection. Following multivariate analysis, both timing to SRL conversion following OHT (OR 0.94 per month, 95% CI: 0.89-0.99, p-value = 0.0054) and age at transplantation (OR 0.96, 95% CI: 0.93-0.99, p-value = 0.0071) were independently associated with early rejection. Rejection following SRL conversion was not associated with increased risk of cardiac allograft vasculopathy (CAV) grade 2-3. CONCLUSIONS In a CNI-free SRL conversion protocol, both earlier SRL conversion following OHT and younger age at transplant are independently associated with early rejection, but rejection is not associated with a net increased risk of prognostically important CAV. Individualization of transition is necessary to mitigate risk, and these findings may aid in improvement of future conversion protocols.
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Affiliation(s)
- Sara S Inglis
- Van Cleve Cardiac Regenerative Medicine Program, Mayo Clinic, Rochester MN, 55905; Deparment of Cardiovascular Medicine, Mayo Clinic, Rochester MN, 55905
| | - Mohsin Abbas
- Van Cleve Cardiac Regenerative Medicine Program, Mayo Clinic, Rochester MN, 55905; Deparment of Cardiovascular Medicine, Mayo Clinic, Rochester MN, 55905
| | - Rabea Asleh
- Deparment of Cardiovascular Medicine, Mayo Clinic, Rochester MN, 55905
| | - Armin Garmany
- Graduate School of Biomedical Sciences, Alix School of Medicine, Medical Scientist Training Program, Mayo Clinic, Rochester MN, 55905
| | - Byron H Smith
- Department of Biostatistics, Mayo Clinic, Rochester, MN, 55905
| | - Sudhir Kushwaha
- Deparment of Cardiovascular Medicine, Mayo Clinic, Rochester MN, 55905
| | - Naveen Pereira
- Deparment of Cardiovascular Medicine, Mayo Clinic, Rochester MN, 55905
| | - Alfredo L Clavell
- Deparment of Cardiovascular Medicine, Mayo Clinic, Rochester MN, 55905
| | | | - Philip J Spencer
- Department of Cardiovascular Surgery, Mayo Clinic, Rochester MN, 55905
| | - Richard C Daly
- Department of Cardiovascular Surgery, Mayo Clinic, Rochester MN, 55905
| | - Atta Behfar
- Van Cleve Cardiac Regenerative Medicine Program, Mayo Clinic, Rochester MN, 55905; Deparment of Cardiovascular Medicine, Mayo Clinic, Rochester MN, 55905
| | - Andrew N Rosenbaum
- Van Cleve Cardiac Regenerative Medicine Program, Mayo Clinic, Rochester MN, 55905; Deparment of Cardiovascular Medicine, Mayo Clinic, Rochester MN, 55905.
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Velleca A, Shullo MA, Dhital K, Azeka E, Colvin M, DePasquale E, Farrero M, García-Guereta L, Jamero G, Khush K, Lavee J, Pouch S, Patel J, Michaud CJ, Shullo M, Schubert S, Angelini A, Carlos L, Mirabet S, Patel J, Pham M, Urschel S, Kim KH, Miyamoto S, Chih S, Daly K, Grossi P, Jennings D, Kim IC, Lim HS, Miller T, Potena L, Velleca A, Eisen H, Bellumkonda L, Danziger-Isakov L, Dobbels F, Harkess M, Kim D, Lyster H, Peled Y, Reinhardt Z. The International Society for Heart and Lung Transplantation (ISHLT) Guidelines for the Care of Heart Transplant Recipients. J Heart Lung Transplant 2022; 42:e1-e141. [PMID: 37080658 DOI: 10.1016/j.healun.2022.10.015] [Citation(s) in RCA: 223] [Impact Index Per Article: 74.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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Velleca A, Shullo MA, Dhital K, Azeka E, Colvin M, DePasquale E, Farrero M, García-Guereta L, Jamero G, Khush K, Lavee J, Pouch S, Patel J, Michaud CJ, Shullo M, Schubert S, Angelini A, Carlos L, Mirabet S, Patel J, Pham M, Urschel S, Kim KH, Miyamoto S, Chih S, Daly K, Grossi P, Jennings D, Kim IC, Lim HS, Miller T, Potena L, Velleca A, Eisen H, Bellumkonda L, Danziger-Isakov L, Dobbels F, Harkess M, Kim D, Lyster H, Peled Y, Reinhardt Z. The International Society for Heart and Lung Transplantation (ISHLT) Guidelines for the Care of Heart Transplant Recipients. J Heart Lung Transplant 2022. [DOI: 10.1016/j.healun.2022.09.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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Acquaro M, Scelsi L, Pellegrini C, Greco A, Klersy C, Guida S, Raineri C, Ghio S, Turco A, Cattadori B, D'Armini AM, Pelenghi S, Visconti LO. Long-Term Effects of the Replacement of Calcineurin Inhibitors With Everolimus and Mycophenolate in Patients With Calcineurin Inhibitor-Related Nephrotoxicity. Transplant Proc 2020; 52:836-842. [PMID: 32113691 DOI: 10.1016/j.transproceed.2020.01.030] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Accepted: 01/10/2020] [Indexed: 12/25/2022]
Abstract
BACKGROUND There is little evidence on the long-term effects of calcineurin inhibitor (CNI) withdrawal and substitution with everolimus and mycophenolate mofetil in maintenance therapy of patients who have received heart transplants and have concurrent CNI nephrotoxicity. Aims of this study were to evaluate the progression of renal dysfunction after discontinuation of CNIs and to monitor for major adverse events after therapy change. METHODS Data from 41 patients who underwent heart transplant and have different degrees of renal dysfunction (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2), without evidence of proteinuria, and in whom CNI therapy was replaced by everolimus, were analyzed. At the time of CNI withdrawal, clinical parameters, echocardiographic data, blood tests of renal function, and monitoring of adverse events were recorded. The median follow-up period was 5 years ± 28 months. RESULTS In 52% of patients, there was a clear improvement in renal function (10.5 mL/min/1.73 m2 of extra eGFR on average). The former were characterized by less advanced age and a short time from the heart transplant. The echocardiographic parameters showed a significant reduction in septum thickness (11.58 ± 2 mm vs 10.29 ± 2 mm; P = .0001) and in left ventricle posterior wall thickness (10.74 ± 1 mm vs 9.74 ± 1 mm; P = .0004). The incidence of late acute rejection and cardiac allograft vasculopathy was similar in our population compared to literature data. CONCLUSIONS A therapeutic switch from CNIs to everolimus and mycophenolate mofetil can improve renal function in patients with CNI nephrotoxicity, especially in those with a shorter time period from transplantation, without exposing them to a higher incidence of late acute rejection and cardiac allograft vasculopathy.
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Affiliation(s)
- Mauro Acquaro
- Division of Cardiology, Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Laura Scelsi
- Division of Cardiology, Fondazione IRCCS San Matteo Hospital, Pavia, Italy.
| | - Carlo Pellegrini
- Division of Cardiac Surgery, Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Alessandra Greco
- Division of Cardiology, Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Catherine Klersy
- Division of Cardiology, Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Stefania Guida
- Division of Cardiology, Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Claudia Raineri
- Division of Cardiology, Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Stefano Ghio
- Division of Cardiology, Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Annalisa Turco
- Division of Cardiology, Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Barbara Cattadori
- Division of Cardiac Surgery, Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | | | - Stefano Pelenghi
- Division of Cardiac Surgery, Fondazione IRCCS San Matteo Hospital, Pavia, Italy
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Index of microvascular resistance after early conversion from calcineurin inhibitor to everolimus in heart transplantation: A sub-study to a 1-year randomized trial. J Heart Lung Transplant 2016; 35:1010-7. [DOI: 10.1016/j.healun.2016.03.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 02/13/2016] [Accepted: 03/11/2016] [Indexed: 11/21/2022] Open
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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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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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