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Khullar D, Panigrahi DK, Bagai S, Abhishek, Singh K, Gandhi KR, Prasad P, Grover R, Chhabra G, Singh NP, Gupta AK. Comparative Efficacy and Safety of Low-Dose Versus Standard-Dose Rabbit Antithymocyte Globulin Induction Strategy in Kidney Transplant Recipients: Insights From a Single-Center Experience in North India. Cureus 2024; 16:e69770. [PMID: 39435237 PMCID: PMC11493324 DOI: 10.7759/cureus.69770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/17/2024] [Indexed: 10/23/2024] Open
Abstract
Background Rabbit antithymocyte globulin (rATG) is frequently utilized as an induction therapy in kidney transplant recipients (KTRs). Full-dose rATG induction therapy (7-10 mg/kg) has been associated with increased morbidity. However, definitive data on the appropriate rATG dosage remains scarce. In this study, we evaluated the efficacy and tolerability of varying rATG doses in KTRs. Methodology A single-center, retrospective, observational study was conducted between 2009 and 2014 in a cohort of 208 KTRs who received rATG induction therapy. Patients included in the study had received two to three consecutive doses of rATG as part of their planned induction protocol. Participants were categorized into the following two groups based on the cumulative dosage of rATG received during induction therapy: group A received 2 or 2.5 mg/kg, while group B received ≥3 mg/kg. The five-year follow-up data were analyzed. Results A cumulative rATG dose of 2 or 2.5 mg/kg and ≥3 mg/kg was given to 122 and 86 patients, respectively. The incidence of delayed graft function (DGF), acute rejection episodes, total graft loss, death, and death-censored graft loss was 6.25%, 3.84%, 7.21%, 4.32%, and 2.88%, respectively. Two malignancies and 141 infectious complications were noted. There was no significant difference between the groups regarding DGF, total graft loss, death, death-censored graft loss, infectious complications, and incidence of acute rejection episodes. Deceased donor kidney transplantation was identified as a significant predictor of acute rejection episodes (odds ratio = 9.19, 95% confidence interval = 1.567-53.907; p = 0.014). Conclusions The dosage for rATG induction therapy for KTRs should be tailored based on immunological and other factors impacting graft survival, along with a comprehensive risk assessment for potential infectious complications. A cumulative dose of 2.0 or 2.5 mg/kg could be optimal, offering effective induction therapy in KTRs with excellent graft survival rates and potentially fewer infectious complications.
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Affiliation(s)
- Dinesh Khullar
- Nephrology, Max Super Speciality Hospital, Saket, New Delhi, IND
| | | | - Sahil Bagai
- Nephrology, Max Super Speciality Hospital, Saket, New Delhi, IND
| | - Abhishek
- Nephrology, Max Super Speciality Hospital, Saket, New Delhi, IND
| | - Kulwant Singh
- Nephrology, Max Super Speciality Hospital, Saket, New Delhi, IND
| | | | - Pallavi Prasad
- Nephrology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, IND
| | - Rahul Grover
- Nephrology, Max Super Speciality Hospital, Saket, New Delhi, IND
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Acharya S, Lama S, Kanigicherla DA. Anti-thymocyte globulin for treatment of T-cell-mediated allograft rejection. World J Transplant 2023; 13:299-308. [PMID: 38174145 PMCID: PMC10758678 DOI: 10.5500/wjt.v13.i6.299] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 11/01/2023] [Accepted: 11/17/2023] [Indexed: 12/15/2023] Open
Abstract
Anti-thymocyte globulin (ATG) is a pivotal immunosuppressive therapy utilized in the management of T-cell-mediated rejection and steroid-resistant rejection among renal transplant recipients. Commercially available as Thymoglobulin (rabbit-derived, Sanofi, United States), ATG-Fresenius S (rabbit-derived), and ATGAM (equine-derived, Pfizer, United States), these formulations share a common mechanism of action centered on their interaction with cell surface markers of immune cells, imparting immunosuppressive effects. Although the prevailing mechanism predominantly involves T-cell depletion via the com plement-mediated pathway, alternate mechanisms have been elucidated. Optimal dosing and treatment duration of ATG have exhibited variance across ran domised trials and clinical reports, rendering the establishment of standardized guidelines a challenge. The spectrum of risks associated with ATG administration spans from transient adverse effects such as fever, chills, and skin rash in the acute phase to long-term concerns related to immunosuppression, including susceptibility to infections and malignancies. This comprehensive review aims to provide a thorough exploration of the current understanding of ATG, encom passing its mechanism of action, clinical utility in the treatment of acute renal graft rejections, specifically steroid-resistant cases, efficacy in rejection episode reversal, and a synthesis of findings from different eras of maintenance immunosuppression. Additionally, it delves into the adverse effects associated with ATG therapy and its impact on long-term graft function. Furthermore, the review underscores the existing gaps in evidence, particularly in the context of the Banff classification of rejections, and highlights the challenges faced by clinicians when navigating the available literature to strike the optimal balance between the risks and benefits of ATG utilization in renal transplantation.
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Affiliation(s)
- Sumit Acharya
- Department of Nephrology, Shahid Dharmabhakta National Transplant Center, Bhaktapur 44800, Nepal
| | - Suraj Lama
- Department of Nephrology, Shahid Dharmabhakta National Transplant Center, Bhaktapur 44800, Nepal
| | - Durga Anil Kanigicherla
- Department of Renal Medicine, Manchester University NHS Foundation Trust, Manchester M13 9WL, United Kingdom
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The Effects of Different Induction Regimes on Serial Lymphocyte Subsets in Kidney Transplant Recipients: A Single Tertiary Center Experience. Transplant Proc 2022; 54:299-306. [PMID: 35181166 DOI: 10.1016/j.transproceed.2022.01.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 01/04/2022] [Accepted: 01/06/2022] [Indexed: 01/19/2023]
Abstract
BACKGROUND Immunosuppressive therapy is the backbone of kidney transplantation in preventing acute rejection. T-cell depletion after doses of thymoglobulin is dose-dependent, as are their side effects. At the same time, basiliximab and other maintenance immunosuppressive drugs act at different signals on T lymphocytes. Therefore, studying the pattern of lymphocyte subset depletion depending on the induction regime given at transplantation could be an added tool in managing post-transplant recipients. METHODOLOGY This prospective observational study recruited kidney transplant recipients from August 2019 through April 2021 at the University of Malaya Medical Centre. Blood tests for lymphocyte subsets were taken at pre-transplant, 1 week, 1 month, 3 months, and 6 months post-transplantation. At transplantation, recipients received either basiliximab, low-dose thymoglobulin (cumulative dose: 1.5 mg/kg), or standard-dose thymoglobulin (cumulative dose: 5 mg/kg). RESULTS A total of 39 patients were recruited: 38.5% received basiliximab (15 of 39), 15.4% received low-dose thymoglobulin (6 of 39), and 46.2% received standard-dose thymoglobulin (18 of 39). Absolute lymphocyte counts 1 week post-transplantation were 1.5 ± 0.84 × 109/L for basiliximab, 0.7 ± 0.57 × 109/L for low-dose thymoglobulin, and 0.1 ± 0.08 × 109/L for standard-dose thymoglobulin (P < .001). The CD4+ and CD8+ counts were severely depleted in the standard-dose thymoglobulin group, with a statistically significant differenceup to 6 months post-transplantation. In the low-dose thymoglobulin group, the CD4+ and CD8+ counts were depleted at 1 week post-transplantation and recovered at 1 month post-transplantation. There was no difference in allograft function and incidence of allograft rejection across groups. CONCLUSIONS The effects on lymphocyte counts, CD4+ and CD8+, vary depending on the type and dose of induction immunosuppression. This could be a guiding tool in managing immunosuppression post-transplantation depending on the patient's immunologic risk.
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Mohammadi K, Khajeh B, Dashti-Khavidaki S, Shab-Bidar S. Association between cumulative rATG induction doses and kidney graft outcomes and adverse effects in kidney transplant patients: a systematic review and meta-analysis. Expert Opin Biol Ther 2021; 21:1265-1279. [PMID: 34304664 DOI: 10.1080/14712598.2021.1960978] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
BACKGROUND This systematic review and meta-analysis were performed to explore the association between rabbit thymoglobulin (rATG) doses and transplant-related efficacy and safety outcomes. METHODS We searched PubMed and Scopus databases from inception up to June 2020. The primary efficacy and safety endpoints in kidney transplant recipients were evaluated. RESULTS Data of 23 cohort studies (3457 patients) and three RCTs (154 patients) were extracted and analyzed. rATG doses of ≤4.5 m/kg was associated with lower rates of biopsy proven acute rejection, cytomegalovirus infection, BK virus infection, and malignancy with a comparable rate of delayed graft function, patients' mortality, and death-censored graft loss compared to rATG total doses of 4.5-6 mg/kg or more than 6 mg/kg. The rATG doses of 3-4.5 mg/kg was associated with better outcomes in dose-response analysis. EXPERT OPINION Cumulative rATG induction doses as much as 3-4.5 mg/kg is as effective as higher doses regarding to allograft and patient outcomes while minimizing potential adverse effects in kidney transplant recipients.
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Affiliation(s)
- Keyhan Mohammadi
- Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Behrouz Khajeh
- Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Sakineh Shab-Bidar
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
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McKay SL, Guo A, Pergam SA, Dooling K. Herpes Zoster Risk in Immunocompromised Adults in the United States: A Systematic Review. Clin Infect Dis 2021; 71:e125-e134. [PMID: 31677266 DOI: 10.1093/cid/ciz1090] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 10/31/2019] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND The primary reported risk factors for herpes zoster (HZ) include increasing age and immunodeficiency, yet estimates of HZ risk by immunocompromising condition have not been well characterized. We undertook a systematic literature review to estimate the HZ risk in immunocompromised patients. METHODS We systematically reviewed studies that examined the risk of HZ and associated complications in adult patients with hematopoietic cell transplants (HCT), cancer, human immunodeficiency virus (HIV), and solid organ transplant (SOT). We identified studies in PubMed, Embase, Medline, Cochrane, Scopus, and clinicaltrials.gov that presented original data from the United States and were published after 1992. We assessed the risk of bias with Cochrane or Grading of Recommendations Assessment, Development, and Evaluation methods. RESULTS We identified and screened 3765 records and synthesized 34 studies with low or moderate risks of bias. Most studies that were included (32/34) reported at least 1 estimate of the HZ cumulative incidence (range, 0-41%). There were 12 studies that reported HZ incidences that varied widely within and between immunocompromised populations. Incidence estimates ranged from 9 to 92 HZ cases/1000 patient-years and were highest in HCT, followed by hematologic malignancies, SOT, and solid tumor malignancies, and were lowest in people living with HIV. Among 17 HCT studies, the absence of or use of antiviral prophylaxis at <1 year post-transplant was associated with a higher HZ incidence. CONCLUSIONS HZ was common among all immunocompromised populations studied, exceeding the expected HZ incidence among immunocompetent adults aged ≥60 years. Better evidence of the incidence of HZ complications and their severity in immunocompromised populations is needed to inform economic and HZ vaccine policies.
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Affiliation(s)
- Susannah L McKay
- Epidemic Intelligence Service, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.,Division of Viral Diseases, National Center Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Angela Guo
- Division of Viral Diseases, National Center Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Steven A Pergam
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington, USA.,Infection Prevention, Seattle Cancer Care Alliance, Seattle, Washington, USA
| | - Kathleen Dooling
- Division of Viral Diseases, National Center Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
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Camilleri B, Pararajasingam R, Buttigieg J, Halawa A. Immunosuppression strategies in elderly renal transplant recipients. Transplant Rev (Orlando) 2020; 34:100529. [DOI: 10.1016/j.trre.2020.100529] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 11/09/2019] [Accepted: 12/18/2019] [Indexed: 01/23/2023]
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Pham C, Kuten SA, Knight RJ, Nguyen DT, Graviss EA, Gaber AO. Assessment of infectious complications in elderly kidney transplant recipients receiving induction with anti-thymocyte globulin vs basiliximab. Transpl Infect Dis 2020; 22:e13257. [PMID: 32031729 DOI: 10.1111/tid.13257] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 12/27/2019] [Accepted: 01/26/2020] [Indexed: 11/27/2022]
Abstract
BACKGROUND Elderly transplant recipients experience lower rates of acute rejection with higher rates of infectious complications compared to their younger counterparts. While less intensive immunosuppression may be preferable, there are no recommendations for depleting versus non-depleting induction strategies. We sought to compare infectious complications between anti-thymocyte globulin (ATG) and basiliximab (IL2RA) induction in elderly kidney transplant recipients (KTRs). METHODS We reviewed 146 KTRs ≥65 years receiving ATG or IL2RA induction. Per institution protocol, ATG was administered to patients with the following characteristics, irrespective of age: African American (AA), PRA ≥20%, and/or re-transplantation. Infectious complications (bacterial, viral, and invasive fungal) at 1 year were compared. RESULTS There were significantly more AA, deceased donors, and sensitized KTRs in the ATG group, reflecting criteria for induction agent. ATG KTRs experienced higher rates of overall infectious complications (77% vs 56%, P = .01), driven by increased bacterial (54% vs 39%, P = .08) and viral infections (51% vs 35%, P = .05). Urinary tract infections (UTIs) and CMV in particular occurred at high rates among ATG patients (46% and 32%, respectively). In multivariate analysis, the only independent risk factor associated with increased risk for infection was induction with ATG (adjusted HR 1.71 [95% CI 1.04-2.83], P = .04). Overall rates of immunologic outcomes were low. CONCLUSION Elderly KTRs receiving ATG are at an increased risk for infectious complications, largely attributed to high rates of UTIs and CMV. Additional strategies aimed at mitigating these complications in elderly patients requiring ATG may be beneficial.
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Affiliation(s)
- Christine Pham
- Department of Pharmacy, Houston Methodist Hospital, Houston, Texas
| | - Samantha A Kuten
- Department of Pharmacy, Houston Methodist Hospital, Houston, Texas
| | - Richard J Knight
- Department of Surgery, Houston Methodist Hospital, Houston, Texas
| | - Duc T Nguyen
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas
| | - Edward A Graviss
- Department of Surgery, Houston Methodist Hospital, Houston, Texas.,Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas
| | - A Osama Gaber
- Department of Surgery, Houston Methodist Hospital, Houston, Texas
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8
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Liu HY, Cheng YT, Luo HL, Huang CC, Chen CH, Shen YC, Lee WC. Modest dose anti-thymocyte globulin administered intraoperatively is safe and effective in kidney transplantations: a retrospective study. PeerJ 2019; 7:e7274. [PMID: 31440428 PMCID: PMC6699478 DOI: 10.7717/peerj.7274] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 06/10/2019] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND Anti-thymocyte globulin (ATG) as induction therapy in renal transplantation is facing the dilemma of reducing the incidence of acute rejection (AR) and delayed graft function (DGF) or increasing risks of infection and malignancy. The purpose of this study was to delineate the safety and efficiency of the optimal ATG dosage. METHODS We retrospectively evaluated 91 deceased donor kidney transplant recipients (KTRs) in our institution between March 2011 and January 2019. The patients were classified into three groups based on induction therapy: (1) Group 1: modest-dose ATG (three mg/kg) intraoperatively (N = 21); (2) Group 2: low-dose ATG (1-1.5 mg/kg) intraoperatively (N = 23); (3) Group 3: basiliximab 20 mg both on day 0 and 4 (N = 47). In Groups 1 and 2, all patients received a daily low-dose program (1-1.5 mg/kg each day) with target dosage of six mg/kg. Induction therapy was combined with standard immunosuppressive regimen consisting of calcineurin inhibitors, mycophenolate/the mammalian target of rapamycin inhibitors and corticosteroids. RESULTS There was no significant difference in patient characteristics among groups. The outcomes of infection rate, biopsy-proven acute rejection, post-transplant diabetes mellitus, graft survival, and patient survival were similar among groups. Compared to the daily low-dose ATG regimen, the intraoperative modest-dose regimen did not cause more dose interruption and hence was more likely to reach the target ATG dosage. The intraoperative modest-dose regimen also seemed to reduce the rate of DGF. DISCUSSION In recent years, a trend of using a "lower" dose of ATG has seemed to emerge. Our results suggest intraoperative modest-dose ATG followed by daily low-dose ATG regimen was safe and effective in cadaveric renal transplantations for preventing DGF, AR, and graft loss.
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Affiliation(s)
- Hui-Ying Liu
- Department of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yuan-Tso Cheng
- Department of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hao Lun Luo
- Department of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chiang-Chi Huang
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chien Hsu Chen
- Department of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yuan-Chi Shen
- Department of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Wen-Chin Lee
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Hemmersbach-Miller M, Wolfe CR, Schmader KE. Solid organ transplantation in older adults. Infectious and other age-related considerations. ACTA ACUST UNITED AC 2019; 3. [PMID: 34113803 PMCID: PMC8189398 DOI: 10.21926/obm.transplant.1901046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
In the U.S., older adults aged 65 or above comprise nearly one quarter of the solid organ transplant (SOT) waitlists, and the number of transplants performed in this age group continues to increase. There are no specific guidelines for the assessment and follow up of the older SOT candidate or recipient. Older adults are at increased risk of infectious complications after SOT. Despite these complications and even with the use of suboptimal donors, overall outcomes are favorable. We provide an overview to specific consideration as they relate to the older SOT candidate and recipient.
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Affiliation(s)
- Marion Hemmersbach-Miller
- Division of Infectious Diseases, Duke University Medical Center, Durham NC, USA.,Duke Clinical Research Institute, Durham NC, USA
| | - Cameron R Wolfe
- Division of Infectious Diseases, Duke University Medical Center, Durham NC, USA
| | - Kenneth E Schmader
- Division of Geriatrics, Duke University Medical Center, Durham NC, USA.,GRECC, Durham VA, Durham NC. USA
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10
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[Focusing on kidney transplantation in the elderly]. Nephrol Ther 2017; 14:71-80. [PMID: 29173815 DOI: 10.1016/j.nephro.2017.06.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 06/14/2017] [Accepted: 06/25/2017] [Indexed: 02/06/2023]
Abstract
Due to the increase in life expectancy and the ageing of end-stage renal disease patients, the number of patients older than 65 years receiving a kidney transplant has been continuously growing over the last fifteen years. The benefits of renal transplantation compared to dialysis in terms of survival and quality of life have been shown in selected recipients over 65, or 70 years. However, the age remains the main limiting factor for the access to the waiting list, and the reluctance of the clinicians can be explained by the multiple comorbidities of these candidates, their limited life expectancy or the shortage of grafts. The challenge is to select the candidates who can benefit from renal transplantation, thanks to rigorous cardiovascular and neoplastic evaluation before enrolment and by taking into account the specific characteristics of elderly patients. The living donor appears to be the ideal option for elderly recipients, the alternative being the extended criteria donor, allowing waiting times to be limited. The choice of immunosuppressive therapy is also crucial in these patients at high risk of infectious and cardiovascular complications in whom the occurrence of acute rejection can have severe consequences. There are currently no specific recommendations for immunosuppression in elderly recipients, and we would need large-scale randomized studies to improve the prognosis of renal transplantation in this population.
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A Proposal for Early Dosing Regimens in Heart Transplant Patients Receiving Thymoglobulin and Calcineurin Inhibition. Transplant Direct 2016; 2:e81. [PMID: 27500271 PMCID: PMC4946520 DOI: 10.1097/txd.0000000000000594] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Accepted: 04/10/2016] [Indexed: 12/19/2022] Open
Abstract
There is currently no consensus regarding the dose or duration of rabbit antithymocyte globulin (rATG) induction in different types of heart transplant patients, or the timing and intensity of initial calcineurin inhibitor (CNI) therapy in rATG-treated individuals. Based on limited data and personal experience, the authors propose an approach to rATG dosing and initial CNI administration. Usually rATG is initiated immediately after exclusion of primary graft failure, although intraoperative initiation may be appropriate in specific cases. A total rATG dose of 4.5 to 7.5 mg/kg is advisable, tailored within that range according to immunologic risk and adjusted according to immune monitoring. Lower doses (eg, 3.0 mg/kg) of rATG can be used in patients at low immunological risk, or 1.5 to 2.5 mg/kg for patients with infection on mechanical circulatory support. The timing of CNI introduction is dictated by renal recovery, varying between day 3 and day 0 after heart transplantation, and the initial target exposure is influenced by immunological risk and presence of infection. Rabbit antithymocyte globulin and CNI dosing should not overlap except in high-risk cases. There is a clear need for more studies to define the optimal dosing regimens for rATG and early CNI exposure according to risk profile in heart transplantation.
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12
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Kim Y, Kang SS, Park WY, Jin K, Park SB, Park UJ, Kim HT, Han S. Optimal Dose of Thymoglobulin for Induction Therapy in High Risk Kidney Transplant Recipients. ACTA ACUST UNITED AC 2016. [DOI: 10.4285/jkstn.2016.30.2.82] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Affiliation(s)
- Yaerim Kim
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
- Department of Internal Medicine, Keimyung University Kidney Institute, Daegu, Korea
| | - Seong Sik Kang
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
- Department of Internal Medicine, Keimyung University Kidney Institute, Daegu, Korea
| | - Woo Yeong Park
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
- Department of Internal Medicine, Keimyung University Kidney Institute, Daegu, Korea
| | - Kyubok Jin
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
- Department of Internal Medicine, Keimyung University Kidney Institute, Daegu, Korea
| | - Sung Bae Park
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
- Department of Internal Medicine, Keimyung University Kidney Institute, Daegu, Korea
| | - Ui Jun Park
- Department of Internal Medicine, Keimyung University Kidney Institute, Daegu, Korea
- Department of Surgery, Keimyung University School of Medicine, Daegu, Korea
| | - Hyoung Tae Kim
- Department of Internal Medicine, Keimyung University Kidney Institute, Daegu, Korea
- Department of Surgery, Keimyung University School of Medicine, Daegu, Korea
| | - Seungyeup Han
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
- Department of Internal Medicine, Keimyung University Kidney Institute, Daegu, Korea
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13
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Mohty M, Bacigalupo A, Saliba F, Zuckermann A, Morelon E, Lebranchu Y. New directions for rabbit antithymocyte globulin (Thymoglobulin(®)) in solid organ transplants, stem cell transplants and autoimmunity. Drugs 2015; 74:1605-34. [PMID: 25164240 PMCID: PMC4180909 DOI: 10.1007/s40265-014-0277-6] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In the 30 years since the rabbit antithymocyte globulin (rATG) Thymoglobulin® was first licensed, its use in solid organ transplantation and hematology has expanded progressively. Although the evidence base is incomplete, specific roles for rATG in organ transplant recipients using contemporary dosing strategies are now relatively well-identified. The addition of rATG induction to a standard triple or dual regimen reduces acute cellular rejection, and possibly humoral rejection. It is an appropriate first choice in patients with moderate or high immunological risk, and may be used in low-risk patients receiving a calcineurin inhibitor (CNI)-sparing regimen from time of transplant, or if early steroid withdrawal is planned. Kidney transplant patients at risk of delayed graft function may also benefit from the use of rATG to facilitate delayed CNI introduction. In hematopoietic stem cell transplantation, rATG has become an important component of conventional myeloablative conditioning regimens, following demonstration of reduced acute and chronic graft-versus-host disease. More recently, a role for rATG has also been established in reduced-intensity conditioning regimens. In autoimmunity, rATG contributes to the treatment of severe aplastic anemia, and has been incorporated in autograft projects for the management of conditions such as multiple sclerosis, Crohn’s disease, and systemic sclerosis. Finally, research is underway for the induction of tolerance exploiting the ability of rATG to induce immunosuppresive cells such as regulatory T-cells. Despite its long history, rATG remains a key component of the immunosuppressive armamentarium, and its complex immunological properties indicate that its use will expand to a wider range of disease conditions in the future.
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Affiliation(s)
- Mohamad Mohty
- Department of Hematology and Cellular Therapy, CHU Hôpital Saint Antoine, 184, rue du Faubourg Saint Antoine, 75571, Paris Cedex 12, France,
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14
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Shi YY, Hesselink DA, van Gelder T. Pharmacokinetics and pharmacodynamics of immunosuppressive drugs in elderly kidney transplant recipients. Transplant Rev (Orlando) 2015; 29:224-30. [PMID: 26048322 DOI: 10.1016/j.trre.2015.04.007] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Revised: 04/29/2015] [Accepted: 04/30/2015] [Indexed: 02/05/2023]
Abstract
Elderly patients are a fast growing population among transplant recipients over the past decades. Both the innate and adaptive immune reactivity decrease with age, which is believed to contribute to the decreased incidence of acute rejection and increased infectious death rate in elderly transplant recipients. In contrast to recipient age, donor age is associated with a higher incidence of acute rejection. Pharmacokinetic studies in renal transplant recipients show that CNI troughs are >5% higher in elderly compared to younger patients given the same dose normalized by body weight. This may impact the starting dose of tacrolimus and cyclosporine. Possibly in elderly patients the intracellular (in lymphocyte) concentrations are relatively high in relation to the whole blood concentration, resulting in a stronger pharmacodynamic effect at the same whole blood trough concentration. For cyclosporine this has been shown, but it is not clear if the same is true for other immunosuppressive drugs. Pharmacodynamic studies have compared the inhibition of target enzymes, or more downstream effects of immunosuppressive drugs, in younger and older patients. Measurement of nuclear factor of activated T-cell (NFAT)-regulated gene expression (RGE), a pharmacodynamic read-out of CNI, is a promising biomarker of immunosuppression. Low levels of NFAT RGE are associated with increased risk of infection and non-melanoma skin cancer in elderly patients. Clinical trials to evaluate the safety and efficacy of immunosuppression regimens in this specific patient population, which is underrepresented in published trials, are lacking. More studies in elderly patients are needed to investigate the impact of age on the pharmacokinetics or pharmacodynamics of immunosuppressive drugs, and to decide on the optimal regimen and target levels for elderly transplant recipients.
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Affiliation(s)
- Yun-Ying Shi
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Nephrology, West China Hospital of Sichuan University, Chengdu, China
| | - Dennis A Hesselink
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Teun van Gelder
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
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Chen GD, Lai XQ, Ko DSC, Qiu J, Wang CX, Han M, Li J, Huang G, He XS, Chen LZ. Comparison of efficacy and safety between rabbit anti-thymocyte globulin and anti-T lymphocyte globulin in kidney transplantation from donation after cardiac death: a retrospective cohort study. Nephrology (Carlton) 2015; 20:539-43. [PMID: 25808082 DOI: 10.1111/nep.12469] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/19/2015] [Indexed: 12/01/2022]
Abstract
AIM To compare the efficacy and safety between rabbit anti-thymocyte globulin (Thymoglobulin) and anti-T lymphocyte globulin (ATG-Fresenius, ATG-F) in donation after cardiac death (DCD) kidney transplantation. METHODS We retrospectively analyzed 255 cases of DCD kidney transplantation performed at our hospital from February 2007 to October 2013. The patients were divided into two groups based on their induction therapies with Thymoglobulin (n = 188) or ATG-F (n = 67). Clinical data were collected and compared between the two groups. RESULTS Delayed graft function (DGF) occurred in 36 (19.1%) patients in the Thymoglobulin group versus 17 (25.4%) patients in the ATG-F group (P = 0.281). However, if we subgroup the patients with increased risk factors for DGF, the DGF rate was 9/40 (22.5%) in the Thymoglobulin group versus 9/16 (56.3%) in the ATG-F group (P = 0.015). Duration of DGF was significantly shorter in the Thymoglobulin group (11.7 days vs. 16.1 days). The acute rejection rate was significantly lower in the Thymoglobulin group (9.6% vs. 19.4%, P = 0.035). One-year graft and patient survival were both comparable between the Thymoglobulin and ATG-F groups. The adjusted odds ratio of DGF was 4.283 (1.137-16.13) between the ATG-F and Thymoglobulin groups in patients with increased risk factors for DGF. CONCLUSION Compared with ATG-F, Thymoglobulin may reduce duration of DGF and acute rejection rate after DCD kidney transplantation. Moreover, Thymoglobulin significantly reduced DGF in patients with increased risk factors for DGF.
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Affiliation(s)
- Guo-Dong Chen
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Xing-Qiang Lai
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Dicken Shiu-Chung Ko
- Departments of Urology and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jiang Qiu
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Chang-Xi Wang
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Ming Han
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jun Li
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Gang Huang
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Xiao-Shun He
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Li-Zhong Chen
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
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16
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Laftavi MR, Sharma R, Feng L, Said M, Pankewycz O. Induction Therapy in Renal Transplant Recipients: A Review. Immunol Invest 2014; 43:790-806. [DOI: 10.3109/08820139.2014.914326] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Mourad G, Morelon E, Noël C, Glotz D, Lebranchu Y. The role of Thymoglobulin induction in kidney transplantation: an update. Clin Transplant 2013; 26:E450-64. [PMID: 23061755 DOI: 10.1111/ctr.12021] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The rabbit antithymocyte globulin Thymoglobulin first became available over 25 yr ago and is the most widely used lymphocyte-depleting preparation in solid organ transplantation. Thymoglobulin targets a wide range of T-cell surface antigens as well as natural killer-cell antigens, B-cell antigens, plasma cell antigens, adhesion molecules and chemokine receptors, resulting in profound, long-lasting T-cell depletion. Randomized studies have established the anti-rejection efficacy of Thymoglobulin in kidney transplantation. Experimental and clinical data suggest that Thymoglobulin administration may ameliorate ischemia reperfusion injury, thus reducing the incidence of delayed graft function (DGF). Studies have demonstrated the benefit of using Thymoglobulin to facilitate immunosuppression minimization, both for corticosteroid and calcineurin inhibitor (CNI) withdrawal or avoidance, with potential improvement in cardiovascular and renal outcomes. The optimal cumulative dose for Thymoglobulin induction is 6-7.5 mg/kg, with vigilant short- and long-term monitoring of hematological status. Induction with Thymoglobulin is now indicated in immunologically high-risk patients, in those at increased risk of DGF and to maintain efficacy in low-risk transplant recipients receiving steroid or CNI minimization or avoidance regimens. We suggest that in future trials Thymoglobulin be tested with costimulation signal blockers and other immunosuppressants with the objective of establishing operational tolerance.
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Affiliation(s)
- Georges Mourad
- Department of Nephrology and Transplantation, Hôpital Lapeyronie, University of Montpellier Medical School, Montpellier.
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18
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Khanmoradi K, Knorr JP, Feyssa EL, Parsikia A, Jawa P, Dinh DB, Campos S, Zaki RF, Ortiz JA. Evaluating safety and efficacy of rabbit antithymocyte globulin induction in elderly kidney transplant recipients. EXP CLIN TRANSPLANT 2013; 11:222-8. [PMID: 23432665 DOI: 10.6002/ect.2012.0211] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES The optimal immunosuppression regimen for elderly kidney transplant recipients is poorly defined. We sought to evaluate the short-term efficacy and safety of thymoglobulin in geriatric recipients of deceased-donor kidneys. MATERIALS AND METHODS A single-center, retrospective analysis was undertaken between elderly (≥ 65 years) (n=137) and nonelderly (n=276) kidney transplant recipients who received rabbit antithymocyte globulin induction and calcineurin inhibitor, mycophenolic acid, and prednisone maintenance. RESULTS The mean age was 70 versus 52 years. Fewer elderly patients had an earlier transplant or panel reactive antibodies > 20%, but had more machine perfused, older, and extended criteria donor kidneys. Elderly patients received lower rabbit antithymocyte globulin (5.4 vs 5.6 mg/kg; P = .04) and initial mycophenolic acid doses (1620 vs 1774 mg; P = .002), and experienced less delayed graft function (31.1% vs 50.0%; P < .001). Death-censored graft survival and graft function at 3 years and biopsy-proven acute rejection at 1 year were comparable; however, there was lower 3-year patient survival in elderly patients. Donor age was the only factor associated with reduced patient survival. Rates of malignancy, infection, or thrombocytopenia were similar; however, leukopenia occurred less frequently in elderly patients (11.7% vs 19.9%; P = .038). CONCLUSIONS Elderly kidney transplant recipients receiving rabbit antithymocyte globulin did not experience different short-term graft survival, graft function or rates of infection, malignancy or hematologic adverse reactions than did nonelderly patients; they experienced fewer episodes of delayed graft function, but had lower 3-year patient survival.
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Affiliation(s)
- Kamran Khanmoradi
- Department of Surgery, Einstein Medical Center, Philadelphia, PA, USA.
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Hurst FP, Altieri M, Nee R, Agodoa LY, Abbott KC, Jindal RM. Poor outcomes in elderly kidney transplant recipients receiving alemtuzumab induction. Am J Nephrol 2011; 34:534-41. [PMID: 22104284 DOI: 10.1159/000334092] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2011] [Accepted: 09/27/2011] [Indexed: 12/30/2022]
Abstract
INTRODUCTION Alemtuzumab and rabbit antithymocyte globulin (rATG) are being used with increasing frequency as induction agents in kidney transplantation. Using the US Renal Data Base System, we analyzed the safety profile of these agents in the elderly. METHODS In a cohort of patients transplanted from January 2000 to July 2009 and followed through 2009, we assessed the effect of induction on allograft loss and death among elderly recipients. Recipients were censored at dates of allograft loss, death or the end of study. Independent associations between induction agents and allograft loss or death were examined using multivariate analysis with forward stepwise Cox regression. RESULTS Among 130,402 patients with first transplants, 14,907 were age 65 years or older. 4,466 (30%), 3,049 (20.5%), 1,501 (10.1%), and 999 (6.7%) were induced with thymoglobulin, basiliximab, daclizumab, and alemtuzumab, respectively. After adjusting for baseline differences, induction with alemtuzumab was associated with an increased risk of graft loss and death, with an adjusted hazard ratio (AHR) of 1.26 (95% CI 1.08-1.48). Risk was also present at other age cutoffs [age >60 (AHR 1.16; 95% CI 1.03-1.31; p = 0.014), age >70 (AHR 1.43; 95% CI 1.13-1.81; p = 0.003) and age >75 (AHR 1.68; 95% CI 1.07-2.63; p = 0.024)]. CONCLUSIONS In the elderly, alemtuzumab is associated with an escalating risk of death and graft loss in recipients of kidney transplantations.
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Affiliation(s)
- Frank P Hurst
- Department of Nephrology, Walter Reed Army Medical Center, Washington, D.C., USA
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