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1
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Yen FS, Hsu CC, Yeh YK, Cheng WY, Liao PL, Hwu CM, Wei JCC. The impact of sodium-glucose cotransporter-2 inhibitors on dialysis risk and mortality in kidney transplant patients with diabetes. Am J Transplant 2025:S1600-6135(25)00148-0. [PMID: 40120646 DOI: 10.1016/j.ajt.2025.03.019] [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: 11/10/2024] [Revised: 03/14/2025] [Accepted: 03/17/2025] [Indexed: 03/25/2025]
Abstract
Kidney transplantation is the optimal treatment for end-stage kidney disease, but many patients also have diabetes mellitus. This study compares long-term outcomes between new users of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and dipeptidyl peptidase-4 inhibitors (DPP-4i) in kidney transplant recipients with diabetes mellitus. Data from the TriNetX Collaborative Network, including 89,710 patients with diabetes mellitus who underwent kidney transplantation between January 1, 2015, and June 30, 2023, were analyzed. From this cohort, 1410 matched pairs of SGLT2i and DPP-4i users were selected based on propensity scores. The results showed that SGLT2i users had a lower risk of dialysis (hazards ratio: 0.694) and all-cause mortality (hazards ratio: 0.687) compared with DPP-4i users. There were no significant differences in the risk of posttransplant infections, transplant rejection, or hospitalization between the 2 groups. Additionally, SGLT2i users had significantly lower cumulative incidences of dialysis and mortality. In conclusion, this study, using data from TriNetX, demonstrated that SGLT2i treatment in kidney transplant recipients with diabetes mellitus is associated with lower risks of dialysis and mortality, suggesting it may help preserve kidney function and improve survival in this population.
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Affiliation(s)
| | - Chih-Cheng Hsu
- Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Miaoli County, Taiwan; Department of Health Services Administration, China Medical University, Taichung, Taiwan; Department of Family Medicine, Min-Sheng General Hospital, Taoyuan, Taiwan; National Center for Geriatrics and Welfare Research, National Health Research Institutes, Huwei Township, Yunlin County, Taiwan
| | - Yun-Kai Yeh
- Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Beitou District, Taipei, Taiwan
| | - Wan-Yin Cheng
- Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Beitou District, Taipei, Taiwan
| | - Pei-Lun Liao
- Institute of Medicine, Chung Shan Medical University, South District, Taichung, Taiwan; Center for Health Data Science, Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chii-Min Hwu
- Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Beitou District, Taipei, Taiwan; Department of Medicine, National Yang-Ming Chiao Tung University School of Medicine, Taipei, Taiwan.
| | - James Cheng-Chung Wei
- Institute of Medicine, Chung Shan Medical University, South District, Taichung, Taiwan; Department of Allergy, Immunology and Rheumatology, Chung Shan Medical University Hospital, South District, Taichung City, Taiwan; Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan.
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2
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Bollano E, Andreassen AK, Eiskjaer H, Gustafsson F, Rådegran G, Gude E, Gullestad L, Broch K, Halden TAS, Karason K, Bartfay SE, Bergh N. Long-term follow-up of the randomized, prospective Scandinavian heart transplant everolimus de novo study with early calcineurin inhibitors avoidance (SCHEDULE) trial. J Heart Lung Transplant 2024; 43:1948-1959. [PMID: 39038562 DOI: 10.1016/j.healun.2024.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 05/08/2024] [Accepted: 07/03/2024] [Indexed: 07/24/2024] Open
Abstract
BACKGROUND Early substitution of calcineurin inhibitor (CNI) with mammalian target of rapamycin inhibitors has been shown to improve kidney function and reduce intimal hyperplasia in heart transplant (HTx) recipients but data on long-term outcome of such a regime are still sparse. METHODS In the SCHEDULE trial, 115 de novo HTx recipients were randomized to (1) everolimus with reduced exposure of CNI followed by CNI withdrawal at week 7-11 post-transplant or (2) standard-exposure with CNI. Both groups received mycophenolate mofetil and corticosteroids. Herein we report on the 10-12-year long-term follow-up of the study. RESULTS A total of 78 patients attended the follow-up visit at a median time of 11 years post-transplant. In the everolimus intention to treat (ITT) group 87.5% (35/40 patients) still received everolimus and in the CNI ITT group 86.8% (33/38) still received CNI. Estimated glomerular filtration rate (eGFR) (least square mean (95% CI)) at the 10-12 years visit was 82.7 (74.2-91.1) ml/min/1.73 m2 and 61.0 (52.3-69.7) ml/min/1.73 m2 in the everolimus and CNI group, respectively (p < 0.001). Graft function measured by ejection fraction, ECG, NT-proBNP and drug safety were comparable between groups. During the study period there was a total of 28 deaths, but there was no difference in survival between the everolimus and the CNI group (aHR 0.61 (95% CI 0.29-1.30) p = 0.20). For the composite endpoint of death, re-transplantation, myocardial infarction, PCI, dialysis, kidney transplantation or cancer no between group differences were found (aHR 1.0 (95% CI 0.57-1.77) p = 0.99). CONCLUSIONS De novo HTx patients randomized to everolimus and low dose CNI followed by CNI free therapy sustained significantly better long-term kidney function than patients randomized to standard therapy. The graft function at 10-12 years was similar in both groups and there was no difference in survival.
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Affiliation(s)
- Entela Bollano
- Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Transplantation, Sahlgrenska University Hospital, Gothenburg, Sweden; Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
| | - Arne K Andreassen
- Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Hans Eiskjaer
- Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
| | - Finn Gustafsson
- Department of Cardiology, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Göran Rådegran
- Section for Heart Failure and Valvular Disease, Skåne University Hospital and Department of Clinical Sciences, Cardiology, Lund University, Lund, Sweden
| | - Einar Gude
- Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Lars Gullestad
- Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway; KG Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Kaspar Broch
- Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway; KG Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | | | - Kristjan Karason
- Department of Transplantation, Sahlgrenska University Hospital, Gothenburg, Sweden; Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Sven-Erik Bartfay
- Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Transplantation, Sahlgrenska University Hospital, Gothenburg, Sweden; Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Niklas Bergh
- Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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Luo H, Wen J, Yang H, Ran Q, Hou Y. Allograft function predicts mortality in kidney transplant recipients with severe COVID-19: a paradoxical risk factor. Front Immunol 2024; 15:1335148. [PMID: 38415244 PMCID: PMC10896886 DOI: 10.3389/fimmu.2024.1335148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 01/29/2024] [Indexed: 02/29/2024] Open
Abstract
Introduction Kidney transplant recipients (KTRs) are at a higher risk of severe coronavirus disease (COVID-19) because of their immunocompromised status. However, the effect of allograft function on the prognosis of severe COVID-19 in KTRs is unclear. In this study, we aimed to analyze the correlation between pre-infection allograft function and the prognosis of severe COVID-19 in KTRs. Methods This retrospective cohort study included 82 patients who underwent kidney transplantation at the Sichuan Provincial Peoples Hospital between October 1, 2014 and December 1, 2022 and were diagnosed with severe COVID-19. The patients were divided into decreased eGFR and normal eGFR groups based on the allograft function before COVID-19 diagnosis (n=32 [decreased eGFR group], mean age: 43.00 years; n=50 [normal eGFR group, mean age: 41.88 years). We performed logistic regression analysis to identify risk factors for death in patients with severe COVID-19. The nomogram was used to visualize the logistic regression model results. Results The mortality rate of KTRs with pre-infection allograft function insufficiency in the decreased eGFR group was significantly higher than that of KTRs in the normal eGFR group (31.25% [10/32] vs. 8.00% [4/50], P=0.006). Pre-infection allograft function insufficiency (OR=6.96, 95% CI: 1.4633.18, P=0.015) and maintenance of a mycophenolic acid dose >1500 mg/day before infection (OR=7.59, 95% CI: 1.0853.20, P=0.041) were independent risk factors, and the use of nirmatrelvir/ritonavir before severe COVID-19 (OR=0.15, 95% CI: 0.030.72, P=0.018) was a protective factor against death in severe COVID-19. Conclusions Pre-infection allograft function is a good predictor of death in patients with severe COVID-19. Allograft function was improved after treatment for severe COVID-19, which was not observed in patients with non-severe COVID-19.
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Affiliation(s)
- Han Luo
- Department of Organ Transplantation, Sichuan Provincial Peoples Hospital, University of Electronic Science and Technology of China, Chengdu, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Jingyu Wen
- Department of Medical Insurance, Sichuan Provincial Peoples Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Hongji Yang
- Department of Organ Transplantation, Sichuan Provincial Peoples Hospital, University of Electronic Science and Technology of China, Chengdu, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province & Organ Transplantation Center, Sichuan Academy of Medical Sciences and Sichuan Provincial Peoples Hospital, Chengdu, China
| | - Qing Ran
- Department of Organ Transplantation, Sichuan Provincial Peoples Hospital, University of Electronic Science and Technology of China, Chengdu, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yifu Hou
- Department of Organ Transplantation, Sichuan Provincial Peoples Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province & Organ Transplantation Center, Sichuan Academy of Medical Sciences and Sichuan Provincial Peoples Hospital, Chengdu, China
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Ciancio G, Gaynor JJ, Guerra G, Tabbara MM, Roth D, Kupin W, Mattiazzi A, Moni L, Burke GW. Long-term effects of average calcineurin inhibitor trough levels (over time) on renal function in a prospectively followed cohort of 150 kidney transplant recipients. Clin Transl Sci 2023; 16:2382-2393. [PMID: 37817405 PMCID: PMC10651634 DOI: 10.1111/cts.13639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 09/01/2023] [Indexed: 10/12/2023] Open
Abstract
More favorable clinical outcomes with medium-term follow-up have been reported among kidney transplant recipients receiving maintenance therapy consisting of "reduced-tacrolimus (TAC) dosing," mycophenolate mofetil (MMF), and low-dose corticosteroids. However, it is not clear whether long-term maintenance therapy with reduced-calcineurin inhibitor (CNI) dosing still leads to reduced renal function. A prospectively followed cohort of 150 kidney transplant recipients randomized to receive TAC/sirolimus (SRL) versus TAC/MMF versus cyclosporine microemulsion (CSA)/SRL, plus low-dose maintenance corticosteroids, now has 20 years of post-transplant follow-up. Average CNI trough levels over time among patients who were still alive with functioning grafts at 60, 120, and 180 months post-transplant were determined and ranked from smallest-to-largest for both TAC and CSA. Stepwise linear regression was used to determine whether these ranked average trough levels were associated with the patient's estimated glomerular filtration rate (eGFR) at those times, particularly after controlling for other significant multivariable predictors. Experiencing biopsy-proven acute rejection (BPAR) and older donor age were the two most significant multivariable predictors of poorer eGFR at 60, 120, and 180 months post-transplant (p < 000001 and 0.000003 for older donor age at 60 and 120 months; p = 0.00008 and <0.000001 for previous BPAR at 60 and 120 months). Assignment to CSA also implied a significantly poorer eGFR (but with less magnitudes of effect) in multivariable analysis at 60 and 120 months (p = 0.01 and 0.002). Higher ranked average CNI trough levels had no association with eGFR at any timepoint in either univariable or multivariable analysis (p > 0.70). Long-term maintenance therapy with reduced-CNI dosing does not appear to cause reduced renal function.
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Affiliation(s)
- Gaetano Ciancio
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
- Department of SurgeryLeonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
| | - Jeffrey J. Gaynor
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
- Department of SurgeryLeonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
| | - Giselle Guerra
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
- Division of Nephrology, Department of Medicine, Leonard M. Miller School of MedicineUniversity of MiamiMiamiFloridaUSA
| | - Marina M. Tabbara
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
| | - David Roth
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
- Division of Nephrology, Department of Medicine, Leonard M. Miller School of MedicineUniversity of MiamiMiamiFloridaUSA
| | - Warren Kupin
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
- Division of Nephrology, Department of Medicine, Leonard M. Miller School of MedicineUniversity of MiamiMiamiFloridaUSA
| | - Adela Mattiazzi
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
- Division of Nephrology, Department of Medicine, Leonard M. Miller School of MedicineUniversity of MiamiMiamiFloridaUSA
| | - Lissett Moni
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
- Department of SurgeryLeonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
| | - George W. Burke
- Miami Transplant Institute, Leonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
- Department of SurgeryLeonard M. Miller School of Medicine, University of MiamiMiamiFloridaUSA
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Calcineurin inhibitors' impact on cardiovascular and renal function, a descriptive study in lung transplant recipients from the North of Spain. Sci Rep 2022; 12:21207. [PMID: 36481797 PMCID: PMC9732215 DOI: 10.1038/s41598-022-25445-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 11/30/2022] [Indexed: 12/13/2022] Open
Abstract
Patients undergoing lung transplantation (LTx) need administration of immunosuppressive therapy following the procedure to prevent graft rejection. However, these drugs are not exempt from potential risks. The development of cardiovascular risk factors and impaired renal function in the post-transplantation period are conditions that may be favoured by the use of calcineurin inhibitor (CNI) drugs which could have repercussions on the quality of life and the post-transplantation evolution. To evaluate the cardiovascular and renal toxicity following the administration of CNI as maintenance immunosuppression in lung transplant recipients (LTRs) we reviewed a total number of 165 patients undergoing LTx between 01/01/2015 and 08/12/2018. They were divided into two groups according to the CNI drug administrated: cyclosporine (CsA-group) with 11 patients or tacrolimus (Tac-group), with 154 patients. We evaluated the de novo occurrence of arterial hypertension (HTN), diabetes mellitus (DM), hyperlipidemia and impaired renal function after initiation of CNI administration. In addition to that, the time until each of these events was assessed. A higher rate for developing HTN (p < 0.001) and impaired renal function (p = 0.047) was observed within the CsA-group. The new onset of hyperlipidemia was similar between both CNI groups and de novo appearance of DM was only documented in those LTRs receiving tacrolimus. In this LTRs retrospective study, it was observed that having ≥ 4 tacrolimus trough levels above the upper limit of the proposed interval for each specific post-LTx period was associated with an increased risk for developing renal impairment. No other statistically significant association was found between supratherapeutic CNIs blood levels and the evaluated toxicities.
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Nakata S, Kakimoto K, Numa K, Kinoshita N, Kawasaki Y, Tatsumi Y, Tawa H, Koshiba R, Hirata Y, Ota K, Sakiyama N, Kojima Y, Nishikawa H, Inoue T, Takeuchi T, Fukunishi S, Miyazaki T, Nakamura S, Higuchi K. Risk Factors for Nephrotoxicity due to Tacrolimus Therapy for Ulcerative Colitis. Digestion 2022; 103:339-346. [PMID: 35705006 PMCID: PMC9932845 DOI: 10.1159/000524594] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 03/25/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS The calcineurin inhibitor tacrolimus is reportedly effective for moderate/severe ulcerative colitis (UC); however, it is also reportedly associated with nephrotoxicity. We investigated the risk factors for tacrolimus-induced nephrotoxicity and whether renal impairment adversely affected the outcomes of tacrolimus treatment in patients with UC. METHODS We conducted a retrospective study of 93 patients with UC who were administered tacrolimus leading to high trough levels (10-15 ng/mL) for 2 weeks and low trough levels (5-10 ng/mL) for 3 months. RESULTS Acute kidney injury (AKI) occurred in 44 patients (47.3%) during tacrolimus treatment. Of these patients, 34 (36.6%) developed AKI during the high trough phase and 17 (18.3%) developed AKI when the trough value exceeded the original target value of 15 ng/mL. Multivariate logistic regression analysis revealed that the male sex was significantly associated with AKI (p = 0.002, AOR = 4.38, 95% CI [1.69-11.3]). Clinical remission rate after 4, 8, 12, and 24 weeks of tacrolimus treatment in patients with AKI was lower than that in patients without AKI. Six patients (6.5%) had chronic kidney disease (CKD) after tacrolimus treatment completion, and all patients with CKD developed AKI during treatment. The median duration of treatment with no improvement in AKI was significantly longer in patients with CKD than in those without CKD (p = 0.016). CONCLUSION We revealed the risk factors for tacrolimus-induced nephrotoxicity. Renal impairment occurrence adversely affected the tacrolimus treatment outcome; therefore, it is important to carefully administer tacrolimus to prevent renal impairment.
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Okabe Y, Noguchi H, Sato Y, Mei T, Kaku K, Ueki K, Tsuchimoto A, Nakamura M. Outcomes of Everolimus Plus Standard-Dose Tacrolimus Immunosuppression in De Novo Kidney Transplant: A Retrospective, Single-Center Study of 225 Transplants. EXP CLIN TRANSPLANT 2022; 20:362-369. [PMID: 35475420 DOI: 10.6002/ect.2022.0028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES In this study, our aim was to compare the outcomes of everolimus versus mycophenolate mofetil plus standard-dose tacrolimus immunosuppression in patients who received de novo kidney transplant at our center in Fukuoka, Japan. MATERIALS AND METHODS In this retrospective, observational, single-center, inverse probability of treatment weighting analysis study, 225 recipients who underwent kidney transplant at our center between January 2013 and December 2018 were included. The variables considered were recipient age/sex, duration of dialysis, cytomegalovirus mismatch (seronegative recipient and seropositive donor), cause of end-stage renal disease, donor age/sex, and number of HLA mismatches. RESULTS Our analyses included 85 transplant recipients in the everolimus group and 141 transplant recipients in the mycophenolate mofetil group (n = 226 overall). There were no significant differences between the groups at 1 year for incidence of patient death and allograft loss, biopsy-proven acute rejection, BK virus-associated nephropathy, surgical complications, delayed graft function, and posttransplant diabetes mellitus. Incidence of cytomegalovirus infection and estimated glomerular filtration rate were significantly lower in the everolimus group than in the mycophenolate mofetil group. Posttransplant triglyceride and low-density lipoprotein were higher in the everolimus group than in the mycophenolate mofetil group. Multivariate ordered logistic analysis showed that older donor age and an acute rejection episode, but not induction with everolimus or mean tacrolimus trough concentration throughoutthe firstpostoperative year,were significant risk factors for severity of interstitial fibrosis/tubular atrophy at the 1-year protocol biopsy (P = .004 and P < .001,respectively). CONCLUSIONS Short-term outcomes with everolimus plus standard-dose tacrolimus in recipients of de novo kidney transplant were comparable to those with mycophenolate mofetil plus standard-dose tacrolimus.
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Affiliation(s)
- Yasuhiro Okabe
- From the Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Yılmaz EA, Özdemir Ö. Solid organ transplantations and COVID-19 disease. World J Transplant 2021; 11:503-511. [PMID: 35070786 PMCID: PMC8713305 DOI: 10.5500/wjt.v11.i12.503] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/04/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Tens of thousands of people worldwide became infected with severe acute respiratory syndrome coronavirus-2. Death rate in the general population is about 1%-6%, but this rate rises up to 15% in those with comorbidities. Recent publications showed that the clinical progression of this disease in organ recipients is more destructive, with a fatality rate of up to 14%-25%. We aimed to review the effect of the pandemic on various transplantation patients. Coronavirus disease 2019 (COVID-19) has not only interrupted the lives of waiting list patients’; it has also impacted transplantation strategies, transplant surgeries and broken donation chains. COVID-19 was directly and indirectly accountable for a 73% surplus in mortality of this population as compared to wait listed patients in earlier years. The impact of chronic immunosuppression on outcomes of COVID-19 remains unclear but understanding the immunological mechanisms related to the virus is critically important for the lifetime of transplantation and immune suppressed patients. It is hard to endorse changing anti-rejection therapy, as the existing data evaluation is not adequate to advise substituting tacrolimus with cyclosporine during severe COVID-19 disease.
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Affiliation(s)
- Emine Aylin Yılmaz
- Division of Pediatric Allergy and Immunology, Sakarya University Medical Faculty, Adapazarı 54100, Sakarya, Turkey
| | - Öner Özdemir
- Division of Pediatric Allergy and Immunology, Sakarya University Medical Faculty, Adapazarı 54100, Sakarya, Turkey
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9
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Jing L, Chen W, Guo L, Zhao L, Liang C, Chen J, Wang C. Acute kidney injury after lung transplantation: a narrative review. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:717. [PMID: 33987415 PMCID: PMC8106087 DOI: 10.21037/atm-20-7644] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Acute kidney injury (AKI) is a commonly recognized complication after lung transplantation (LT) and is related to increased mortality and morbidity. With the improvement of survival after LT and the increasing number of lung transplant recipients, the detrimental impact of current management on renal function has become increasingly apparent. Multifarious risk factors in the perioperative setting contribute to the development of AKI, including the preoperative status and complications of the recipient, complex perioperative problems especially hemodynamic fluctuation, and exposure to nephrotoxic agents, mainly calcineurin inhibitors (CNIs) and antimicrobial drugs. Identification and minimization of the effects of these risk factors can relieve AKI severity and incidence in high-risk patients. Close monitoring of urine output and serum creatinine (sCr) levels and of specific biomarkers may promote early recognition of AKI and rapid nephrology intervention to improve outcomes. This review summarizes advances in the epidemiology, diagnostic criteria, biological markers of AKI, and further recommends appropriate treatment strategies for the long-term management of AKI related manifestations in lung transplant recipients. Future work will need to focus on developing more accurate measures of renal function and identifying patients before the occurrence of early renal damage. Combining renal protection strategies with the use of new biomarkers to develop early kidney risk identification and protection protocols is a promising idea that requires further investigation.
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Affiliation(s)
- Lei Jing
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of Lung Transplantation, Centre of Lung Transplantation, Centre of Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China.,National Center for Respiratory Medicine, Beijing, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.,National Clinical Research Center for Respiratory Diseases, Beijing, China.,WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, Beijing, China
| | - Wenhui Chen
- Department of Lung Transplantation, Centre of Lung Transplantation, Centre of Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China.,National Center for Respiratory Medicine, Beijing, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.,National Clinical Research Center for Respiratory Diseases, Beijing, China.,WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, Beijing, China
| | - Lijuan Guo
- Department of Lung Transplantation, Centre of Lung Transplantation, Centre of Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China.,National Center for Respiratory Medicine, Beijing, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.,National Clinical Research Center for Respiratory Diseases, Beijing, China.,WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, Beijing, China
| | - Li Zhao
- Department of Lung Transplantation, Centre of Lung Transplantation, Centre of Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China.,National Center for Respiratory Medicine, Beijing, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.,National Clinical Research Center for Respiratory Diseases, Beijing, China.,WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, Beijing, China
| | - Chaoyang Liang
- Department of Lung Transplantation, Centre of Lung Transplantation, Centre of Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China.,National Center for Respiratory Medicine, Beijing, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.,National Clinical Research Center for Respiratory Diseases, Beijing, China.,WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, Beijing, China
| | - Jingyu Chen
- Department of Lung Transplantation, Centre of Lung Transplantation, Centre of Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China.,National Center for Respiratory Medicine, Beijing, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.,National Clinical Research Center for Respiratory Diseases, Beijing, China.,WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, Beijing, China
| | - Chen Wang
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of Lung Transplantation, Centre of Lung Transplantation, Centre of Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China.,National Center for Respiratory Medicine, Beijing, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.,National Clinical Research Center for Respiratory Diseases, Beijing, China.,WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, Beijing, China
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10
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Kim HE, Paik HC, Jeong SJ, Park MS, Kim SY, Lee JG. Basiliximab Induction with Delayed Calcineurin Inhibitors for High-Risk Lung Transplant Candidates. Yonsei Med J 2021; 62:164-171. [PMID: 33527796 PMCID: PMC7859690 DOI: 10.3349/ymj.2021.62.2.164] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 11/30/2020] [Accepted: 12/07/2020] [Indexed: 12/17/2022] Open
Abstract
PURPOSE Calcineurin inhibitor (CNI) use has improved lung transplantation outcomes. However, significant perioperative complications in patients receiving CNI can deteriorate the early course of lung transplantation. To date, there is no consensus regarding the optimal agent for the induction regimen after lung transplantation. We aimed to determine the efficacy of basiliximab induction with delayed CNI initiation in the prevention of acute complications without compromising immunosuppression in high-risk patients. MATERIALS AND METHODS Between January 2013 and December 2019, 236 patients at a single lung transplant center were retrospectively reviewed. Forty-one patients (17.4%) received basiliximab induction, and 195 patients (82.6%) received a routine triple-drug regimen without induction. The primary endpoint was postoperative acute kidney injury with several other postoperative outcomes as secondary end-points. RESULTS Preoperatively, the induction group had a higher proportion of patients who were admitted before transplantation (95.1% vs. 47.7%, p<0.001) and received intensive unit care (90.2% vs. 33.8%, p<0.001) and extracorporeal membrane oxygenation (ECMO) (87.8% vs. 20.0%, p<0.001) compared to the non-induction group. No significant differences were observed in the incidence of acute rejection between groups (p=0.657), although lower incidence of postoperative complications, including acute kidney injuries or culture-proven infections, were observed in the induction group. However, the differences were not statistically significant. A subgroup analysis of high-risk and preoperative ECMO support groups showed similar results. CONCLUSION Basiliximab induction with delayed CNI initiation for high-risk patients might decrease the incidence of perioperative complications, including acute renal failure, without increasing the risk of acute rejection.
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Affiliation(s)
- Ha Eun Kim
- Department of Thoracic and Cardiovascular Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hyo Chae Paik
- Department of Thoracic and Cardiovascular Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Su Jin Jeong
- Division of Infectious Disease, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Moo Suk Park
- Division of Pulmonology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Song Yee Kim
- Division of Pulmonology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jin Gu Lee
- Department of Thoracic and Cardiovascular Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
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Ito A, Murasugi S, Omori T, Nakamura S, Tokushige K. Relationship between mucosal healing by tacrolimus and relapse of refractory ulcerative colitis: a retrospective study. BMC Gastroenterol 2020; 20:203. [PMID: 32590945 PMCID: PMC7320561 DOI: 10.1186/s12876-020-01317-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 05/22/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Tacrolimus (TAC) is a powerful remission-inducing drug for refractory ulcerative colitis (UC). However, it is unclear whether mucosal healing (MH) influences relapse after completion of TAC.We investigated whether MH is related to relapse after TAC. PATIENTS Among 109 patients treated with TAC, 86 patients achieved clinical remission and 55 of them underwent colonoscopy at the end of TAC. These 55 patients were investigated. METHODS Patients with MH at the end of TAC were classified into the MH group (n = 41), while patients without MH were classified into the non-MH group (n = 14). These groups were compared with respect to 1) clinical characteristics before treatment, 2) clinical characteristics on completion of treatment, and 3) the relapse rate and adverse events rates. This is a retrospective study conducted at a single institution. RESULTS 1) There was a significant difference in baseline age between the two groups before TAC therapy, but there were no significant differences in other clinical characteristics. The NMH group was younger (MH group: 48.1 (23-79) years, NMH group: 36.3 (18-58) years, P = 0.007). Endoscopic scores showed significant differences between the 2 groups at the end of TAC. There were also significant differences in the steroid-free rate after 24 weeks (MH group: 85.3%, NMH group 50%, P = 0.012). There was no significant difference in the relapse rate between the 2 groups at 100 days after remission, but a significant difference was noted at 300 days (17% vs. 43%), 500 days (17% vs. 75%), and 1000 days (17% vs. 81%) (all P < 0.05). CONCLUSIONS TAC is effective for refractory ulcerative colitis. However, even if clinical remission is achieved, relapse is frequent when colonoscopy shows that MH has not been achieved. It is important to evaluate the mucosal response by colonoscopy on completion of TAC.
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Affiliation(s)
- Ayumi Ito
- Department of Gastroenterology, Tokyo Women's Medical University, Kawada-cho 8-1 Shinjuku-ku, Tokyo, 162-8666, Japan.
| | - Syun Murasugi
- Department of Gastroenterology, Tokyo Women's Medical University, Kawada-cho 8-1 Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Teppei Omori
- Department of Gastroenterology, Tokyo Women's Medical University, Kawada-cho 8-1 Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Shinichi Nakamura
- Department of Gastroenterology, Tokyo Women's Medical University, Kawada-cho 8-1 Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Katsutoshi Tokushige
- Department of Gastroenterology, Tokyo Women's Medical University, Kawada-cho 8-1 Shinjuku-ku, Tokyo, 162-8666, Japan
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One-year Outcome of Everolimus With Standard-dose Tacrolimus Immunosuppression in De Novo ABO-incompatible Living Donor Kidney Transplantation: A Retrospective, Single-center, Propensity Score Matching Comparison With Mycophenolate in 42 Transplants. Transplant Direct 2020; 6:e514. [PMID: 32047842 PMCID: PMC6964930 DOI: 10.1097/txd.0000000000000962] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 10/09/2019] [Accepted: 11/01/2019] [Indexed: 12/18/2022] Open
Abstract
Background. Despite improvement in immunosuppressive therapy, long-term kidney allograft survival remains a major challenge. The outcomes of therapy with everolimus (EVR) and standard-dose tacrolimus (Tac) have not been compared with those of mycophenolate mofetil (MMF) and standard-dose Tac in recipients of de novo ABO-incompatible (ABOi) living donor kidney transplantation (LDKT). Methods. This retrospective, observational, single-center, propensity score matching (PSM) study compared the outcomes of EVR and standard-dose Tac with those of MMF and standard-dose Tac following de novo ABOi LDKT. In total, 153 recipients of ABOi LDKT between January 2008 and March 2018 were screened for inclusion in the study. The variables considered for PSM were: recipient age/sex, duration of dialysis, cytomegalovirus mismatch (seronegative recipient and seropositive donor), cause of kidney disease, donor age/sex, and numbers of mismatches (HLA-A, HLA-B, and HLA-DR). After PSM, there were 21 patients in each group (n = 42 overall). Results. Four patients in the EVR group and 1 patient in the MMF group were withdrawn because of adverse effects. There were no significant differences between the 2 groups in 1-year outcomes regarding patient death, graft loss, delayed graft function, biopsy-proven acute rejection, infection requiring hospital admission, or estimated glomerular filtration rate. The 1-year protocol biopsy showed that the severity of interstitial fibrosis/tubular atrophy was significantly milder in the EVR group than in the MMF group. Conclusions. The findings suggest that the renal efficacy and safety of EVR and standard-dose Tac in recipients of de novo ABOi LDKT are comparable with those of MMF and standard-dose Tac.
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Benjanuwattra J, Pruksakorn D, Koonrungsesomboon N. Mycophenolic Acid and Its Pharmacokinetic Drug‐Drug Interactions in Humans: Review of the Evidence and Clinical Implications. J Clin Pharmacol 2019; 60:295-311. [DOI: 10.1002/jcph.1565] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 11/08/2019] [Indexed: 12/14/2022]
Affiliation(s)
| | - Dumnoensun Pruksakorn
- Musculoskeletal Science and Translational Research Center Chiang Mai University Chiang Mai Thailand
- Department of Orthopedics, Faculty of Medicine Chiang Mai University Chiang Mai Thailand
| | - Nut Koonrungsesomboon
- Department of Pharmacology, Faculty of Medicine Chiang Mai University Chiang Mai Thailand
- Musculoskeletal Science and Translational Research Center Chiang Mai University Chiang Mai Thailand
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Efficacy and Safety of Empagliflozin in the Management of Diabetes Mellitus in Heart Transplant Recipients. Transplant Direct 2019; 5:e450. [PMID: 31165085 PMCID: PMC6511439 DOI: 10.1097/txd.0000000000000885] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 02/15/2019] [Indexed: 12/27/2022] Open
Abstract
Background Type 2 diabetes mellitus (T2DM) is prevalent in patients undergoing heart transplant, and in those without preexisting T2DM, posttransplant diabetes mellitus may develop. Both T2DM and posttransplant diabetes mellitus have been associated with increased morbidity and mortality following heart transplantation. Empagliflozin is an effective glucose-lowering therapy that reduces the incidence of major cardiovascular events in patients with T2DM. The safety and efficacy of empagliflozin in transplant patients with diabetes mellitus has yet to be established. Methods Clinical outcomes were retrospectively examined in 22 heart transplant recipients treated with empagliflozin and compared with those of 79 heart transplant patients with diabetes mellitus receiving alternative glucose-lowering therapies. Results Three adverse events were recorded in empagliflozin-treated patients, leading to treatment discontinuation in 1. There were no genitourinary infections. Treatment with empagliflozin for 12 months was associated with reductions in weight, body mass index, glycated hemoglobin, and frusemide dose that were not seen in the control group. There were no large changes observed in blood pressure (systolic or diastolic) or renal function (serum urea, creatinine, or estimated glomerular filtration rate) after 12 months of treatment with empagliflozin or alternative glucose-lowering therapies. Conclusions Empagliflozin appears safe and effective in the management of selected patients with diabetes mellitus following heart transplantation.
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Abstract
PURPOSE OF REVIEW Organ transplantation is a life-saving procedure and the only option for patients with end-organ failure. Immune therapeutics have been key to the success of organ transplantation. However, immune therapeutics are still unable to eliminate graft rejection and their toxicity has been implicated in poorer long-term transplant outcomes. Targeted nanodelivery has the potential to enhance not only the therapeutic index but also the bioavailability of the immune therapeutics. One of the key sites of immune therapeutics delivery is lymph node where the priming of immune cells occur. The focus of this review is on nanomedicine research to develop the targeted delivery of immune therapeutics to lymph nodes for controlling immune activation. RECENT FINDINGS As nanomedicine creates its niche in clinical care, it provides novel immunotherapy platforms for transplant recipients. Draining lymph nodes are the primary loci of immune activation and represent a formidable site for delivery of wide variety of immune therapeutics. There have been relentless efforts to improve the properties of nanomedicines, to have in-depth knowledge of antigen and drug loading, and, finally, to explore various routes of passive and active targeted delivery to lymph nodes. SUMMARY The application of nanotechnology principles in the delivery of immune therapeutics to the lymph node has created enormous excitement as a paradigm shifting approach that enables targeted delivery of a gamut of molecules to achieve a desired immune response. Therefore, innovative strategies that improve their efficacy while reducing their toxicity are among the highest unmet needs in transplantation.
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16
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Liu J, Ma B, Cao W, Li M, Bramer WM, Peppelenbosch MP, Pan Q. Direct-acting antiviral agents for liver transplant recipients with recurrent genotype 1 hepatitis C virus infection: Systematic review and meta-analysis. Transpl Infect Dis 2019; 21:e13047. [PMID: 30615227 PMCID: PMC6850617 DOI: 10.1111/tid.13047] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 12/18/2018] [Accepted: 12/23/2018] [Indexed: 12/15/2022]
Abstract
Background Comprehensive evaluation of safety and efficacy of different combinations of direct‐acting antivirals (DAAs) in liver transplant recipients with genotype 1 (GT1) hepatitis C virus (HCV) recurrence remains limited. Therefore, we performed this systematic review and meta‐analysis in order to evaluate the clinical outcome of DAA treatment in liver transplant patients with HCV GT1 recurrence. Methods Studies were included if they contained information of 12 weeks sustained virologic response (SVR12) after DAA treatment completion as well as treatment related complications for liver transplant recipients with GT1 HCV recurrence. Results We identified 16 studies comprising 885 patients. The overall pooled estimate proportion of SVR12 was 93% (95% confidence interval (CI): 0.89, 0.96), with moderate heterogeneity observed (τ2 = 0.01, P < 0.01, I2=75%). High tolerability was observed in liver transplant recipients reflected by serious adverse events (sAEs) with pooled estimate proportion of 4% (95% CI: 0.01, 0.07; τ2 = 0.02, P < 0.01, I2 = 81%). For subgroup analysis, a total of five different DAA regimens were applied for treating these patients. Sofosbuvir/Ledipasvir (SOF/LDV) led the highest pooled estimate SVR12 proportion, followed by Paritaprevir/Ritonavir/Ombitasivir/Dasabuvir (PrOD), Daclatasvir (DCV)/Simeprevir (SMV) ± Ribavirin (RBV), and SOF/SMV ± RBV, Asunaprevir (ASV)/DCV. There was a tendency for favoring a higher pooled SVR12 proportion in patients with METAVIR Stage F0‐F2 of 97% (95% CI: 0.93, 0.99) compared to 85% (95% CI: 0.79, 0.90) for stage F3‐F4 (P < 0.01). There was no significant difference between LT recipients treated with or without RBV (P = 0.23). Conclusions Direct‐acting antiviral treatment is highly effective and well‐tolerated in liver transplant recipients with recurrent GT1 HCV infection.
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Affiliation(s)
- Jiaye Liu
- Biomedical Research Center, Northwest Minzu University, Lanzhou, China.,Erasmus MC Cancer Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Buyun Ma
- Erasmus MC Cancer Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Wanlu Cao
- Erasmus MC Cancer Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Meng Li
- Erasmus MC Cancer Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Wichor M Bramer
- Department of Medical Library, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Maikel P Peppelenbosch
- Erasmus MC Cancer Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Qiuwei Pan
- Biomedical Research Center, Northwest Minzu University, Lanzhou, China.,Erasmus MC Cancer Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
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Reuberson J, Horsley H, Franklin RJ, Ford D, Neuss J, Brookings D, Huang Q, Vanderhoydonck B, Gao LJ, Jang MY, Herdewijn P, Ghawalkar A, Fallah-Arani F, Khan AR, Henshall J, Jairaj M, Malcolm S, Ward E, Shuttleworth L, Lin Y, Li S, Louat T, Waer M, Herman J, Payne A, Ceska T, Doyle C, Pitt W, Calmiano M, Augustin M, Steinbacher S, Lammens A, Allen R. Discovery of a Potent, Orally Bioavailable PI4KIIIβ Inhibitor (UCB9608) Able To Significantly Prolong Allogeneic Organ Engraftment in Vivo. J Med Chem 2018; 61:6705-6723. [PMID: 29952567 DOI: 10.1021/acs.jmedchem.8b00521] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The primary target of a novel series of immunosuppressive 7-piperazin-1-ylthiazolo[5,4- d]pyrimidin-5-amines was identified as the lipid kinase, PI4KIIIβ. Evaluation of the series highlighted their poor solubility and unwanted off-target activities. A medicinal chemistry strategy was put in place to optimize physicochemical properties within the series, while maintaining potency and improving selectivity over other lipid kinases. Compound 22 was initially identified and profiled in vivo, before further modifications led to the discovery of 44 (UCB9608), a vastly more soluble, selective compound with improved metabolic stability and excellent pharmacokinetic profile. A co-crystal structure of 44 with PI4KIIIβ was solved, confirming the binding mode of this class of inhibitor. The much-improved in vivo profile of 44 positions it as an ideal tool compound to further establish the link between PI4KIIIβ inhibition and prolonged allogeneic organ engraftment, and suppression of immune responses in vivo.
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Affiliation(s)
- James Reuberson
- UCB Pharma , 208 Bath Road , Slough , Berkshire SL1 3WE , United Kingdom
| | - Helen Horsley
- UCB Pharma , 208 Bath Road , Slough , Berkshire SL1 3WE , United Kingdom
| | - Richard J Franklin
- UCB Pharma , 208 Bath Road , Slough , Berkshire SL1 3WE , United Kingdom
| | - Daniel Ford
- UCB Pharma , 208 Bath Road , Slough , Berkshire SL1 3WE , United Kingdom
| | - Judi Neuss
- UCB Pharma , 208 Bath Road , Slough , Berkshire SL1 3WE , United Kingdom
| | - Daniel Brookings
- UCB Pharma , 208 Bath Road , Slough , Berkshire SL1 3WE , United Kingdom
| | - Qiuya Huang
- Interface Valorization Platform , KU Leuven , Campus St.-Rafaël, Blok I, 8°, Kapucijnenvoer 33 B 7001 , 3000 Leuven , Belgium
| | - Bart Vanderhoydonck
- Interface Valorization Platform , KU Leuven , Campus St.-Rafaël, Blok I, 8°, Kapucijnenvoer 33 B 7001 , 3000 Leuven , Belgium
| | - Ling-Jie Gao
- Interface Valorization Platform , KU Leuven , Campus St.-Rafaël, Blok I, 8°, Kapucijnenvoer 33 B 7001 , 3000 Leuven , Belgium
| | - Mi-Yeon Jang
- Interface Valorization Platform , KU Leuven , Campus St.-Rafaël, Blok I, 8°, Kapucijnenvoer 33 B 7001 , 3000 Leuven , Belgium
| | - Piet Herdewijn
- Interface Valorization Platform , KU Leuven , Campus St.-Rafaël, Blok I, 8°, Kapucijnenvoer 33 B 7001 , 3000 Leuven , Belgium
| | - Anant Ghawalkar
- SAI Life Sciences Ltd , International Biotech Park , Hinjewadi, Pune 411 057 , India
| | | | - Adnan R Khan
- UCB Pharma , 208 Bath Road , Slough , Berkshire SL1 3WE , United Kingdom
| | - Jamie Henshall
- UCB Pharma , 208 Bath Road , Slough , Berkshire SL1 3WE , United Kingdom
| | - Mark Jairaj
- UCB Pharma , 208 Bath Road , Slough , Berkshire SL1 3WE , United Kingdom
| | - Sarah Malcolm
- UCB Pharma , 208 Bath Road , Slough , Berkshire SL1 3WE , United Kingdom
| | - Eleanor Ward
- UCB Pharma , 208 Bath Road , Slough , Berkshire SL1 3WE , United Kingdom
| | | | - Yuan Lin
- Interface Valorization Platform , KU Leuven , Campus St.-Rafaël, Blok I, 8°, Kapucijnenvoer 33 B 7001 , 3000 Leuven , Belgium
| | - Shengqiao Li
- Interface Valorization Platform , KU Leuven , Campus St.-Rafaël, Blok I, 8°, Kapucijnenvoer 33 B 7001 , 3000 Leuven , Belgium
| | - Thierry Louat
- Interface Valorization Platform , KU Leuven , Campus St.-Rafaël, Blok I, 8°, Kapucijnenvoer 33 B 7001 , 3000 Leuven , Belgium
| | - Mark Waer
- Interface Valorization Platform , KU Leuven , Campus St.-Rafaël, Blok I, 8°, Kapucijnenvoer 33 B 7001 , 3000 Leuven , Belgium
| | - Jean Herman
- Interface Valorization Platform , KU Leuven , Campus St.-Rafaël, Blok I, 8°, Kapucijnenvoer 33 B 7001 , 3000 Leuven , Belgium
| | - Andrew Payne
- UCB Pharma , 208 Bath Road , Slough , Berkshire SL1 3WE , United Kingdom
| | - Tom Ceska
- UCB Pharma , 208 Bath Road , Slough , Berkshire SL1 3WE , United Kingdom
| | - Carl Doyle
- UCB Pharma , 208 Bath Road , Slough , Berkshire SL1 3WE , United Kingdom
| | - Will Pitt
- UCB Pharma , 208 Bath Road , Slough , Berkshire SL1 3WE , United Kingdom
| | - Mark Calmiano
- UCB Pharma , 208 Bath Road , Slough , Berkshire SL1 3WE , United Kingdom
| | - Martin Augustin
- Proteros Biostructures GmbH , Bunsenstrasse 7a , 82152 Martinsried , Germany
| | - Stefan Steinbacher
- Proteros Biostructures GmbH , Bunsenstrasse 7a , 82152 Martinsried , Germany
| | - Alfred Lammens
- Proteros Biostructures GmbH , Bunsenstrasse 7a , 82152 Martinsried , Germany
| | - Rodger Allen
- UCB Pharma , 208 Bath Road , Slough , Berkshire SL1 3WE , United Kingdom
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18
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Zhang Y, Luo J, Hu B, Ma T. Efficacy and safety of tacrolimus combined with glucocorticoid treatment for IgA nephropathy: a meta-analysis. J Int Med Res 2018; 46:3236-3250. [PMID: 29882450 PMCID: PMC6134674 DOI: 10.1177/0300060518776566] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Objective As a classical immunosuppressant, tacrolimus (TAC) has been widely used in organ transplantation therapy, but the general benefits of TAC for the treatment of IgA nephropathy (IgAN) remain uncertain. We conducted a meta-analysis to examine the effects of TAC combined with glucocorticoid on IgAN. Methods We searched the information databases PubMed/Medline, Embase, Science Citation Index, Chinese Biomedical Literature and the Chinese databases VIP, CNKI and Wan Fang for randomized controlled trials of TAC combined with glucocorticoid as a therapy for IgAN. Results Ten relevant studies involving 472 patients were included in a meta-analysis. Overall, the TAC group showed a significant decrease in proteinuria compared with the control group (MD: −0.18 g/d, 95% CI: −0.32 to −0.04). No increased risk of adverse events was observed (OR: 0.93, 95% CI: 0.65 to 1.33). In general, the TAC group showed good tolerance. Conclusion Evidence to date clearly indicates that TAC combined with glucocorticoid is quite effective in reducing proteinuria and albuminuria in patients with IgAN. Moreover, we found that patients receiving TAC therapy did not show an increased risk of side effects compared with control group patients. TAC combined with glucocorticoid is a promising medication and merits further research.
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Affiliation(s)
- Yong Zhang
- 1 Department of Nephrology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China
| | - Jun Luo
- 2 Department of Pediatrics, Renhe Hospital, China Three Gorges University, Yichang, Hubei, China
| | - Bin Hu
- 3 Department of Nephrology, Renhe Hospital, China Three Gorges University, Yichang, Hubei, China
| | - Tean Ma
- 1 Department of Nephrology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China
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Abstract
Immunosuppressive therapy is arguably the most important component of medical care after lung transplantation. The goal of immunosuppression is to prevent acute and chronic rejection while maximizing patient survival and long-term allograft function. However, the benefits of immunosuppressive therapy must be balanced against the side effects and major toxicities of these medications. Immunosuppressive agents can be classified as induction agents, maintenance therapies, treatments for acute rejection and chronic rejection and antibody directed therapies. Although induction therapy remains an area of controversy in lung transplantation, it is still used in the majority of transplant centers. On the other hand, maintenance immunosuppression is less contentious; but, unfortunately, since the creation of three-drug combination therapy, including a glucocorticoid, calcineurin inhibitor and anti-metabolite, there have been relatively modest improvements in chronic maintenance immunosuppressive regimens. The presence of HLA antibodies in transplant candidates and development of de novo antibodies after transplantation remain a major therapeutic challenge before and after lung transplantation. In this chapter we review the medications used for induction and maintenance immunosuppression along with their efficacy and side effect profiles. We also review strategies and evidence for HLA desensitization prior to lung transplantation and management of de novo antibody formation after transplant. Finally, we review immune tolerance and the future of lung transplantation to limit the toxicities of conventional immunosuppressive therapy.
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Affiliation(s)
- Luke J Benvenuto
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Columbia University Medical Center, New York, USA
| | - Michaela R Anderson
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Columbia University Medical Center, New York, USA
| | - Selim M Arcasoy
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Columbia University Medical Center, New York, USA
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20
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Host response to pulmonary fungal infections: A highlight on cell-driven immunity to Cryptococcus species and Aspergillus fumigatus. ACTA ACUST UNITED AC 2018; 3:335-345. [PMID: 29430385 DOI: 10.1007/s40495-017-0111-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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21
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Abstract
PURPOSE OF REVIEW Heart transplantation is the best option for irreversible and critically advanced heart failure. However, limited donor pool, the risk of rejection, infection, and right ventricular dysfunction in short-term post-transplant period, as well as, the development of coronary allograft vasculopathy and malignancy in the long-term post-transplant period limits the utility of heart transplantation for all comers with advanced heart failure. Therefore, selection of appropriate candidates is very important for the best short and long-term prognosis. In this article, we discuss the principles of selection of candidates and compare to the recently updated International Society for Heart and Lung Transplantation (ISHLT) listing criteria with the goal of updating current clinical practice. RECENT FINDINGS We found that while most of the recommendations in the new listing criteria are continuous with the previous criteria, updated recommendations are made on the risk stratification models in choosing transplantation candidates. Recommendation on hepatic dysfunction is not directly included in the updated ISHLT listing criteria; however, adoption of the Model for End-stage Liver Disease (MELD) score and modified MELD scores in the evaluation of risk are suggested in recent studies. In conclusion, evaluation of patient selection for heart transplantation should be comprehensive and individualized with respect to indications and the risk of comorbidities of candidates. With the advancement of mechanical circulatory support (MCS), the selection of heart transplantation candidate is continuously evolving and widened. MCS as bridge to candidacy should be considered when the candidate has potentially reversible risk factors for transplantation.
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22
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Helmschrott M, Rivinius R, Bruckner T, Katus HA, Doesch AO. Renal function in heart transplant patients after switch to combined mammalian target of rapamycin inhibitor and calcineurin inhibitor therapy. DRUG DESIGN DEVELOPMENT AND THERAPY 2017; 11:1673-1680. [PMID: 28652705 PMCID: PMC5472407 DOI: 10.2147/dddt.s135503] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
BACKGROUND A calcineurin inhibitor (CNI)-based immunosuppression combined with mammalian target of rapamycin inhibitors (mTORs) seems to be attractive in patients after heart transplantation (HTX) in special clinical situations, for example, in patients with adverse drug effects of prior immunosuppression. Previous studies in patients after HTX detected advantageous effects regarding renal function of a tacrolimus (TAC)-based vs cyclosporine-A (CSA)-based immunosuppression (in combination with mycophenolate mofetil). However, data regarding renal function after HTX in mTOR/CNI patients remain limited. AIM Primary end point of the present study was to analyze renal function in HTX patients 1 year after switch to an mTOR/CNI-based immunosuppression. METHODS Data of 80 HTX patients after change to mTOR/CNI-based immunosuppression were retrospectively analyzed. Renal function was assessed by measured serum creatinine and by estimated glomerular filtration rate (eGFR) calculated from Modification of Diet in Renal Disease equation. RESULTS Twenty-nine patients received mTOR/CSA-based treatment and 51 patients received mTOR/TAC-based therapy. At time of switch and at 1-year follow-up, serum creatinine and eGFR did not differ significantly between both study groups (all P=not statistically significant). Analysis of variances with repeated measurements detected a similar change of renal function in both study groups. CONCLUSION The present study detected no significant differences between both mTOR/CNI study groups, indicating a steady state of renal function in HTX patients after switch of immunosuppressive regimen.
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Affiliation(s)
| | | | - Thomas Bruckner
- Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany
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Abstract
BACKGROUND We hypothesized that nicotinamide adenosine diphosphate oxidase 2 (Nox2) plays an important role in cyclosporine A (CsA)-induced chronic hypoxia. METHODS We tested this hypothesis in Fisher 344 rats, C57BL/6 J wild type and Nox2-/- mice, and in liver transplant recipients with chronic CsA nephrotoxicity. We used noninvasive molecular imaging (blood oxygen level-dependent magnetic resonance imaging and dynamic contrast-enhanced magnetic resonance imaging) and molecular diagnostic tools to assess intrarenal oxygenation and perfusion, and the molecular phenotype of CsA nephrotoxicity. RESULTS We observed that chemical and genetic inhibition of Nox2 in rats and mice resulted in the prevention of CsA-induced hypoxia independent of regional perfusion (blood oxygen level-dependent magnetic resonance imaging and dynamic contrast-enhanced magnetic resonance imaging, pimonidazole, HIF-1α). Nicotinamide adenosine diphosphate oxidase 2 knockout was also associated with decreased oxidative stress (Nox2, HIF-1α, hydrogen peroxide, hydroxynonenal), and fibrogenesis (α-smooth muscle actin, picrosirius red, trichrome, vimentin). The molecular signature of chronic CsA nephrotoxicity using transcriptomic analyses demonstrated significant changes in 40 genes involved in injury repair, metabolism, and oxidative stress in Nox2-/- mice. Immunohistochemical analyses of kidney biopsies from liver transplant recipients with chronic CsA nephrotoxicity showed significantly greater Nox2, α-smooth muscle actin and picrosirius levels compared with controls. CONCLUSIONS These studies suggest that Nox2 is a modulator of CsA-induced hypoxia upstream of HIF-1α and define the molecular characteristics that could be used for the diagnosis and monitoring of chronic calcineurin inhibitor nephrotoxicity.
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The CECARI Study: Everolimus (Certican®) Initiation and Calcineurin Inhibitor Withdrawal in Maintenance Heart Transplant Recipients with Renal Insufficiency: A Multicenter, Randomized Trial. J Transplant 2017; 2017:6347138. [PMID: 28316834 PMCID: PMC5337890 DOI: 10.1155/2017/6347138] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2016] [Accepted: 01/31/2017] [Indexed: 12/28/2022] Open
Abstract
In this 3-year, open-label, multicenter study, 57 maintenance heart transplant recipients (>1 year after transplant) with renal insufficiency (eGFR 30–60 mL/min/1.73 m2) were randomized to start everolimus with CNI withdrawal (N = 29) or continue their current CNI-based immunosuppression (N = 28). The primary endpoint, change in measured glomerular filtration rate (mGFR) from baseline to year 3, did not differ significantly between both groups (+7.0 mL/min in the everolimus group versus +1.9 mL/min in the CNI group, p = 0.18). In the on-treatment analysis, the difference did reach statistical significance (+9.4 mL/min in the everolimus group versus +1.9 mL/min in the CNI group, p = 0.047). The composite safety endpoint of all-cause mortality, major adverse cardiovascular events, or treated acute rejection was not different between groups. Nonfatal adverse events occurred in 96.6% of patients in the everolimus group and 57.1% in the CNI group (p < 0.001). Ten patients (34.5%) in the everolimus group discontinued the study drug during follow-up due to adverse events. The poor adherence to the everolimus therapy might have masked a potential benefit of CNI withdrawal on renal function.
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25
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Abud TB, Di Zazzo A, Kheirkhah A, Dana R. Systemic Immunomodulatory Strategies in High-risk Corneal Transplantation. J Ophthalmic Vis Res 2017; 12:81-92. [PMID: 28299010 PMCID: PMC5340067 DOI: 10.4103/2008-322x.200156] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
The cornea is the most commonly transplanted tissue in the body. Although corneal grafts generally have high success rates, transplantation onto inflamed and vascularized host beds, or so-called high-risk corneal transplantation, has a high rate of graft rejection. The management of this high-risk corneal transplantation is challenging and involves numerous measures. One of the key measures to prevent graft rejection in these cases is the use of systemic immunosuppressive agents. In this article, we will review the systemic immunosuppressive agents most commonly used for high-risk corneal transplantation, which include corticosteroids, cysclosporine A, tacrolimus, mycophenolate mofetil, and rapamycin. Benefits, risks, and published data on the use of these medications for high-risk corneal transplantation will be detailed. We will also summarize novel immunoregulatory approaches that may be used to prevent graft rejection in high-risk corneal transplantation.
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Affiliation(s)
- Tulio B Abud
- Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Antonio Di Zazzo
- Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Ahmad Kheirkhah
- Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Reza Dana
- Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
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26
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Management of high-risk corneal transplantation. Surv Ophthalmol 2016; 62:816-827. [PMID: 28012874 DOI: 10.1016/j.survophthal.2016.12.010] [Citation(s) in RCA: 95] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 12/14/2016] [Accepted: 12/15/2016] [Indexed: 12/14/2022]
Abstract
The cornea is the most commonly transplanted tissue in medicine. The main cause of corneal graft failure is allograft rejection. The incidence of graft rejection depends on the presence of high-risk characteristics, most notably corneal neovascularization. Although corneal grafting has high success rates in the absence of these risk factors, high-risk keratoplasty is associated with low success rates because of a high incidence of immune-mediated graft rejection. To improve the survival of high-risk corneal transplantation, various preoperative, intraoperative, and postoperative measures can be considered; however, the key step in the management of these grafts is the long-term use of local and/or systemic immunosuppressive agents. Although a number of immunosuppressive agents have been used for this purpose, the results vary significantly across different studies. This is partly due to the lack of an optimized method for their use, as well as the lack of a precise stratification of the degree of risk in each individual patient. New targeted biologic treatments, as well as tolerance-inducing methods, show promising horizons in the management of high-risk corneal transplantation in near future.
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27
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Cruzado JM, Pascual J, Sánchez‐Fructuoso A, Serón D, Díaz JM, Rengel M, Oppenheimer F, Hernández D, Paravisini A, Saval N, Morales JM. Controlled randomized study comparing the cardiovascular profile of everolimus with tacrolimus in renal transplantation. Transpl Int 2016; 29:1317-1328. [DOI: 10.1111/tri.12862] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Revised: 05/03/2016] [Accepted: 09/16/2016] [Indexed: 01/06/2023]
Affiliation(s)
- Josep M. Cruzado
- Nephrology Department IDIBELL Hospital de Bellvitge Barcelona Spain
| | - Julio Pascual
- Nephrology Department Hospital del Mar Barcelona Spain
| | | | - Daniel Serón
- Nephrology Department Hospital Vall Hebron Barcelona Spain
| | - Joan M. Díaz
- Nephrology Department Fundació Puigvert Barcelona Spain
| | - Manuel Rengel
- Nephrology Department Hospital Gregorio Marañón Madrid Spain
| | - Federico Oppenheimer
- Kidney Transplant Department Hospital Clínic i Provincial de Barcelona Barcelona Spain
| | | | | | - Núria Saval
- Medical Department Novartis Farmacéutica Barcelona Spain
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28
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Wan QJ, Hu HF, He YC, Luan SD, Chen HT, Li T, Xu Y, Xu HL, Liao Y. Tacrolimus combined with low-dose corticosteroids is an effective and safe therapeutic option for refractory IgA nephropathy. Exp Ther Med 2016; 12:1934-1938. [PMID: 27602099 DOI: 10.3892/etm.2016.3523] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Accepted: 06/14/2016] [Indexed: 12/13/2022] Open
Abstract
Tacrolimus (TAC) has been shown to improve remission from proteinuria in patients with refractory IgA nephropathy (IgAN); however, the efficacy and safety of TAC in such patients have not been fully explored. Therefore, the present study was conducted to evaluate the tolerance to and efficacy of TAC combined with low-dose corticosteroids in patients with refractory IgAN. This was a single-center retrospective study. A total of 28 patients with refractory IgAN were randomly included and received TAC plus corticosteroid; 26 patients received TAC and prednisone, and 2 patients received TAC and methylprednisolone. In addition, all patients were treated with an angiotensin inhibitor. Total urinary protein excretion, serum albumin, blood glucose, complete remission (CR), partial remission (PR), cholesterol, low-density lipoprotein (LDL), serum creatinine (Scr) and estimated GFR (eGFR) were tested at baseline and at 3, 6 and 12 months after the initiation of treatment in all patients. The primary endpoints were CR and PR. Secondary endpoints included changes of Scr, eGFR, clinical data and adverse events. After 12 months, CR was achieved in 40.1% of patients and PR in 43.4%, yielding a total response rate of 83.5%, and the total urinary protein excretion, serum albumin, cholesterol and LDL results were improved significantly compared with those at baseline. Proteinuria and serum albumin results were significantly improved by month 3 of treatment. Two patients relapsed during months 3-6 of follow-up. At the 12-month follow-up, renal function was improved compared with the baseline level as evidenced by eGFR and Scr, respectively. The blood glucose level was stable. One case of pneumococcal pneumonia developed in a patient treated with TAC plus low-dose methylprednisolone and one case of upper gastrointestinal hemorrhage was found in a patient treated with TAC plus low-dose prednisone; both cases completely recovered after treatment. In conclusion, TAC combined with low-dose corticosteroids may be an effective and safe therapeutic option for the treatment of refractory IgAN. However, given the small number of patients in this study, further prospective randomized controlled trials are required with a larger sample of participants and longer follow-up period.
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Affiliation(s)
- Qi-Jun Wan
- Department of Nephrology, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Hao-Fei Hu
- Department of Nephrology, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Yong-Cheng He
- Department of Nephrology, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Shao-Dong Luan
- Department of Nephrology, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Hong-Tao Chen
- Department of Nephrology, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Tong Li
- Department of Nephrology, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Yi Xu
- Department of Nephrology, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Hui-Li Xu
- Department of Nephrology, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Ying Liao
- Department of Nephrology, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
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29
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Yeboah MM, Hye Khan MA, Chesnik MA, Sharma A, Paudyal MP, Falck JR, Imig JD. The epoxyeicosatrienoic acid analog PVPA ameliorates cyclosporine-induced hypertension and renal injury in rats. Am J Physiol Renal Physiol 2016; 311:F576-85. [PMID: 27358055 DOI: 10.1152/ajprenal.00288.2016] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Accepted: 06/28/2016] [Indexed: 01/05/2023] Open
Abstract
The introduction of calcineurin inhibitors (CNI) into clinical practice in the late 1970s transformed organ transplantation and led to significant improvement in acute rejection episodes. However, despite their significant clinical utility, the use of these agents is hampered by the development of hypertension and nephrotoxicity, which ultimately lead to end-stage kidney disease and overt cardiovascular outcomes. There are currently no effective agents to treat or prevent these complications. Importantly, CNI-free immunosuppressive regimens lack the overall efficacy of CNI-based treatments and put patients at risk of allograft rejection. Cytochrome P-450 epoxygenase metabolites of arachidonic acid, epoxyeicosatrienoic acids (EETs), have potent vasodilator and antihypertensive properties in addition to many cytoprotective effects, but their effects on CNI-induced nephrotoxicity have not been explored. Here, we show that PVPA, a novel, orally active analog of 14,15-EET, effectively prevents the development of hypertension and ameliorates kidney injury in cyclosporine-treated rats. PVPA treatment reduced proteinuria and renal dysfunction induced by cyclosporine. PVPA inhibited inflammatory cell infiltration into the kidney and decreased renal fibrosis. PVPA also reduced tubular epithelial cell apoptosis, attenuated the generation of reactive oxygen species, and modulated the unfolded protein response that is associated with endoplasmic reticulum stress. Consistent with the in vivo data, PVPA attenuated cyclosporine-induced apoptosis of NRK-52E cells in vitro. These data indicate that the cytochrome P-450/EET system offers a novel therapeutic strategy to treat or prevent CNI-induced nephrotoxicity.
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Affiliation(s)
- Michael M Yeboah
- Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin;
| | - Md Abdul Hye Khan
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin; and
| | - Marla A Chesnik
- Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Amit Sharma
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin; and
| | - Mahesh P Paudyal
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas
| | - John R Falck
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas
| | - John D Imig
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin; and
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Azzi J, Yin Q, Uehara M, Ohori S, Tang L, Cai K, Ichimura T, McGrath M, Maarouf O, Kefaloyianni E, Loughhead S, Petr J, Sun Q, Kwon M, Tullius S, von Andrian UH, Cheng J, Abdi R. Targeted Delivery of Immunomodulators to Lymph Nodes. Cell Rep 2016; 15:1202-13. [PMID: 27134176 PMCID: PMC4973867 DOI: 10.1016/j.celrep.2016.04.007] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Revised: 02/21/2016] [Accepted: 03/28/2016] [Indexed: 11/03/2022] Open
Abstract
Active-targeted delivery to lymph nodes represents a major advance toward more effective treatment of immune-mediated disease. The MECA79 antibody recognizes peripheral node addressin molecules expressed by high endothelial venules of lymph nodes. By mimicking lymphocyte trafficking to the lymph nodes, we have engineered MECA79-coated microparticles containing an immunosuppressive medication, tacrolimus. Following intravenous administration, MECA79-bearing particles showed marked accumulation in the draining lymph nodes of transplanted animals. Using an allograft heart transplant model, we show that targeted lymph node delivery of microparticles containing tacrolimus can prolong heart allograft survival with negligible changes in tacrolimus serum level. Using MECA79 conjugation, we have demonstrated targeted delivery of tacrolimus to the lymph nodes following systemic administration, with the capacity for immune modulation in vivo.
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Affiliation(s)
- Jamil Azzi
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Qian Yin
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61820, USA
| | - Mayuko Uehara
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Shunsuke Ohori
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Li Tang
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61820, USA
| | - Kaimin Cai
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61820, USA
| | - Takaharu Ichimura
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Martina McGrath
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Omar Maarouf
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Eirini Kefaloyianni
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Scott Loughhead
- Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA
| | - Jarolim Petr
- Department of Pathology, Clinical Laboratories Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Qidi Sun
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61820, USA
| | - Mincheol Kwon
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61820, USA
| | - Stefan Tullius
- Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Ulrich H von Andrian
- Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; The Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
| | - Jianjun Cheng
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61820, USA.
| | - Reza Abdi
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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Hibberd AD, Clark DA, Trevillian PR, Mcelduff P. Interaction between castanospermine an immunosuppressant and cyclosporin A in rat cardiac transplantation. World J Transplant 2016; 6:206-214. [PMID: 27011919 PMCID: PMC4801797 DOI: 10.5500/wjt.v6.i1.206] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 11/05/2015] [Accepted: 01/04/2016] [Indexed: 02/05/2023] Open
Abstract
AIM: To investigate the interaction between castanospermine and cyclosporin A (CsA) and to provide an explanation for it.
METHODS: The alkaloid castanospermine was prepared from the seeds of Castanospermum austral consistently achieving purity. Rat heterotopic cardiac transplantation and mixed lymphocyte reactivity were done using genetically inbred strains of PVG (donor) and DA (recipient). For the mixed lymphocyte reaction stimulator cells were irradiated with 3000 rads using a linear accelerator. Cyclosporin A was administered by gavage and venous blood collected 2 h later (C2). The blood levels of CsA (Neoral) were measured by immunoassay which consisted of a homogeneous enzyme assay (EMIT) on Cobas Mira. Statistical analyses of interactions were done by an accelerated failure time model with Weibull distribution for allograft survival and logistic regression for the mixed lymphocyte reactivity.
RESULTS: Castanospermine prolonged transplant survival times as a function of dose even at relatively low doses. Cyclosporin A also prolonged transplant survival times as a function of dose particularly at doses above 2 mg/kg. There were synergistic interactions between castanospermine and CsA in the prolongation of cardiac allograft survival for dose ranges of CsA by castanospermine of (0 to 2) mg/kg by (0 to 200) mg/kg (HR = 0.986; 95%CI: 0.981-0.992; P < 0.001) and (0 to 3) mg/kg by (0 to 100) mg/kg (HR = 0.986; 95%CI: 0.981-0.992; P < 0.001) respectively. The addition of castanospermine did not significantly increase the levels of cyclosporin A on day 3 or day 6 for all doses of CsA. On the contrary, cessation of castanospermine in the presence of CsA at 2 mg/kg significantly increased the CsA level (P = 0.002). Castanospermine inhibited mixed lymphocyte reactivity in a dose dependent manner but without synergistic interaction.
CONCLUSION: There is synergistic interaction between castanospermine and CsA in rat cardiac transplantation. Neither the mixed lymphocyte reaction nor the metabolism of CsA provides an explanation.
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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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Tedesco Silva H, Rosso Felipe C, Medina Pestana JO. Reviewing 15 years of experience with sirolimus. Transplant Res 2015; 4:6. [PMID: 27293553 PMCID: PMC4895289 DOI: 10.1186/s13737-015-0028-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Here, we review 15 years of clinical use of sirolimus in our transplant center, in context with the developing immunosuppressive strategies use worldwide. The majority of studies were conducted in de novo kidney transplant recipients, using sirolimus (SRL) in combination with calcineurin inhibitors (CNIs). We also explored steroid (ST) or CNI-sparing therapies, including CNI minimization, elimination, or conversion strategies in combination with mycophenolate (MMF/MPS). Pooled long-term outcomes were comparable with those obtained with CNI and antimetabolite combination. Surprisingly, there are still several areas that need further investigation to improve the risk/benefit profile of SRL in kidney transplantation, including pharmacokinetic/pharmacodynamic drug-to-drug interaction with cyclosporine (CsA) or tacrolimus (TAC), mechanisms of SRL-associated adverse reactions and combinations with other drugs such as belatacept and once-daily TAC, possibly leading to improved long-term adherence. These studies, along with others investigating the benefits of SRL associated lower viral infections and malignancies, are essential as we do not expect the introduction of new immunosuppressive drugs in the near future.
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Affiliation(s)
- Helio Tedesco Silva
- Nephrology Division, Hospital do Rim, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Claudia Rosso Felipe
- Nephrology Division, Hospital do Rim, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Jose Osmar Medina Pestana
- Nephrology Division, Hospital do Rim, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
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Stevens RB, Foster KW, Miles CD, Kalil AC, Florescu DF, Sandoz JP, Rigley TH, Malik T, Wrenshall LE. A Randomized 2x2 Factorial Clinical Trial of Renal Transplantation: Steroid-Free Maintenance Immunosuppression with Calcineurin Inhibitor Withdrawal after Six Months Associates with Improved Renal Function and Reduced Chronic Histopathology. PLoS One 2015; 10:e0139247. [PMID: 26465152 PMCID: PMC4605789 DOI: 10.1371/journal.pone.0139247] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 09/08/2015] [Indexed: 12/28/2022] Open
Abstract
INTRODUCTION The two most significant impediments to renal allograft survival are rejection and the direct nephrotoxicity of the immunosuppressant drugs required to prevent it. Calcineurin inhibitors (CNI), a mainstay of most immunosuppression regimens, are particularly nephrotoxic. Until less toxic antirejection agents become available, the only option is to optimize our use of those at hand. AIM To determine whether intensive rabbit anti-thymocyte globulin (rATG) induction followed by CNI withdrawal would individually or combined improve graft function and reduce graft chronic histopathology-surrogates for graft and, therefore, patient survival. As previously reported, a single large rATG dose over 24 hours was well-tolerated and associated with better renal function, fewer infections, and improved patient survival. Here we report testing whether complete CNI discontinuation would improve renal function and decrease graft pathology. METHODS Between April 20, 2004 and 4-14-2009 we conducted a prospective, randomized, non-blinded renal transplantation trial of two rATG dosing protocols (single dose, 6 mg/kg vs. divided doses, 1.5 mg/kg every other day x 4; target enrollment = 180). Subsequent maintenance immunosuppression consisted of tacrolimus, a CNI, and sirolimus, a mammalian target of rapamycin inhibitor. We report here the outcome of converting patients after six months either to minimized tacrolimus/sirolimus or mycophenolate mofetil/sirolimus. Primary endpoints were graft function and chronic histopathology from protocol kidney biopsies at 12 and 24 months. RESULTS CNI withdrawal (on-treatment analysis) associated with better graft function (p <0.001) and lower chronic histopathology composite scores in protocol biopsies at 12 (p = 0.003) and 24 (p = 0.013) months, without affecting patient (p = 0.81) or graft (p = 0.93) survival, or rejection rate (p = 0.17). CONCLUSION CNI (tacrolimus) withdrawal at six months may provide a strategy for decreased nephrotoxicity and improved long-term function in steroid-free low immunological risk renal transplant patients. TRIAL REGISTRATION ClinicalTrials.gov NCT00556933.
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Affiliation(s)
- R. Brian Stevens
- Department of Surgery, Wright State University Boonshoft School of Medicine, Dayton, Ohio, United States of America
- * E-mail:
| | - Kirk W. Foster
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Clifford D. Miles
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Andre C. Kalil
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Diana F. Florescu
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - John P. Sandoz
- Department of Surgery, Wright State University Boonshoft School of Medicine, Dayton, Ohio, United States of America
| | - Theodore H. Rigley
- Department of Surgery, Wright State University Boonshoft School of Medicine, Dayton, Ohio, United States of America
| | - Tamer Malik
- Department of Surgery, Wright State University Boonshoft School of Medicine, Dayton, Ohio, United States of America
| | - Lucile E. Wrenshall
- Department of Surgery, Wright State University Boonshoft School of Medicine, Dayton, Ohio, United States of America
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Koo TY, Yang J. Current progress in ABO-incompatible kidney transplantation. Kidney Res Clin Pract 2015; 34:170-9. [PMID: 26484043 PMCID: PMC4608875 DOI: 10.1016/j.krcp.2015.08.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2015] [Revised: 08/12/2015] [Accepted: 08/12/2015] [Indexed: 02/07/2023] Open
Abstract
ABO-incompatible kidney transplantation (ABOi KT) was introduced to expand the donor pool and minimize shortage of kidneys for transplantation. Because improved outcomes of ABOi KT were reported in Japan in the early 2000s, the number of ABOi KTs has been increasing worldwide. In addition, a better understanding of immune pathogenesis and subsequent aggressive immunosuppression has helped to make effective desensitization protocols. Current strategies of ABOi KT consist of pretransplant antibody removal using plasmapheresis or immunoadsorption to prevent hyperacute rejection and potent maintenance immunosuppression, such as tacrolimus and mycophenolate mofetil, to inhibit antibody-mediated rejection. Recent outcomes of ABOi KT are comparable with ABO-compatible KT. However, there are still many problems to be resolved. Very high anti-ABO antibody producers are difficult to desensitize. In addition, ABOi KT is associated with an increased risk of infection and possibly malignancy due to aggressive immunosuppression. Optimization of desensitization and patient-tailored immunosuppression protocols are needed to achieve better outcomes of ABOi KT. This review provides an overview of the history, immune mechanism, immunosuppressive protocol, outcomes, current obstacles, and future perspectives in ABOi KT.
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Affiliation(s)
- Tai Yeon Koo
- Transplantation Center, Seoul National University Hospital, Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jaeseok Yang
- Transplantation Center, Seoul National University Hospital, Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Carmellini M, Garcia V, Wang Z, Vergara M, Russ G. Efficacy of everolimus with reduced-exposure cyclosporine in de novo kidney transplant patients at increased risk for efficacy events: analysis of a randomized trial. J Nephrol 2015; 28:633-9. [PMID: 25708913 DOI: 10.1007/s40620-015-0180-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Accepted: 02/05/2015] [Indexed: 01/05/2023]
Abstract
The efficacy of de novo everolimus with reduced-exposure calcineurin inhibitor (CNI) was examined in kidney transplant subpopulations from the A2309 study that were identified to be at increased risk for efficacy events. A2309 was a 24-month, multicenter, open-label trial in which 833 de novo kidney transplant recipients were randomized to everolimus targeting 3-8 or 6-12 ng/ml with reduced-exposure cyclosporine (CsA), or mycophenolic acid (MPA) with standard-exposure CsA, all with basiliximab induction. The composite efficacy endpoint was treated biopsy-proven acute rejection (BPAR), graft loss, death, or loss to follow-up. Cox proportional hazard modeling showed male gender, younger recipient age, black race, delayed graft function, human leukocyte antigen (HLA) mismatch ≥3 and increasing donor age to be significantly predictive for the composite efficacy endpoint at months 12 or 24 post-transplant. CsA exposure was 53-75 % lower, and 46-75 % lower, in patients receiving everolimus 3-8 ng/ml or receiving everolimus 6-12 ng/ml, respectively, versus MPA-treated patients. The incidence of the composite endpoint was similar in all three treatment groups within each subpopulation analyzed. The incidence of treated BPAR was similar with everolimus 3-8 ng/ml or MPA in all subpopulations, but less frequent with everolimus 6-12 ng/ml versus MPA in patients with HLA mismatch ≥3 (p = 0.049). This post hoc analysis of a large, randomized trial suggests that a de novo regimen of everolimus with reduced-exposure CsA maintains immunosuppressive efficacy even in kidney transplant patients at increased risk for efficacy events despite substantial reductions in CsA exposure.
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Affiliation(s)
- Mario Carmellini
- Department of Surgery and Bioengineering, University of Siena, Siena, Italy. .,Centro Trapianti di Rene, Az. Osped Universitaria Senese Ospedale S Maria alle Scotte, U.O.C. Chirugira dei Trpianti-Dip. Chirugria Gen. e Spec, Viale Bracci 1, 53100, Siena, Italy.
| | - Valter Garcia
- Hospital Don Vicente Scherer, Santa Casa de Misericordia do Porto Alegre, Porto Alegre, Brazil
| | | | | | - Graeme Russ
- Renal Unit, The Queen Elizabeth Hospital, Woodville, Australia
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A randomized 2×2 factorial trial, part 1: single-dose rabbit antithymocyte globulin induction may improve renal transplantation outcomes. Transplantation 2015; 99:197-209. [PMID: 25083614 PMCID: PMC4281164 DOI: 10.1097/tp.0000000000000250] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Supplemental digital content is available in the text. Background We conducted a randomized and unblinded 2×2 sequential-factorial trial, composed of an induction arm (part 1) comparing single-dose (SD) versus divided-dose rabbit antithymocyte globulin (rATG), and a maintenance arm (part 2) comparing tacrolimus minimization versus withdrawal. We report the long-term safety and efficacy of SD-rATG induction in the context of early steroid withdrawal and tacrolimus minimization or withdrawal. Methods Patients (n=180) received 6 mg/kg rATG, SD or four alternate-day doses (1.5 mg/kg/dose), with early steroid withdrawal and tacrolimus or sirolimus maintenance. After 6 months targeted maintenance levels were tacrolimus, 2 to 4 ng/mL and sirolimus, 4 to 6 ng/mL or, if calcineurin inhibitor–withdrawn, sirolimus 8 to 12 ng/mL with mycophenolate mofetil 2 g two times per day. Primary endpoints were renal function (abbreviated modification of diet in renal disease) and chronic graft histopathology (Banff). Secondary endpoints included patient survival, graft survival, biopsy-proven rejection, and infectious or noninfectious complications. Results Follow-up averaged longer than 4 years. Tacrolimus or sirolimus and mycophenolate mofetil exposure was identical between groups. The SD-rATG associated with improved renal function (2-36 months; P<0.001) in deceased donor recipients. The SD-rATG associated with quicker lymphocyte, CD4 T cell, and CD4-CD8 recovery and fewer infections. Cox multivariate hazard modeling showed divided-dose–rATG (P=0.019), deceased donor (P=0.003), serious infection (P=0.0.018), and lower lymphocyte count (P=0.001) associated with increased mortality. Patients with all four covariates showed a 27-fold increased likelihood of death (P=0.00002). Chronic graft histopathology, rejection rates, and death-censored graft survival were not significantly different between groups. Conclusion The SD-rATG induction improves the 3-year renal function in recipients of deceased donor kidneys. This benefit, along with possibly improved patient survival and fewer infections suggest that how rATG is administered may impact its efficacy and safety.
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Verghese PS, Dunn TB, Chinnakotla S, Gillingham KJ, Matas AJ, Mauer MS. Calcineurin inhibitors in HLA-identical living related donor kidney transplantation. Nephrol Dial Transplant 2014; 29:209-18. [PMID: 24414376 DOI: 10.1093/ndt/gft447] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Given the nephrotoxicity of calcineurin inhibitors (CNIs), we asked whether their addition improved living related donor (LRD) human leukocyte antigen (HLA) identical kidney transplant recipient outcomes. METHODS We performed a comprehensive literature review and a single-center study comparing patient survival (PS) and graft survival (GS) of LRD HLA-identical kidney transplants for three different immunosuppression eras: Era 1 (up to 1984): anti-lymphocyte globulin (ALG) induction and maintenance immunosuppression with prednisone and azathioprine (AZA) (n = 114); Era 2a (1984-99): CNI added; evolution from ALG to thymoglobulin; AZA to mycophenolate (n = 262). Era 2b (1999-2011): rapid discontinuation of prednisone (thymoglobulin induction, CNI and mycophenolate) in recipients having first or second transplant and not previously on prednisone (n = 77). RESULTS Demographics differed by era: recipient (P < 0.0001) and donor age (P < 0.0001) increased and the proportion of Caucasian donors (P = 0.02) and recipients (P = 0.003) decreased with each advancing era. There was no significant difference in PS (P = 0.6); cause of death (P = 0.5); death-censored GS (P = 0.8) or graft loss from acute rejection by era. Graft loss from chronic allograft nephropathy (P = 0.02) and hypertension (P = 0.005) were greater in the CNI eras. There were no significant differences in the 1/creatinine slopes between eras for the first (P = 0.6), second (P = 0.9) or >2 years post-transplant (P = 0.4). Literature review revealed no clear benefits for CNI in these human leukocyte antigen (HLA) identical LRD graft recipients. CONCLUSIONS This study confirmed that there are no benefits of CNIs for HLA-identical LRD recipients. Moreover, we did find evidence of potential harm. Thus, monotherapy or early discontinuation of CNI should be given consideration in these patients.
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Affiliation(s)
- Priya S Verghese
- Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA
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Abstract
Approximately 18% of patients undergoing cardiac surgery experience AKI (on the basis of modern standardized definitions of AKI), and approximately 2%-6% will require hemodialysis. The development of AKI after cardiac surgery portends poor short- and long-term prognoses, with those developing RIFLE failure or AKI Network stage III having an almost 2-fold increase in the risk of death. AKI is caused by a variety of factors, including nephrotoxins, hypoxia, mechanical trauma, inflammation, cardiopulmonary bypass, and hemodynamic instability, and it may be affected by the clinician's choice of fluids and vasoactive agents as well as the transfusion strategy used. The risk of AKI may be ameliorated by avoidance of nephrotoxins, achievement of adequate glucose control preoperatively, and use of goal-directed therapy hemodynamic strategies. Remote ischemic preconditioning is an exciting future strategy, but more work is needed before widespread implementation. Unfortunately, there are no pharmacologic agents known to reduce the risk of AKI or treat established AKI.
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Affiliation(s)
| | | | - Mitchell H Rosner
- Medicine, University of Virginia Health System, Charlottesville, Virginia
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Goodyear SJ, Barnes J, Imray CE, Higgins R, Lam FT, Kashi SH, Tan LC, Imray CHE. The feasibility and applications of non-invasive cardiac output monitoring, thromboelastography and transit-time flow measurement in living-related renal transplantation surgery: results of a prospective pilot observational study. Transplant Res 2014; 3:16. [PMID: 25206974 PMCID: PMC4158354 DOI: 10.1186/2047-1440-3-16] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2014] [Accepted: 08/11/2014] [Indexed: 11/23/2022] Open
Abstract
INTRODUCTION Delayed graft function (DGF) remains a significant and detrimental postoperative phenomenon following living-related renal allograft transplantation, with a published incidence of up to 15%. Early therapeutic vasodilatory interventions have been shown to improve DGF, and modifications to immunosuppressive regimens may subsequently lessen its impact. This pilot study assesses the potential applicability of perioperative non-invasive cardiac output monitoring (NICOM), transit-time flow monitoring (TTFM) of the transplant renal artery and pre-/perioperative thromboelastography (TEG) in the early prediction of DGF and perioperative complications. METHODS Ten consecutive living-related renal allograft recipients were studied. Non-invasive cardiac output monitoring commenced immediately following induction of anaesthesia and was maintained throughout the perioperative period. Doppler-based TTFM was performed during natural haemostatic pauses in the transplant surgery: immediately following graft reperfusion and following ureteric implantation. Central venous blood sampling for TEG was performed following induction of anaesthesia and during abdominal closure. RESULTS A single incidence of DGF was seen within the studied cohort and one intra-operative (thrombotic) complication noted. NICOM confirmed a predictable trend of increased cardiac index (CI) following allograft reperfusion (mean CI - clamped: 3.17 ± 0.29 L/min/m(2), post-reperfusion: 3.50 ± 0.35 L/min/m(2); P < 0.05) mediated by a significant reduction in total peripheral resistance. Reduced TTFM at the point of allograft reperfusion (227 ml/min c.f. mean; 411 ml/min (95% CI: 358 to 465)) was identified in a subject who experienced intra-operative transplant renal artery thrombosis. TEG data exhibited significant reductions in clot lysis (LY30 (%): pre-op: 1.0 (0.29 to 1.71), post reperfusion 0.33 (0.15 to 0.80); P = 0.02) and a trend towards increased clot initiation following allograft reperfusion. CONCLUSIONS Reduced renal arterial blood flow (falling without the 95% CI of the mean), was able to accurately predict anastomotic complications within this pilot study. TEG data suggest the emergence of a prothrombotic state, of uncertain clinical significance, following allograft reperfusion. Abrogation of characteristic haemodynamic trends, as determined by NICOM, following allograft reperfusion may permit prediction of individuals at risk of DGF. The findings of this pilot study mandate a larger definitive trial to determine the clinical applications and predictive value of these technologies.
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Affiliation(s)
- Stephen J Goodyear
- University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK
| | - James Barnes
- University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK
| | - Caitlin E Imray
- University of Sheffield Medical School, Beech Hill Rd, Sheffield, South Yorkshire S10 2RX, UK
| | - Robert Higgins
- University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK
| | - For T Lam
- University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK
| | - S Habib Kashi
- University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK
| | - Lam C Tan
- University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK
| | - Christopher HE Imray
- University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK
- Warwick Medical School, University of Warwick, Gibbet Hill Rd, Coventry CV4 7AL, UK
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Hao JC, Wang WT, Yan LN, Li B, Wen TF, Yang JY, Xu MQ, Zhao JC, Wei YG. Effect of low-dose tacrolimus with mycophenolate mofetil on renal function following liver transplantation. World J Gastroenterol 2014; 20:11356-11362. [PMID: 25170222 PMCID: PMC4145776 DOI: 10.3748/wjg.v20.i32.11356] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2014] [Revised: 03/05/2014] [Accepted: 04/23/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine whether low-dose tacrolimus (TAC) combined with mycophenolate mofetil (MMF) is a safe approach to decrease the incidence of chronic kidney disease (CKD) in liver transplantation (LT) recipients.
METHODS: We analyzed the medical records of 689 patients who underwent LT between March 1999 and December 2012 in a single Chinese center. Immunosuppression was initiated with a calcineurin inhibitor (TAC or CSA) and prednisone with or without MMF. CKD is defined by the glomerular filtration rate (GFR), estimated by an abbreviated Modification of Diet in Renal Disease formula, < 60 mL/min per 1.73 m2 for at least 3 consecutive months after LT. Individuals with TAC trough concentrations ≤ 8 ng/mL at 3 mo after LT were defined as the low-dose group. The incidence of CKD within 5 years was compared between the TAC group and the CSA group, as well as between four subgroups (low-dose and high-dose TAC groups with or without MMF).
RESULTS: No difference regarding the occurrence of pre-LT renal dysfunction or that of post-LT rejection was found between the TAC and CSA groups or between the four subgroups. With a definition of GFR < 60 mL/min per 1.73 m2, the overall incidence of CKD was significantly higher in the CSA group than in the TAC group. The incidence of CKD in the low-dose TAC + MMF group (7.7%) was significantly lower than that observed in the low-dose TAC group (15.9%), high-dose TAC group (24.6%) and high-dose TAC + MMF group (18.5%). The cumulative 1-, 3- and 5-year incidence rates of CKD were 12.7%, 14.5% and 16.7%, respectively. The cumulative 5-year survival rates were 61.7% and 82.2% in patients with or without CKD, respectively.
CONCLUSION: In LT patients, the choice of immunosuppressive therapy appears to affect renal function and patient survival.
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Scheffert JL, Raza K. Immunosuppression in lung transplantation. J Thorac Dis 2014; 6:1039-53. [PMID: 25132971 DOI: 10.3978/j.issn.2072-1439.2014.04.23] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Accepted: 04/16/2014] [Indexed: 01/10/2023]
Abstract
Lung transplantation can be a life-saving procedure for those with end-stage lung diseases. Unfortunately, long term graft and patient survival are limited by both acute and chronic allograft rejection, with a median survival of just over 6 years. Immunosuppressive regimens are employed to reduce the rate of rejection, and while protocols vary from center to center, conventional maintenance therapy consists of triple drug therapy with a calcineurin inhibitor (cyclosporine or tacrolimus), antiproliferative agents [azathioprine (AZA), mycophenolate, sirolimus (srl), everolimus (evl)], and corticosteroids (CS). Roughly 50% of lung transplant centers also utilize induction therapy, with polyclonal antibody preparations [equine or rabbit anti-thymocyte globulin (ATG)], interleukin 2 receptor antagonists (IL2RAs) (daclizumab or basiliximab), or alemtuzumab. This review summarizes these agents and the data surrounding their use in lung transplantation, as well as additional common and novel therapies in lung transplantation. Despite the progression of the management of lung transplant recipients, they continue to be at high risk of treatment-related complications, and poor graft and patient survival. Randomized clinical trials are needed to allow for the development of better agents, regimens and techniques to address above mentioned issues and reduce morbidity and mortality among lung transplant recipients.
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Affiliation(s)
- Jenna L Scheffert
- 1 NewYork-Presbyterian Hospital/Columbia University Medical Center, Department of Pharmacy, USA ; 2 Lung Transplant Program, Department of Pulmonary, Allergy and Critical Care Medicine, Columbia University Medical Center, USA
| | - Kashif Raza
- 1 NewYork-Presbyterian Hospital/Columbia University Medical Center, Department of Pharmacy, USA ; 2 Lung Transplant Program, Department of Pulmonary, Allergy and Critical Care Medicine, Columbia University Medical Center, USA
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Song L, Ma A, Dun H, Hu Y, Zeng L, Bai J, Zhang G, Kinugasa F, Sudo Y, Miyao Y, Okimura K, Miura T, Daloze P, Chen H. Effects of ASKP1240 combined with tacrolimus or mycophenolate mofetil on renal allograft survival in Cynomolgus monkeys. Transplantation 2014; 98:267-76. [PMID: 24992357 PMCID: PMC4175122 DOI: 10.1097/tp.0000000000000236] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Accepted: 04/04/2014] [Indexed: 01/22/2023]
Abstract
BACKGROUND Blocking the CD40-CD154 signal pathway has previously shown promise as a strategy to prevent allograft rejection. In this study, the efficacy of a novel fully human anti-CD40 monoclonal antibody-ASKP1240, administered as a monotherapy or combination therapy (subtherapeutic dose of tacrolimus or mycophenolate mofetil), on the prevention of renal allograft rejection was evaluated in Cynomolgus monkeys. METHODS Heterotopic kidney transplants were performed in ABO-compatible, stimulation index 2.5 or higher in the two-way mixed lymphocyte reaction monkey pairs. Animals were divided into 12 groups and observed for a maximum of 180 days. Histopathologic, hematology, and biochemistry analyses were conducted in all groups. Cytokine release (interleukin [IL]-2, IL-4, IL-5, IL-6, tumor necrosis factor, and interferon-γ) was investigated in several groups. RESULTS ASKP1240 prolonged renal allograft survival in a dose-dependent manner in monotherapy. Low-dose (2 mg/kg) or high-dose (5 mg/kg) ASKP1240, in combination with mycophenolate mofetil (15 mg/kg) or tacrolimus (1 mg/kg), showed a significantly longer allograft survival time compared with monotherapy groups. No obvious side effects including drug-related thromboembolic complications were found. Cytokine release was not induced by ASKP1240 administration. CONCLUSION The present study indicates that ASKP1240, alone or in combination with other immunosuppressive drugs, could be a promising antirejection agent in organ transplantation.
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Affiliation(s)
- Lijun Song
- 1 Department of Surgery, Research Center, CHUM, Notre-Dame Hospital, University of Montreal, Montreal, Quebec, Canada. 2 Laboratory Animals Center, the Academy of Military Medical Sciences, Beijing, China. 3 Translational and Development Pharmacology-US, Drug Discovery Research, Astellas Research Institute of America LLC, Northbrook, IL. 4 Astellas Research Technology Inc., Osaka, Japan. 5 Drug Metabolism Research Labs. Astellas Pharma Inc., Osaka, Japan. 6 Pharmacological Research Labs., Kyowa Hakko Kirin Co., Ltd., Shizuoka, Japan. 7 Address correspondence to: Huifang Chen, M.D., Ph.D., Laboratory of Experimental Surgery, Research Center, CHUM, Notre-Dame Hospital, University of Montréal, 2099 Alexandre de Sève, Montréal, Room Y1611, Québec, Canada H2L 2W5
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Mathis AS, Egloff G, Ghin HL. Calcineurin inhibitor sparing strategies in renal transplantation, part one: Late sparing strategies. World J Transplant 2014; 4:57-80. [PMID: 25032096 PMCID: PMC4094953 DOI: 10.5500/wjt.v4.i2.57] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2014] [Revised: 03/25/2014] [Accepted: 05/14/2014] [Indexed: 02/05/2023] Open
Abstract
Kidney transplantation improves quality of life and reduces the risk of mortality. A majority of the success of kidney transplantation is attributable to the calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, and their ability to reduce acute rejection rates. However, long-term graft survival rates have not improved over time, and although controversial, evidence does suggest a role of chronic CNI toxicity in this failure to improve outcomes. Consequently, there is interest in reducing or removing CNIs from immunosuppressive regimens in an attempt to improve outcomes. Several strategies exist to spare calcineurin inhibitors, including use of agents such as mycophenolate mofetil (MMF), mycophenolate sodium (MPS), sirolimus, everolimus or belatacept to facilitate late calcineurin inhibitor withdrawal, beyond 6 mo post-transplant; or using these agents to plan early withdrawal within 6 mo; or to avoid the CNIs all together using CNI-free regimens. Although numerous reviews have been written on this topic, practice varies significantly between centers. This review organizes the data based on patient characteristics (i.e., the baseline immunosuppressive regimen) as a means to aid the practicing clinician in caring for their patients, by matching up their situation with the relevant literature. The current review, the first in a series of two, examines the potential of immunosuppressive agents to facilitate late CNI withdrawal beyond 6 mo post-transplant, and has demonstrated that the strongest evidence resides with MMF/MPS. MMF or MPS can be successfully introduced/maintained to facilitate late CNI withdrawal and improve renal function in the setting of graft deterioration, albeit with an increased risk of acute rejection and infection. Additional benefits may include improved blood pressure, lipid profile and serum glucose. Sirolimus has less data directly comparing CNI withdrawal to an active CNI-containing regimen, but modest improvement in short-term renal function is possible, with an increased risk of proteinuria, especially in the setting of baseline renal dysfunction and/or proteinuria. Renal outcomes may be improved when sirolimus is used in combination with MMF. Although data with everolimus is less robust, results appear similar to those observed with sirolimus.
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Abstract
The enduring success of lung transplantation is built on the use of immunosuppressive drugs to stop the immune system from rejecting the newly transplanted lung allograft. Most patients receive a triple-drug maintenance immunosuppressive regimen consisting of a calcineurin inhibitor, an antiproliferative and corticosteroids. Induction therapy with either an antilymphocyte monoclonal or an interleukin-2 receptor antagonist are prescribed by many centres aiming to achieve rapid inhibition of recently activated and potentially alloreactive T lymphocytes. Despite this generic approach acute rejection episodes remain common, mandating further fine-tuning and augmentation of the immunosuppressive regimen. While there has been a trend away from cyclosporine and azathioprine towards a preference for tacrolimus and mycophenolate mofetil, this has not translated into significant protection from the development of chronic lung allograft dysfunction, the main barrier to the long-term success of lung transplantation. This article reviews the problem of lung allograft rejection and the evidence for immunosuppressive regimens used both in the short- and long-term in patients undergoing lung transplantation.
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Assis-Borba L, Cristelli MP, Paula MI, Franco MF, Tedesco-Silva H, Medina-Pestana JO. Expanding the use of expanded criteria donors in kidney transplantation. Int Urol Nephrol 2014; 46:1663-71. [PMID: 24677001 DOI: 10.1007/s11255-014-0695-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2013] [Accepted: 03/17/2014] [Indexed: 01/16/2023]
Abstract
PURPOSE Although the use of kidney allografts from expanded criteria donors (ECD) has increased in recent years, the reported discard rates are also growing. The influence of ECD characteristics on transplant outcomes is still underevaluated. METHODS This retrospective study investigated the influence of preimplantation biopsy findings and delayed graft function (DGF) on patient and graft survivals and renal function at 36 months in a cohort of 372 ECD kidney transplant recipients. RESULTS Patient and graft survivals were 91.6 and 68.9 %. The incidence of biopsy-proven acute rejection was 31 %. There were no differences in patient (88.6 vs. 91.1 vs. 94.7 vs. 78.6 %, p = 0.10) or graft (78.1 vs. 72.2 vs. 60.5 vs. 62.6 %, p = 0.14) survivals and renal function (41.7 ± 25.6 vs. 39.9 ± 29.9 vs. 38.1 ± 30.6 vs. 37.4 ± 29.2 mL/min, p = 0.79) comparing ECD kidneys with mild, moderate, and severe histological changes or with no preimplantation biopsy, respectively. However, severe scored transplants had the worst death-censored graft survival (OR 3.1, 95 % CI 1.4-6.9, p = 0.007). No significant differences in patient (86.2 vs. 83.4 %, p = 0.17) or graft (73.7 vs. 65.9 %, p = 0.06) survivals and renal function (38.9 ± 28.6 vs. 39.9 ± 28.4 mL/min, p = 0.72) were observed comparing patients with or without DGF. Multivariable analysis found diabetes history as the only independent risk factor for graft loss (OR 2.1, 95 % CI 1.3-3.3, p = 0.003) or patient death (OR 3.1, 95 % CI 1.5-5.8, p < 0.001). CONCLUSIONS Within the limitations of sample size and short follow-up time, in this cohort of ECD kidney transplant recipients the severity of histological changes observed in preimplantation biopsies was independently associated with graft loss.
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Affiliation(s)
- Luciana Assis-Borba
- Transplant Division, Hospital do Rim e Hipertensão, UNIFESP, São Paulo, SP, Brazil
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Muramatsu M, Gonzalez HD, Cacciola R, Aikawa A, Yaqoob MM, Puliatti C. ABO incompatible renal transplants: Good or bad? World J Transplant 2014; 4:18-29. [PMID: 24669364 PMCID: PMC3964193 DOI: 10.5500/wjt.v4.i1.18] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2013] [Revised: 01/21/2014] [Accepted: 02/19/2014] [Indexed: 02/05/2023] Open
Abstract
ABO incompatible kidney transplantation (ABOi-KT) was previously considered to be an absolute contraindication for patients with end-stage kidney disease (ESKD) due to hyperacute rejection related to blood type barrier. Since the first successful series of ABOi-KT was reported, ABOi-KT is performed increasingly all over the world. ABOi-KT has led to an expanded donor pool and reduced the number of patients with ESKD awaiting deceased kidney transplantation (KT). Intensified immunosuppression and immunological understanding has helped to shape current desensitization protocols. Consequently, in recent years, ABOi-KT outcome is comparable to ABO compatible KT (ABOc-KT). However, many questions still remain unanswered. In ABOi-KT, there is an additional residual immunological risk that may lead to allograft damage, despite using current diverse but usually intensified immunosuppressive protocols at the expense of increasing risk of infection and possibly malignancy. Notably, in ABOi-KT, desensitization and antibody reduction therapies have increased the cost of KT. Reassuringly, there has been an evolution in ABOi-KT leading to a simplification of protocols over the last decade. This review provides an overview of the history, outcome, protocol, advantages and disadvantages in ABOi-KT, and focuses on whether ABOi-KT should be recommended as a therapeutic option of KT in the future.
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Klintmalm GB, Nashan B. The Role of mTOR Inhibitors in Liver Transplantation: Reviewing the Evidence. J Transplant 2014; 2014:845438. [PMID: 24719752 PMCID: PMC3955586 DOI: 10.1155/2014/845438] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Revised: 09/20/2013] [Accepted: 09/21/2013] [Indexed: 12/14/2022] Open
Abstract
Despite the success of liver transplantation, long-term complications remain, including de novo malignancies, metabolic syndrome, and the recurrence of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC). The current mainstay of treatment, calcineurin inhibitors (CNIs), can also worsen posttransplant renal dysfunction, neurotoxicity, and diabetes. Clearly there is a need for better immunosuppressive agents that maintain similar rates of efficacy and renal function whilst minimizing adverse effects. The mammalian target of rapamycin (mTOR) inhibitors with a mechanism of action that is different from other immunosuppressive agents has the potential to address some of these issues. In this review we surveyed the literature for reports of the use of mTOR inhibitors in adult liver transplantation with respect to renal function, efficacy, safety, neurological symptoms, de novo tumors, and the recurrence of HCC and HCV. The results of our review indicate that mTOR inhibitors are associated with efficacy comparable to CNIs while having benefits on renal function in liver transplantation. We also consider newer dosing schedules that may limit side effects. Finally, we discuss evidence that mTOR inhibitors may have benefits in the oncology setting and in relation to HCV-related allograft fibrosis, metabolic syndrome, and neurotoxicity.
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Affiliation(s)
- Goran B. Klintmalm
- Baylor Simmons Transplant Institute, Baylor University Medical Center, 3410 Worth Street, Suite 950, Dallas, TX 75246, USA
| | - Björn Nashan
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Medical Center Eppendorf, Martinistraβe 52, 20246 Hamburg, Germany
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49
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Abstract
Solid organ transplantation has transformed the lives of many children and adults by providing treatment for patients with organ failure who would have otherwise succumbed to their disease. The first successful transplant in 1954 was a kidney transplant between identical twins, which circumvented the problem of rejection from MHC incompatibility. Further progress in solid organ transplantation was enabled by the discovery of immunosuppressive agents such as corticosteroids and azathioprine in the 1950s and ciclosporin in 1970. Today, solid organ transplantation is a conventional treatment with improved patient and allograft survival rates. However, the challenge that lies ahead is to extend allograft survival time while simultaneously reducing the side effects of immunosuppression. This is particularly important for children who have irreversible organ failure and may require multiple transplants. Pediatric transplant teams also need to improve patient quality of life at a time of physical, emotional and psychosocial development. This review will elaborate on the long-term outcomes of children after kidney, liver, heart, lung and intestinal transplantation. As mortality rates after transplantation have declined, there has emerged an increased focus on reducing longer-term morbidity with improved outcomes in optimizing cardiovascular risk, renal impairment, growth and quality of life. Data were obtained from a review of the literature and particularly from national registries and databases such as the North American Pediatric Renal Trials and Collaborative Studies for the kidney, SPLIT for liver, International Society for Heart and Lung Transplantation and UNOS for intestinal transplantation.
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Affiliation(s)
- Jon Jin Kim
- Department of Pediatric Nephrology, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, England, United Kingdom
| | - Stephen D Marks
- Department of Pediatric Nephrology, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, England, United Kingdom
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Penninga L, Møller CH, Penninga EI, Iversen M, Gluud C, Steinbrüchel DA. Antibody induction therapy for lung transplant recipients. Cochrane Database Syst Rev 2013; 2013:CD008927. [PMID: 24282128 PMCID: PMC6486205 DOI: 10.1002/14651858.cd008927.pub2] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
BACKGROUND Lung transplantation has become a valuable and well-accepted treatment option for most end-stage lung diseases. Lung transplant recipients are at risk of transplanted organ rejection, and life-long immunosuppression is necessary. Clear evidence is essential to identify an optimal, safe and effective immunosuppressive treatment strategy for lung transplant recipients. Consensus has not yet been achieved concerning use of immunosuppressive antibodies against T-cells for induction following lung transplantation. OBJECTIVES We aimed to assess the benefits and harms of immunosuppressive T-cell antibody induction with ATG, ALG, IL-2RA, alemtuzumab, or muromonab-CD3 for lung transplant recipients. SEARCH METHODS We searched the Cochrane Renal Group's Specialised Register to 4 March 2013 through contact with the Trials Search Co-ordinator using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE and EMBASE. SELECTION CRITERIA We included all randomised controlled trials (RCTs) that compared immunosuppressive monoclonal and polyclonal T-cell antibody induction for lung transplant recipients. An inclusion criterion was that all participants must have received the same maintenance immunosuppressive therapy within each study. DATA COLLECTION AND ANALYSIS Three authors extracted data. We derived risk ratios (RR) for dichotomous data and mean differences (MD) for continuous data with 95% confidence intervals (CI). Methodological risk of bias was assessed using the Cochrane risk of bias tool and trial sequential analyses were undertaken to assess the risk of random errors (play of chance). MAIN RESULTS Our review included six RCTs (representing a total of 278 adult lung transplant recipients) that assessed the use of T-cell antibody induction. Evaluation of the included studies found all to be at high risk of bias.We conducted comparisons of polyclonal or monoclonal T-cell antibody induction versus no induction (3 studies, 140 participants); polyclonal T-cell antibody versus no induction (3 studies, 125 participants); interleukin-2 receptor antagonists (IL-2RA) versus no induction (1 study, 25 participants); polyclonal T-cell antibody versus muromonab-CD3 (1 study, 64 participants); and polyclonal T-cell antibody versus IL-2RA (3 studies, 100 participants). Overall we found no significant differences among interventions in terms of mortality, acute rejection, adverse effects, infection, pneumonia, cytomegalovirus infection, bronchiolitis obliterans syndrome, post-transplantation lymphoproliferative disease, or cancer.We found a significant outcome difference in one study that compared antithymocyte globulin versus muromonab-CD3 relating to adverse events (25/34 (74%) versus 12/30 (40%); RR 1.84, 95% CI 1.13 to 2.98). This suggested that antithymocyte globulin increased occurrence of adverse events. However, trial sequential analysis found that the required information size had not been reached, and the cumulative Z-curve did not cross the trial sequential alpha-spending monitoring boundaries.None of the studies reported quality of life or kidney injury. Trial sequential analyses indicated that none of the meta-analyses achieved required information sizes and the cumulative Z-curves did not cross the trial sequential alpha-spending monitoring boundaries, nor reached the area of futility. AUTHORS' CONCLUSIONS No clear benefits or harms associated with the use of T-cell antibody induction compared with no induction, or when different types of T-cell antibodies were compared were identified in this review. Few studies were identified that investigated use of antibodies against T-cells for induction after lung transplantation, and numbers of participants and outcomes were also limited. Assessment of the included studies found that all were at high risk of methodological bias.Further RCTs are needed to perform robust assessment of the benefits and harms of T-cell antibody induction for lung transplant recipients. Future studies should be designed and conducted according to methodologies to reduce risks of systematic error (bias) and random error (play of chance).
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Affiliation(s)
- Luit Penninga
- Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812Blegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Christian H Møller
- Rigshospitalet, Copenhagen University HospitalDepartment of Cardiothoracic Surgery, RT 2152Blegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Elisabeth I Penninga
- Bispebjerg HospitalDepartment of Clinical PharmacologyBispebjerg Bakke 23CopenhagenDenmarkDK‐2400
| | - Martin Iversen
- Rigshospitalet, Copenhagen University HospitalMedical Department B‐2142, Division of Lung TransplantationBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Daniel A Steinbrüchel
- Rigshospitalet, Copenhagen University HospitalDepartment of Cardiothoracic Surgery, RT 2152Blegdamsvej 9CopenhagenDenmarkDK‐2100
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