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Wang CJ, Tuffaha A, Phadnis MA, Mahnken JD, Wetmore JB. Association of Slow Graft Function with Long-Term Outcomes in Kidney Transplant Recipients. Ann Transplant 2018. [PMID: 29610451 PMCID: PMC6248282 DOI: 10.12659/aot.907397] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Background Whether slow graft function (SGF) represents an intermediate phenotype between immediate graft function (IGF) and delayed graft function (DGF) in kidney transplant recipients is unknown. Material/Methods In a retrospective cohort analysis of 1,222 kidney transplant recipients, we classified patients as having IGF, SGF, and DGF using two different schemas. SGF was defined as serum creatinine (Cr) ≥3.0 mg/dL by postoperative day 5 in Schema 1, and in Schema 2, SGF was defined as Cr >1.5 mg/dL plus a creatinine reduction ratio <20% between postoperative days 1 and 3. A complementary log-log model was used to examine the association of graft function with graft survival and patient survival. Results Mean age of study patients was 51.5±13.3 years, 59.9% were male, and 66.7% were white. In Schema 1, SGF and DGF were associated with comparable increases in risk of graft failure compared to IGF (hazard ratio (HR) 1.46, 95% confidence intervals (CI) 1.02–2.10 for SGF and HR 1.56, CI 1.11–2.22 for IGF); estimates were similar for Schema 2 (HR 1.52, CI 1.05–2.20 for SGF and HR 1.54, CI 1.10–2.17 for IGF). However, for mortality, outcomes for SGF were similarly to IGF, both SGF and IGF were associated with lower risk relative to DGF (HR 0.54, CI 0.36–0.80 for SGF in Schema 1; HR 0.58, CI 0.39–0.85 for SGF in Schema 2). Conclusions These findings suggest that SGF may be a marker for graft failure but not for mortality, and SGF may therefore represent a phenotype separate from IGF and DGF.
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Affiliation(s)
- Connie J Wang
- Division of Nephrology, Hennepin County Medical Center, Minneapolis, MN, USA
| | - Ahmad Tuffaha
- Division of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, KS, USA.,The Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
| | - Milind A Phadnis
- Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Jonathan D Mahnken
- Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA
| | - James B Wetmore
- Division of Nephrology, Hennepin County Medical Center, Minneapolis, MN, USA.,Chronic Disease Research Group, Minneapolis, MN, USA
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Grenda R. Delayed graft function and its management in children. Pediatr Nephrol 2017; 32:1157-1167. [PMID: 27778091 DOI: 10.1007/s00467-016-3528-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 09/27/2016] [Accepted: 09/29/2016] [Indexed: 01/06/2023]
Abstract
Delayed graft function (DGF) is commonly defined as the requirement for dialysis within the first 7 days following renal transplantation. The major underlying mechanism is related to ischaemia/reperfusion injury, which includes microvascular inflammation and cell death and apoptosis, and to the regeneration processes. Several clinical factors related to donor, recipient and organ procurement/transplantation procedures may increase the risk of DGF, including donor cardiovascular instability, older donor age, donor creatinine concentration, long cold ischaemia time and marked body mass index of both the donor and recipient. Some of these parameters have been used in specific predictive formulas created to assess the risk of DGF. A variety of other pre-, intra- and post-transplant clinical factors may also increase the risk of DGF, such as potential drug nephrotoxicity, surgical problems and/or hyperimmunization of the recipient. DGF may decrease the long-term graft function, but data on this effect are inconsistent, partially due to the many different types of organ donation. Relevant management strategies may be classified into the classic clinical approach, which has the aim of minimizing the individual risk factors of DGF, and specific pharmacologic strategies, which are designed to prevent or treat ischaemia/reperfusion injury. Both strategies are currently being evaluated in clinical trials.
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Affiliation(s)
- Ryszard Grenda
- Department of Nephrology & Kidney Transplantation, The Children's Memorial Health Institute, Warsaw, Poland.
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Filiopoulos V, Boletis JN. Renal transplantation with expanded criteria donors: Which is the optimal immunosuppression? World J Transplant 2016; 6:103-114. [PMID: 27011908 PMCID: PMC4801786 DOI: 10.5500/wjt.v6.i1.103] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Revised: 11/03/2015] [Accepted: 01/04/2016] [Indexed: 02/05/2023] Open
Abstract
The growing gap between demand and supply for kidney transplants has led to renewed interest in the use of expanded criteria donor (ECD) kidneys in an effort to increase the donor pool. Although most studies of ECD kidney transplantation confirm lower allograft survival rates and, generally, worse outcomes than standard criteria donor kidneys, recipients of ECD kidneys generally have improved survival compared with wait-listed dialysis patients, thus encouraging the pursuit of this type of kidney transplantation. The relative benefits of transplantation using kidneys from ECDs are dependent on patient characteristics and the waiting time on dialysis. Because of the increased risk of poor graft function, calcineurin inhibitor (CNI)-induced nephrotoxicity, increased incidence of infections, cardiovascular risk, and malignancies, elderly recipients of an ECD kidney transplant are a special population that requires a tailored immunosuppressive regimen. Recipients of ECD kidneys often are excluded from transplant trials and, therefore, the optimal induction and maintenance immunosuppressive regimen for them is not known. Approaches are largely center specific and based upon expert opinion. Some data suggest that antithymocyte globulin might be the preferred induction agent for elderly recipients of ECD kidneys. Maintenance regimens that spare CNIs have been advocated, especially for older recipients of ECD kidneys. CNI-free regimens are not universally accepted due to occasionally high rejection rates. However, reduced CNI exposure and CNI-free regimens based on mammalian target of rapamycin inhibitors have shown acceptable outcomes in appropriately selected ECD transplant recipients.
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Le Meur Y. What immunosuppression should be used for old-to-old recipients? Transplant Rev (Orlando) 2015; 29:231-6. [PMID: 26409505 DOI: 10.1016/j.trre.2015.08.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Revised: 08/25/2015] [Accepted: 08/31/2015] [Indexed: 12/18/2022]
Abstract
Elderly patients receiving a kidney from old donors (old-to-old) are a growing population of transplant recipients. This population cumulates risks of complications due to the co-morbidities and the immunodeficiency state and the frailty of the recipients together with the kidney senescence of the donors. In this context, the choice of immunosuppression is complicated and must take into account some contradictory principles explaining why no consensus exists today.
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Affiliation(s)
- Yannick Le Meur
- Department of Nephrology, University Hospital La Cavale Blanche, European University of Brittany, Brest, France.
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5
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Center-level variation in the development of delayed graft function after deceased donor kidney transplantation. Transplantation 2015; 99:997-1002. [PMID: 25340600 DOI: 10.1097/tp.0000000000000450] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Patient-level risk factors for delayed graft function (DGF) have been well described. However, the Organ Procurement and Transplantation Network definition of DGF is based on dialysis in the first week, which is subject to center-level practice patterns. It remains unclear if there are center-level differences in DGF and if measurable center characteristics can explain these differences. METHODS Using the 2003 to 2012 Scientific Registry of Transplant Recipients data, we developed a hierarchical (multilevel) model to determine the association between center characteristics and DGF incidence after adjusting for known patient risk factors and to quantify residual variability across centers after adjustment for these factors. RESULTS Of 82,143 deceased donor kidney transplant recipients, 27.0% developed DGF, with a range across centers of 3.2% to 63.3%. A center's proportion of preemptive transplants (odds ratio [OR], 0.83; per 5% increment; 95% confidence interval [95% CI], 0.74-;0.93; P = 0.001) and kidneys with longer than 30 hr of cold ischemia time (CIT) (OR, 0.95; per 5% increment; 95% CI, 0.92-;0.98; P = 0.001) were associated with less DGF. A center's proportion of donation after cardiac death donors (OR, 1.12; per 5% increment; 95% CI, 1.03-;1.17; P < 0.001) and imported kidneys (OR, 1.06; per 5% increment; 95% CI, 1.03-;1.10; P < 0.001) were associated with more DGF. After patient-level and center-level adjustments, only 41.8% of centers had DGF incidences consistent with the national median and 28.2% had incidences above the national median. CONCLUSION Significant heterogeneity in DGF incidences across centers, even after adjusting for patient-level and center-level characteristics, calls into question the generalizability and validity of the current DGF definition. Enhanced understanding of center-level variability and improving the definition of DGF accordingly may improve DGF's utility in clinical care and as a surrogate endpoint in clinical trials.
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Tahir W, Hakeem A, Dawrant M, Prasad P, Lee M, Menon K, Attia M, Baker R, Ahmad N. Early Sirolimus Conversion as Rescue Therapy in Kidneys With Prolonged Delayed Graft Function in Deceased Donor Renal Transplant. Transplant Proc 2015; 47:1610-5. [DOI: 10.1016/j.transproceed.2015.04.102] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Revised: 03/23/2015] [Accepted: 04/07/2015] [Indexed: 12/25/2022]
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Mohty M, Bacigalupo A, Saliba F, Zuckermann A, Morelon E, Lebranchu Y. New directions for rabbit antithymocyte globulin (Thymoglobulin(®)) in solid organ transplants, stem cell transplants and autoimmunity. Drugs 2015; 74:1605-34. [PMID: 25164240 PMCID: PMC4180909 DOI: 10.1007/s40265-014-0277-6] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In the 30 years since the rabbit antithymocyte globulin (rATG) Thymoglobulin® was first licensed, its use in solid organ transplantation and hematology has expanded progressively. Although the evidence base is incomplete, specific roles for rATG in organ transplant recipients using contemporary dosing strategies are now relatively well-identified. The addition of rATG induction to a standard triple or dual regimen reduces acute cellular rejection, and possibly humoral rejection. It is an appropriate first choice in patients with moderate or high immunological risk, and may be used in low-risk patients receiving a calcineurin inhibitor (CNI)-sparing regimen from time of transplant, or if early steroid withdrawal is planned. Kidney transplant patients at risk of delayed graft function may also benefit from the use of rATG to facilitate delayed CNI introduction. In hematopoietic stem cell transplantation, rATG has become an important component of conventional myeloablative conditioning regimens, following demonstration of reduced acute and chronic graft-versus-host disease. More recently, a role for rATG has also been established in reduced-intensity conditioning regimens. In autoimmunity, rATG contributes to the treatment of severe aplastic anemia, and has been incorporated in autograft projects for the management of conditions such as multiple sclerosis, Crohn’s disease, and systemic sclerosis. Finally, research is underway for the induction of tolerance exploiting the ability of rATG to induce immunosuppresive cells such as regulatory T-cells. Despite its long history, rATG remains a key component of the immunosuppressive armamentarium, and its complex immunological properties indicate that its use will expand to a wider range of disease conditions in the future.
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Affiliation(s)
- Mohamad Mohty
- Department of Hematology and Cellular Therapy, CHU Hôpital Saint Antoine, 184, rue du Faubourg Saint Antoine, 75571, Paris Cedex 12, France,
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8
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Kang SH, Yun WS, Cho KH, Do JY, Yoon KW, Park JW. Recovery of Delayed Graft Function after Calcineurin Inhibitor Sparing Regimen in a Renal Transplant Patient with Calcineurin Inhibitor Toxicity: A Case Report. KOREAN JOURNAL OF TRANSPLANTATION 2014. [DOI: 10.4285/jkstn.2014.28.3.165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- Seok Hui Kang
- Division of Nephrology, Department of Internal Medicine, Yeungnam University Medical Center, Yeungnam University College of Medicine, Daegu, Korea
| | - Woo Sung Yun
- Division of Vascular and Endovascular Surgery, Department of Surgery, Yeungnam University Medical Center, Yeungnam University College of Medicine, Daegu, Korea
| | - Kyu Hyang Cho
- Division of Nephrology, Department of Internal Medicine, Yeungnam University Medical Center, Yeungnam University College of Medicine, Daegu, Korea
| | - Jun Young Do
- Division of Nephrology, Department of Internal Medicine, Yeungnam University Medical Center, Yeungnam University College of Medicine, Daegu, Korea
| | - Kyung Woo Yoon
- Division of Nephrology, Department of Internal Medicine, Yeungnam University Medical Center, Yeungnam University College of Medicine, Daegu, Korea
| | - Jong Won Park
- Division of Nephrology, Department of Internal Medicine, Yeungnam University Medical Center, Yeungnam University College of Medicine, Daegu, Korea
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Abstract
UNLABELLED Sirolimus (SRL) has demonstrated beneficial impacts on the development of chronic allograft dysfunction (CAD). In living donor transplantation, strategies mostly seek to prevent graft dysfunction and respond to a decline in renal function. The present study focused on proactive, preemptive SRL administration for patients with repeated renal transplantations and those engrafted with an extended criteria donor organ. MATERIAL AND METHODS This retrospective, monocenter study describes 7 renal transplant recipients with stable graft function receiving SRL within the first year posttransplantation and 3 recipients of second transplantations who started SRL treatment before obtaining their repeat grafts. RESULTS A proactive use of SRL revealed stable renal function parameters at 1 year after SRL introduction: Creatinine 1.33 ± 0.21 mg/dL; Modification of Diet in Renal Disease (MDRD) equation glomerular filtration rate, 57 ± 19 mL/min; PU 452 ± 338 mg/24 hours. Cell counts, hemoglobin concentrations, as well as triglyceride and total cholesterol levels did not differ over the 1-year follow-up. SRL administration before retransplantation provided good graft survival and renal function with a creatinine of 1.2 ± .32 mg/dL, MDRD of 60 ± 28 mg/dL, and PU 502 ± 432 mg/24 hour. Cell counts, hemoglobin concentrations, as well as triglyceride and total cholesterol levels did not differ over 1-year follow-up. CONCLUSION Preemptive SRL-induction before signs of graft deterioration or chronic injury may be a useful approach to prevent CAD.
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10
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Gaber AO, Monaco AP, Russell JA, Lebranchu Y, Mohty M. Rabbit antithymocyte globulin (thymoglobulin): 25 years and new frontiers in solid organ transplantation and haematology. Drugs 2010; 70:691-732. [PMID: 20394456 DOI: 10.2165/11315940-000000000-00000] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The more than 25 years of clinical experience with rabbit antithymocyte globulin (rATG), specifically Thymoglobulin, has transformed immunosuppression in solid organ transplantation and haematology. The utility of rATG has evolved from the treatment of allograft rejection and graft-versus-host disease to the prevention of various complications that limit the success of solid organ and stem cell transplantation. Today, rATG is being successfully incorporated into novel therapeutic regimens that seek to reduce overall toxicity and improve long-term outcomes. Clinical trials have demonstrated the efficacy and safety of rATG in recipients of various types of solid organ allografts, recipients of allogeneic stem cell transplants who are conditioned with both conventional and nonconventional regimens, and patients with aplastic anaemia. Over time, clinicians have learnt how to better balance the benefits and risks associated with rATG. Advances in the understanding of the multifaceted mechanism of action will guide research into new therapeutic areas and future applications.
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Affiliation(s)
- A Osama Gaber
- Department of Surgery, The Methodist Hospital, Houston, Texas 77030, USA.
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11
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Morelon E, Lefrançois N, Besson C, Prévautel J, Brunet M, Touraine JL, Badet L, Touraine-Moulin F, Thaunat O, Malcus C. Preferential increase in memory and regulatory subsets during T-lymphocyte immune reconstitution after Thymoglobulin induction therapy with maintenance sirolimus vs cyclosporine. Transpl Immunol 2010; 23:53-8. [PMID: 20406686 DOI: 10.1016/j.trim.2010.04.004] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2009] [Revised: 02/17/2010] [Accepted: 04/05/2010] [Indexed: 11/19/2022]
Abstract
BACKGROUND Sirolimus maintenance therapy with Thymoglobulin induction is a promising regimen that may preserve renal function. Data are lacking, however, about the immunologic effects of combined Thymoglobulin-sirolimus. METHODS In a 12-month, prospective, randomised, open-label, single-centre pilot study, de novo deceased-donor kidney transplant patients were randomised to receive cyclosporine or sirolimus, with Thymoglobulin induction, mycophenolate mofetil and corticosteroids. Flow cytometry analysis of peripheral blood was used to evaluate immune reconstitution. RESULTS Nineteen patients were recruited (sirolimus 9, cyclosporine 10). Reconstitution of the CD4(+) T-lymphocyte subset was significantly lower with sirolimus versus cyclosporine over year 1, but CD8(+) reconstitution did not differ significantly between groups. The proportion of naïve CD4(+) T-lymphocytes showed an initial decrease with sirolimus versus cyclosporine. Naïve CD8(+) T-lymphocytes increased versus baseline in the cyclosporine cohort at months 1 and 3, but remained unchanged with sirolimus. Memory CD4(+) T-lymphocytes occurred more frequently in sirolimus- versus cyclosporine-treated patients during year 1. The proportion of memory CD8(+) T-lymphocytes decreased at months 1 and 3 compared to baseline in the CsA arm, but did not change in the sirolimus cohort. By month 12, the proportion of both naïve and memory CD4(+) and CD8(+) T-lymphocytes had become similar with sirolimus or cyclosporine. There were fewer naïve B-lymphocytes in the sirolimus cohort and more CD19(-)IgD(+/-)CD27(+) memory B-lymphocytes. CONCLUSIONS In this small population, homeostatic reconstitution after Thymoglobulin induction showed disproportionately high recovery of memory T-lymphocyte subsets during sirolimus therapy, which may explain the higher rejection rate seen with sirolimus versus cyclosporine following kidney transplantation.
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12
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Molinari M, Berman K, Meeberg G, Shapiro JA, Bigam D, Trotter JF, Kneteman N. Multicentric outcome analysis of sirolimus-based immunosuppression in 252 liver transplant recipients. Transpl Int 2009; 23:155-68. [PMID: 19765266 DOI: 10.1111/j.1432-2277.2009.00969.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
SUMMARY The use of sirolimus (SRL) in orthotopic liver transplantation (OLT) has been controversial after experimental data suggested an increased risk of hepatic artery thrombosis (HAT). To assess the safety and efficacy of SRL as de novo immunosuppression in OLT recipients. Outcomes of 252 OLT patients who received SRL were compared with outcomes of 291 OLT recipients who received calcineurin inhibitor in a retrospective study. Primary outcomes of this study were: patient- and graft survivals, vascular, biliary, wound complications and rejection rates. Secondary outcomes were: postoperative infection rate, bone marrow and renal function and changes of lipid levels. Patient- and graft survivals, rejection and infection rates were similar. In the SRL group, HAT occurred in 1.2%, biliary complications in 19.4%, and incisional hernias in 9.1%. In the control group the incidence of HAT was 5.8% (P = 0.004), biliary complications 18.5% (P = NS) and incisional hernias 7.2% (P = NS). Patients on SRL experienced significantly higher levels of serum triglycerides but fewer acute cellular rejections. Bone marrow and renal functions were similar in both the groups. Our findings would suggest that SRL is safe and effective for very selected OLT recipients. Randomized controlled trials are necessary to confirm our results.
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Affiliation(s)
- Michele Molinari
- Department of Surgery, Dalhousie University Medical Center, Halifax, NS, Canada.
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13
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Re L, Curcio D, Rial M, Goldberg J, Casadei D. Results of a prospective allocation policy of expanded criteria donors kidneys based on clinical parameters. Clin Transplant 2009; 24:229-35. [DOI: 10.1111/j.1399-0012.2009.01053.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Pascual J, Zamora J, Pirsch JD. A systematic review of kidney transplantation from expanded criteria donors. Am J Kidney Dis 2008; 52:553-86. [PMID: 18725015 DOI: 10.1053/j.ajkd.2008.06.005] [Citation(s) in RCA: 233] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2007] [Accepted: 06/04/2008] [Indexed: 12/14/2022]
Abstract
BACKGROUND During the past few years, there has been renewed interest in the use of expanded criteria donors (ECD) for kidney transplantation to increase the numbers of deceased donor kidneys available. More kidney transplants would result in shorter waiting times and limit the morbidity and mortality associated with long-term dialysis therapy. STUDY DESIGN Systematic review of the literature. SETTING & POPULATION Kidney transplantation population. SELECTION CRITERIA FOR STUDIES Studies were identified by using a comprehensive search through MEDLINE and EMBASE databases. Inclusion criteria were case series, cohort studies, and randomized controlled trials assessing kidney transplantation in adult recipients using ECDs. PREDICTOR A special focus was given to studies comparing the evolution of kidney transplantation between standard criteria donors (defined as a donor who does not meet criteria for donation after cardiac death or ECD) and ECDs (defined as any brain-dead donor aged > 60 years or a donor aged > 50 years with 2 of the following conditions: history of hypertension, terminal serum creatinine level >or= 1.5 mg/dL, or death resulting from a cerebrovascular accident). OUTCOMES Criteria used to define and select ECDs, practice patterns, long-term outcomes, early complications, and some patient issues, such as selection criteria and immunosuppressive management. RESULTS ECD kidneys have worse long-term survival than standard criteria donor kidneys. The optimal ECD kidney for donation depends on adequate glomerular filtration rate and acceptable donor kidney histological characteristics, albeit the usefulness of biopsy is debated. LIMITATIONS This review is based mainly on data from observational studies, and varying amounts of bias could be present. We did not attempt to quantitatively analyze the effect of ECD kidneys on kidney transplantation because of the huge heterogeneity found in study designs and definitions of ECD. CONCLUSIONS Based on the available evidence, we conclude that patients younger than 40 years or scheduled for kidney retransplantation should not receive an ECD kidney. Patients 40 years or older, especially with diabetic nephropathy or nondiabetic disease, but a long expected waiting time for kidney transplantation, show better survival receiving an ECD kidney than remaining on dialysis therapy.
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Affiliation(s)
- Julio Pascual
- Servicio de Nefrología, Hospital Ramón y Cajal, Madrid, Spain
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15
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Luke PPW, Nguan CY, Horovitz D, Gregor L, Warren J, House AA. Immunosuppression without calcineurin inhibition: optimization of renal function in expanded criteria donor renal transplantation. Clin Transplant 2008; 23:9-15. [PMID: 18713265 DOI: 10.1111/j.1399-0012.2008.00880.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
INTRODUCTION To assess the efficacy of calcineurin inhibitor (CNI)-free immunosuppression vs. calcineurin-based immunosuppression in patients receiving expanded criteria donor (ECD) kidneys. PATIENT AND METHODS Thirteen recipients of ECD kidneys were enrolled in this pilot study and treated with induction therapy and maintained on sirolimus, mycophenolate mofetil (MMF) and prednisone. A contemporaneous control group was randomly selected comprised of 13 recipients of ECD kidneys who had been maintained on CNI plus MMF and prednisone. RESULTS For the study group vs. the control group, two-yr graft survival was 92.3% vs. 84.6% (p = NS), two-yr patient survival was 100% vs. 92.3% (p = NS) and the acute rejection rates were 23% vs. 31% (p = NS), respectively. Renal function was significantly better in the study group compared with control up to the six-month mark, after which, it remained numerically but not statistically significant. Complications were more common in the study group, but serious adverse events requiring discontinuation were rare. CONCLUSION This pilot study demonstrates that CNI-free regimens can be safely implemented in patients receiving ECD kidneys with excellent two-yr patient and graft survival and good renal allograft function. Longer follow-up in larger randomized controlled trials are necessary to establish these findings.
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Affiliation(s)
- Patrick P W Luke
- Multi Organ Transplant Program, London Health Sciences Center, London, ON, Canada.
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16
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Neipp M, Jackobs S, Klempnauer J. Renal transplantation today. Langenbecks Arch Surg 2008; 394:1-16. [PMID: 18478256 DOI: 10.1007/s00423-008-0335-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2008] [Accepted: 03/31/2008] [Indexed: 01/20/2023]
Abstract
BACKGROUND The first successful renal transplant was carried out more than five decades ago between identical twins. At these early days, acute rejection was the limiting factor. DISCUSSION Due to tremendous progress in immunosuppressive therapy and surgical technique, today, renal transplantation is the gold standard therapy for patients with end-stage renal disease. In fact, in comparison with chronic hemodialysis, renal transplantation offers an increase in quality of life while reducing comorbidities associated with dialysis treatment. RESULTS Despite numerous beneficial achievements, no further improvement regarding patient outcome can be observed over the last two decades. Graft survival rates remain unchanged. The leading causes for graft loss are chronic allograft nephropathy and death with functioning graft. This might be related to a constant increase of the proportion of donors presenting extended donor criteria as well as a more liberal acceptance of candidates for a renal transplant. CONCLUSION In the near future, one has to focus more closely on the posttransplant patient care to minimize factors associated with chronic allograft damage. These include post-transplant diabetes, hyperlipidemia, high blood pressure, cytomegalovirus infection, etc.
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Affiliation(s)
- Michael Neipp
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
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17
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Bajjoka I, Hsaiky L, Brown K, Abouljoud M. Preserving renal function in liver transplant recipients with rabbit anti-thymocyte globulin and delayed initiation of calcineurin inhibitors. Liver Transpl 2008; 14:66-72. [PMID: 18161842 DOI: 10.1002/lt.21309] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Early renal dysfunction following liver transplantation is associated with increased morbidity and mortality. To evaluate the impact of delayed initiation of calcineurin inhibitor on renal function, we conducted a retrospective study comparing 118 liver transplant recipients who received rabbit anti-thymocyte globulin and delayed initiation of calcineurin inhibitor with 80 liver transplant recipients who received no antibody and early initiation of calcineurin inhibitor (control group). All patients received mycophenolate mofetil and steroids. Delayed calcineurin inhibitor initiation with anti-thymocyte globulin was associated with significant improvement in renal function throughout the first year post-transplant. At 12 months post-transplant, patients treated with this regimen experienced lower serum creatinine (1.4 +/- 0.5 versus 1.7 +/- 0.5 mg/dL, P < 0.001), a higher estimated glomerular filtration rate (57.4 +/- 20.5 versus 43.7 +/- 14.4 mL/min/1.73 m(2), P < 0.001), and less dependence on dialysis (0.8% versus 13%, P < 0.001) in comparison with no antibody and early calcineurin inhibitor initiation. Patient survival and graft survival were similar between groups; however, there was a trend of a lower incidence of early biopsy-proven acute rejection with anti-thymocyte globulin. Overall infection and cytomegalovirus infection were significantly lower in anti-thymocyte globulin-treated patients, and there was no increased incidence of hepatitis C recurrence in comparison with controls. In conclusion, delayed initiation of calcineurin inhibitor with anti-thymocyte globulin in liver transplant recipients is safe and is associated with improvements in renal function and a lower incidence of early acute rejection in comparison with no antibody and early initiation of calcineurin inhibitor.
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Affiliation(s)
- Iman Bajjoka
- Transplant Institute, Henry Ford Hospital, Detroit, MI 48202, USA.
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Audard V, Matignon M, Dahan K, Lang P, Grimbert P. Renal transplantation from extended criteria cadaveric donors: problems and perspectives overview. Transpl Int 2007; 21:11-7. [PMID: 17850235 DOI: 10.1111/j.1432-2277.2007.00543.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The critical shortage of organs available for renal transplantation has led to the consideration of alternative strategies for increasing the donor pool. Recently, the cadaveric kidney donor pool extended to donors who might have been deemed unsuitable in early times, leading to the concept of marginal donors and more recently to the notion of expanded criteria donors. Such organs are eligible for organ donation but, because of extreme age and other clinical characteristics, are expected to produce allograft at risk for diminished post-transplant function. Thus, the challenge is now to reduce the difference between graft outcome from patients grafted with marginal and 'optimal' donors. This implies appropriate transplantation strategies during pre-, peri- and post-transplantation phases including reduction of cold ischemia time, recipient selection, adaptation of immunosuppressive drug regimens, increase in nephron mass by dual kidney transplantation, and improvement in the graft selection process using histological criteria. This review summarizes current definition of a marginal donor and provides some guidance for clinical management of such transplant.
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Affiliation(s)
- Vincent Audard
- Service de Néphrologie et Transplantation Rénale, CHU Henri Mondor, et Institut Francilien de Recherche en Néphrologie et Transplantation, Université Paris XII, Créteil, France
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19
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Furian L, Baldan N, Margani G, Ekser B, Silvestre C, Marchini F, Bonfante L, Rossi B, Valente ML, Rigotti P. Calcineurin inhibitor-free immunosuppression in dual kidney transplantation from elderly donors. Clin Transplant 2007; 21:57-62. [PMID: 17302592 DOI: 10.1111/j.1399-0012.2006.00583.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND Kidneys from expanded-criteria donors may be particularly susceptible to calcineurin inhibitor (CI)-mediated vasoconstriction and nephrotoxicity. In the early post-transplant phase, using CI may prolong ischemic injury and, in the long term, chronic CI nephrotoxicity is an even greater concern. To avoid the acute and chronic consequences of CI in kidneys from marginal donors, CI-free protocols have been introduced for maintenance immunosuppressive therapy. A CI-free protocol of anti-thymocyte globulin (ATG) induction, sirolimus, mycophenolate mofetil (MMF) and steroids has been adopted at our center in recipients of dual kidney transplantation (DKT) from elderly donors (EDs). METHODS Dual kidney transplantations performed since April 2003 on CI-free immunosuppression (group 1 = 31) were compared with earlier DKTs in recipients treated with CI-based therapy (group 2 = 25), retrospectively analyzing patient and graft survival, surgical and medical complications, rejection episodes and renal function. RESULTS No deaths occurred after a mean follow-up of 10.1 +/- 7.6 (group 1) and 48.2 +/- 17.4 months (group 2). Graft loss occurred in one patient in group 1 (bilateral renal vein thrombosis) and in three patients in group 2 (one primary non-function [PNF], one chronic rejection, one Kaposi's sarcoma). The incidence of acute rejection was 19% in group 1 and 16% in group 2. Delayed graft function (DGF) was recorded in 16% and 48%, respectively. Renal function was better in group 1, with a mean S-Cr of 135 +/- 48 vs. 210 +/- 141 micromol/L at one month and 116 +/- 30 vs. 149 +/- 49 micromol/L at six months. CONCLUSIONS After DKT from EDs, a CI-free immunosuppressive regimen including ATG induction, sirolimus, MMF and steroids affords excellent results, with a lower DGF rate and a better renal function.
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Affiliation(s)
- Lucrezia Furian
- Operative Unit of Kidney and Pancreas Transplantation, Padova University Hospital, Padova, Italy.
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20
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Abstract
Induction therapy to prevent the acute rejection of mismatched allografts with the ultimate aim of prolonging the life of the allograft has been the cornerstone of immunosuppression since the introduction of renal transplantation. Agents used for induction therapy have changed over time. Their role in transplantation is expanding to include corticosteroid avoidance and immunosuppression minimization. This review provides an overview of induction therapies for renal transplantation including historic therapies such as total lymphoid irradiation and Minnesota antilymphocyte globulin, and current therapies with polyclonal and monoclonal antibodies and chemical agents, with special emphasis on children. Data from adult studies, and pediatric studies whenever available, are summarized. A brief summary of experimental therapies with fingolimod and belatacept is provided. Historically, induction therapies were targeted at T cells. The role of induction therapies targeted at B cells is emerging in select groups of patients that include highly sensitized recipients and those receiving transplants from blood group incompatible donors. With the advent of newer maintenance immunosuppressive medications and with very low rates of acute rejection, induction protocols for renal transplantation need to be targeted so that excessive immunosuppression and infections are avoided. Several single-center and registry data analyses in children suggest that the addition of an interleukin (IL)-2 receptor antagonist may improve graft survival compared with no induction. The safety profile of IL-2 receptor antagonists is indistinguishable from that of placebo, with no apparent difference in the incidence of infection or post-transplant lymphoproliferative disease. IL-2 receptor antagonists and polyclonal lymphocyte-depleting antibodies offer equivalent efficacy in standard-risk populations. However, in high-risk patients, acute rejection rates and graft outcomes may be improved with the use of lymphocyte-depleting agents such as Thymoglobulin. However, cytomegalovirus infection and other infections may be more common with this therapy. Therefore, in patients at high risk of graft loss, Thymoglobulin may be the preferred choice for induction therapy, while for all other patients, IL-2 receptor antagonists should be considered the first-line choice for induction therapy. Newer lymphocyte-depleting agents such as alemtuzumab may be better utilized in minimization regimens involving one or two oral maintenance immunosuppressive agents.
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Affiliation(s)
- Asha Moudgil
- Department of Nephrology, Children's National Medical Center, Washington, District of Columbia 20010, USA.
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21
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Abstract
Mycophenolate mofetil (MMF) and sirolimus (SRL) are potent non-nephrotoxic xenobiotic immunosuppressants. Their complementary properties may provide the rationale for their combination in induction and maintenance regimens. MMF, a reversible inhibitor of inosin monophosphate dehydrogenase (IMPDH) acts as an antiproliferative drug; and SRL, an mTOR (mammalian target of rapamycin) inhibitor, inhibits cell proliferation driven by growth factors. Early experiences with the use of the SRL, MMF and steroid combination yielded insufficient prophylaxis of acute rejection. However, the introduction of induction therapy with mono- or polyclonal antilymphocyte antibodies to the SRL-MMF and steroid combination brings an efficient acute rejection prophylaxis, while improving renal function and/or reducing of chronic allograft nephropathy (CAN). However, adverse events related to the use of this drug combination (mainly haematological and surgery-related) result in a high rate of discontinuations in some trials, which may hamper the potential benefits of this calcineurin-inhibitor (CNI)-free strategy. Also, currently under investigation is whether in long-term immunosuppression, in MMF-treated patients, CNIs can be replaced by SRL to avoid and/or halt progression of chronic nephropathy and to improve graft survival. However, some authors reported a high proportion of patients with oral ulcers and proteinuria after switching to SRL. In short, refining the use of MMF and SRL may provide a better risk/benefit ratio to pave the way towards non-nephrotoxic immunosuppression.
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Affiliation(s)
- J M Grinyó
- Servei de Nefrologia, Hospital Universitari de Bellvitge, University of Barcelona, Feixa Llarga s/n, L'Hospitalet de Llobregat, 08907 Barcelona, Spain.
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22
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Berry V, Magill A, Yost M, Janosky J, Sindhi R. Individualizing combination of two antiproliferative immunosuppressants with pharmacodynamic modeling of stimulated lymphocyte responses. Cytometry A 2006; 69:95-103. [PMID: 16369935 DOI: 10.1002/cyto.a.20200] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
BACKGROUND Unpredictable serious adverse events (SAE) of immunosuppression, e.g. nephrotoxicity, with the nephrotoxic immunosuppressants have fostered interest in alternative regimens, which contain two antiproliferative agents, and individualized therapy. However, titration of such combinations to individual needs is not understood. SPECIFIC AIM To determine concentration (C) mixtures of mycophenolate mofetil (MMF) and sirolimus (SRL), which produce half-maximal inhibitory effect (EC(50)) on human lymphocytes from individual subjects. METHODS Concentration mixtures of MMF (0-5 mug/ml) and SRL (0-30 ng/ml) were incubated with whole blood from each of five healthy human subjects. The intracellular cytokines IL-2, TNF-alpha, and IFN-gamma were measured in PMA-ionomycin-stimulated T-cells (CD4+), while CD54, CD95, CD86, CD25, CD69, and CD71 were measured in pokeweed mitogen-stimulated B-cells, by flow cytometry. Pharmacodynamic (PD) relationships were evaluated using Hill equations modified for single and multidrug regimens, and expressed as EC(50) for each target receptor. RESULTS No change was seen in the expression of the T-cell cytokines with either MMF or SRL. Each B-cell receptor was inhibited with increasing concentrations of either MMF or SRL. Each B-cell receptor was also inhibited half-maximally at lower concentrations of MMF in the presence of SRL, than with either agent alone, for the test population of five subjects together, and for each of five individual subjects. However, each subject showed distinctly different amounts of MMF and SRL that needed to be present together, in order to produce an identical inhibitory effect on lymphocyte function. CONCLUSIONS PD analysis of biological effect can potentially predict optimal concentration mixtures of two immunosuppressants for individual recipients, and enhance rejection prophylaxis and safety. While this holds promise for drug development efforts, clinical application must await correlation of lymphocyte markers with post-transplant clinical outcomes.
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Affiliation(s)
- Vishal Berry
- Division of Transplantation, Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15217, USA
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23
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Végsö G, Máthé Z, Péter A, Perner F, Járay J, Langer RM. Improving results of renal transplantation with the use of elderly donors: the Budapest experience. Transplant Proc 2006; 37:4225-7. [PMID: 16387084 DOI: 10.1016/j.transproceed.2005.10.096] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2005] [Indexed: 11/24/2022]
Abstract
The use of elderly donors has become a necessity with the increasing demand for deceased donor organs resulting in transplant centers worldwide expanding their donor criteria. We, therefore, thought it appropriate to review our experience using elderly (>60 years) brain-dead donors for kidney transplantation. We investigated the influence of donor parameters on early graft function and survival. A retrospective comparative analysis of three periods was performed: 1994 to 1998 (P1) n = 40; 1999 to 2000 (P2) n = 28; and 2001 to 2002 (P3) with n = 31 donors. Mean donor age in each period was 63.4 +/- 3.3, 64.5 +/- 3.4, and 63.8 +/- 2.7 years; mean diuresis was 473 +/- 450, 307 +/- 316, and 276 +/- 185 mL/hour; and the need for vasopressors during donor management was 81%, 85%, and 70% respectively. The number of kidney recipients was 59, 30, and 37, mean age was 49 +/- 13, 53 +/- 11 and 54 +/- 8 years, the recipient ratio of patients >60 years was 17%, 33%, and 27% respectively, and no differences among the groups in the HLA mismatch. Primary nonfunction occurred in 8.5%, 0%, and 2.8%; acute rejection ratio at 1 year was 35%, 36%, and 32%, the mean serum creatinine at 12 months was 183.7 +/- 66.0, 157.8 +/- 41.2 and 160.7 +/- 46.5 mumol/L. The 1-year graft survival was 71.2%, 91.0% and 92.0% and the 1-year patient survival 88.2%, 96.6%, and 97.2%, respectively, for periods 1, 2, and 3. There has been a considerable improvement in the 1-year graft and patient survivals. With careful donor and recipient evaluation, individualized immunosuppression, and age matching the results of renal transplantation from elderly deceased donors can be comparable to the results of the "optimal" deceased donor kidney transplantation.
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Affiliation(s)
- G Végsö
- Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary.
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24
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Rerolle JP, Szelag JC, Diaconita M, Saada F, Aldigier JC, Le Meur Y. Transplantation rénale du sujet âgé. Nephrol Ther 2006; 2:8-14. [PMID: 16895710 DOI: 10.1016/j.nephro.2005.12.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2004] [Revised: 12/03/2005] [Accepted: 12/28/2005] [Indexed: 11/21/2022]
Abstract
For ten years, an increase in the number of elderly patients on renal transplant waiting lists has occured. In an attempt to close the widening gap between supply and demand and because the demand for kidneys for younger patients already surpasses the supply, transplant physicians nowadays accept organs from older donors that might have been deemed inappropriate in the past. Programs of age matching between donors and recipients and of dual-kidneys transplantation have emerged. The initial results of these programs are encouraging with excellent patient and graft survival at one and three years.
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Affiliation(s)
- Jean-Philippe Rerolle
- Service de Néphrologie et Transplantation Rénale, CHRU Dupuytren, Martin-Luther-King, Limoges, France.
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25
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Segoloni GP, Messina M, Squiccimarro G, Mazzucco G, Torta E, Leonardi G, Fop F, Roggero S, Vigotti F, Piccoli GB. Preferential allocation of marginal kidney allografts to elderly recipients combined with modified immunosuppression gives good results. Transplantation 2006; 80:953-8. [PMID: 16249744 DOI: 10.1097/01.tp.0000174134.80947.0a] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND There is an increasing tendency to allocate kidneys from marginal donors in older recipients. This combination optimizes the uses of an expanded donor pool but demands attention for the higher nephrotoxic sensitivity of the kidney and the increased immunosuppression vulnerability of the elderly recipients. We aimed to reduce these hazards by means of a calcineurin-free induction therapy followed by a maintenance regimen targeted to minimize/withdraw steroid. METHODS Eighty-eight single (43%) or double (57%) transplant recipients (58.4+/-5.7 years) from 88 marginal donors (67+/-8.3 years) received monoclonal anti-IL-2 receptor antibodies, mycophenolate mofetil (MMF), and steroid. When serum creatinine was less than 2.6 mg/dL, tacrolimus was started and MMF was withdrawn when the tacrolimus trough level was above 15 ng/ml. Steroid was tapered to 5 mg at day 45 and then progressively reduced. RESULTS Overall patient and graft survival at the first and fourth year were respectively 100 and 96%, and 98 and 79%. Acute rejection rate was 13.6% (12/88), creatinine clearance remained stable (48.2 ml/min at the sixth month, 50.9 ml/min at 48th month). At the first, second, third, and fourth years, 23, 69, 80, and 100% of recipients were off steroids. For those on steroids, mean dose was respectively 2.6 mg/day from month 12. No recipient re-assumed steroids CONCLUSIONS In the "old-for-old" allocation, the calcineurin-inhibitor avoidance at induction and the steroid withdrawal/minimization during the tacrolimus-based maintenance regimen allow a low acute rejection rate, a stable renal function, and favorable recipient and graft outcomes.
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Affiliation(s)
- Giuseppe P Segoloni
- Renal Transplant Unit, Nephrology, Dialysis and Transplantation Department, S.Giovanni Battista Hospital, Turin, Italy.
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26
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Abstract
Sirolimus (Rapamycin, Wyeth Pharmaceuticals Australia Pty Ltd, Baulkham Hills, NSW, Australia) (SRL) has received increasing attention as an immunosuppressant in renal and other solid organ transplantation. Sirolimus is the first marketed agent in a new class of drugs with a novel mechanism of action. Sirolimus binds, like tacrolimus, to a member of the FK binding protein (FKBP) family. The SRL/FKBP complex binds to the protein kinase mTOR. Binding to mTOR blocks activation of signal transduction pathways causing arrest of the cell cycle in the G1 phase. It is now known that mTOR is a central regulator of cell growth and proliferation. The immunosuppressive properties of SRL are due primarily to blockade of interleukin-2 (IL-2)-induced proliferation of T cells. There is still much to be learnt about how best to use the drug. The key advantage over the current choice of immunosuppressive agents is the ability to preserve renal function and pathology while producing excellent rejection-free, graft survival rates. Thus, SRL may find its pivotal role as a calcineurin inhibitors replacement in patients whose grafts are affected by chronic allograft nephropathy. A second major driver for use may prove to be the impact of SRL on cancer incidence and prognosis. Studies still need to be performed to evaluate the best timing for commencement of SRL and the optimal dosage to minimize side-effects.
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Affiliation(s)
- Vincent Ws Lee
- Department of Renal Medicine, Westmead Hospital, New South Wales, Australia.
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27
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Gruessner RWG, Kandaswamy R, Humar A, Gruessner AC, Sutherland DER. Calcineurin inhibitor- and steroid-free immunosuppression in pancreas-kidney and solitary pancreas transplantation. Transplantation 2005; 79:1184-9. [PMID: 15880067 DOI: 10.1097/01.tp.0000161221.17627.8a] [Citation(s) in RCA: 90] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Calcineurin inhibitors and steroids are standard immunosuppressants in solid organ transplantation, but (long-term) side effects are harmful to the recipient and the graft. The authors present a novel strategy for posttransplant immunosuppression that combines a depleting antibody with an antimetabolite, avoiding calcineurin inhibitors and steroids. METHODS In a prospective, nonrandomized, observational cohort study, 75 pancreas-kidney and solitary pancreas recipients received alemtuzumab (4 doses for induction and up to 12 doses within the first year) and mycophenolate mofetil (> or = 2 g/day) for induction and maintenance therapy. Minimum follow-up was 6 months. We compared the results with a historical group of 266 consecutive pancreas recipients on Thymoglobulin (induction) and tacrolimus (maintenance). RESULTS Differences in patient and graft survival rates between the study and control groups at 6 months were not statistically significant. However, the incidence of a first reversible rejection episode was significantly higher for simultaneous pancreas-kidney recipients in the study (vs. control) group. We noted a trend toward higher modification of renal disease levels at 6 months posttransplant in the study (vs. control) groups. CONCLUSIONS The combination of alemtuzumab and mycophenolate mofetil was associated with an acceptable rejection rate, a good safety profile, and good (graft and native) kidney function; it eliminated undesired calcineurin inhibitor- and steroid-related side effects. Longer follow-up is warranted before expanded application can be recommended.
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Parada B, Mota A, Nunes P, Macário F, Pratas J, Bastos C, Figueiredo A. Calcineurin Inhibitor–Free Immunosuppression in Renal Transplantation. Transplant Proc 2005; 37:2759-61. [PMID: 16182803 DOI: 10.1016/j.transproceed.2005.05.044] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
PURPOSE To describe our initial results using a calcineurin inhibitor-free immunosuppression protocol in renal transplants. PATIENTS AND METHODS Between October 2001 and June 2003, 56 recipients of a renal allografts were started on an immunosuppression protocol without calcineurin inhibitors, consisting of basiliximab, sirolimus, mycophenolate mofetil, and steroids. We analyzed patient and graft survival, acute rejection episodes, and renal function. RESULTS The mean follow-up was 19.6 months. Actuarial patient survival at 1 and 2 years was 98.1% and 95.3%, respectively. Actuarial graft survival at 1 and 2 years was 92.9% and 87.6%, respectively. Acute rejection occurred in 27.8% of the patients, usually Banff 1 (73.3%). There was stable renal function with mean serum creatinine of 1.3, 1.4, 1.3, and 1.3 mg/dL at 1, 6, 12, and 24 months after transplant. CONCLUSIONS The use of immunosuppression free of calcineurin inhibitors is effective and safe. Further follow-up is needed to evaluate the impact on long-term results.
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Affiliation(s)
- B Parada
- Department of Urology and Renal Transplantation, University Hospital of Coimbra, Coimbra, Portugal.
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Sánchez-Fructuoso AI, Marques M, Conesa J, Ridao N, Rodríguez A, Blanco J, Barrientos A. Use of different immunosuppressive strategies in recipients of kidneys from nonheart-beating donors. Transpl Int 2005; 18:596-603. [PMID: 15819810 DOI: 10.1111/j.1432-2277.2005.00100.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
In nonheart-beating donor (NHBD) kidney transplants, immunosuppressive management is difficult mainly because of the high incidence of acute tubular necrosis. This has meant that since the start of our NHBD transplant program, several immunosuppression regimes have been used. The aim of this retrospective study was to evaluate the results obtained over 7 years using different treatment protocols. A total of 172 consecutive NHBD transplants performed between April 1996 and December 2002 were treated as follows: G-I (n = 21), cyclosporine (8 mg/kg/day) plus azathioprine plus steroids; G-II (n = 65), low-dose cyclosporine (5 mg/kg/day) plus mycophenolate plus steroids; G-III (n =17), low-dose tacrolimus (0.1 mg/kg/day) plus mycophenolate plus steroids; and G-IV (n = 69), daclizumab plus low-dose tacrolimus plus mycophenolate plus steroids. Delayed graft function rates were 76.2%, 72.3%, 76.5%, and 42%, respectively, for the four groups (P = 0.000). Rejection-free patient rates were 76.2%, 46.2%, 35.3%, and 71% (P < 0.001). Vascular rejection rates were 19%, 30.8%, 52.9%, and 18.8%, (P = 0.025). Two-year graft survival was 71.4% in group I, 95.4% in group II, 94.1 in group III, and 93.8% in group IV (P =0.004). Patient survival was worse in group I (75.2% in group I, 100% in group II, 100% in group III, and 96.7% in group IV at 2 years; P < 0.001). The use of daclizumab and low-dose tacrolimus could be effective at lowering the incidence of delayed graft function in NHBDT, with no negative repercussions on acute rejection.
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Affiliation(s)
- Ana I Sánchez-Fructuoso
- Department of Nephrology, Hospital Clínico San Carlos, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
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Boratyńska M, Banasik M, Patrzalek D, Szyber P, Klinger M. Sirolimus Delays Recovery From Posttransplant Renal Failure in Kidney Graft Recipients. Transplant Proc 2005; 37:839-42. [PMID: 15848550 DOI: 10.1016/j.transproceed.2004.12.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The aim of this study was to evaluate the impact of sirolimus and cyclosporine (CsA) combined therapy on the incidence and duration of delayed graft function (DGF), and the impact of the latter on 1-year graft function. The study entailed 23 cadaveric renal recipients treated with sirolimus-CsA-prednisone regimen (sirolimus group). The reference group entailed 23 patients treated with CsA-azathioprine-prednisone. In the sirolimus group the frequency of DGF was 39% and was essentially the same as in reference group (34.8%). The duration of DGF was significantly longer in SRL group and lasted 21.2 +/- 12.2 days versus 6.8 +/- 2.5 in reference group (P = .004). Serum creatinine level decreased below 3.0 mg/dL after 36 +/- 22 days in sirolimus group versus 16.8 +/- 6 days in reference group (P < .04). Cold ischemia was slightly longer and donors were older in DGF patients in both groups. Sirolimus dose during first month was higher in DGF patients (3.5 versus 2.6 mg), whereas level of CsA was lower (230 versus 310 ng/mL). Biopsy-proven acute rejection (AR) occurred in most of DGF patients and during the DGF period. Serum creatinine level at the 12th month posttransplant was higher in DGF versus non-DGF patients (2.0 +/- 0.5 versus 1.5 +/- 0.4 mg/dL). One-year patient and graft survival was 100% in sirolimus group and 100% and 95% in reference group. In conclusion, sirolimus significantly retards the recovery from posttransplant renal failure; however, it does not increase the incidence of DGF. Patients who suffered from posttransplant acute renal failure had worse renal function at 1 year after transplantation, independent of the treatment protocol.
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Affiliation(s)
- M Boratyńska
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland.
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Hale DA, Kirk AD. Mammalian target of rapamycin inhibitors in transplantation: novel immunosuppressive strategies with sirolimus. Curr Opin Organ Transplant 2004. [DOI: 10.1097/01.mot.0000145087.34739.14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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