| 1. |
- Arora, Satish, et al.
(författare)
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Effect of Everolimus Introduction on Cardiac Allograft Vasculopathy-Results of a Randomized, Multicenter Trial
- 2011
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Ingår i: Transplantation. - : Williams and Wilkins. - 0041-1337 .- 1534-6080. ; 92:2, s. 235-243
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Tidskriftsartikel (refereegranskat)abstract
- Background. Everolimus reduces the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant (HTx) recipients, but the influence on established CAV is unknown. Methods. In this Nordic Certican Trial in Heart and lung Transplantation substudy, 111 maintenance HTx recipients (time post-HTx 5.8 +/- 4.3 years) randomized to everolimus+reduced calcineurin inhibitor (CNI) or standard CNI had matching (intravascular ultrasound) examinations at baseline and 12 months allowing accurate assessment of CAV progression. Results. No significant difference in CAV progression was evident between the treatment groups (P=0.30). When considering patients receiving concomitant azathioprine (AZA) therapy (n=39), CAV progression was attenuated with everolimus versus standard CNI (Delta maximal intimal thickness 0.00 +/- 0.04 and 0.04 +/- 0.04 mm, Delta percent atheroma volume 0.2%+/- 3.0% and 2.6%+/- 2.5%, and Delta total atheroma volume 0.25 +/- 14.1 and 19.8 +/- 20.4 mm(3), respectively [Pless than0.05]). When considering patients receiving mycophenolate mofetil (MMF), accelerated CAV progression occurred with everolimus versus standard CNI (Delta maximal intimal thickness 0.06 +/- 0.12 vs. 0.02 +/- 0.06 mm and Delta percent atheroma volume 4.0%+/- 6.3% vs. 1.4%+/- 3.1%, respectively; Pless than0.05). The levels of C-reactive protein and vascular cell adhesion molecule-1 declined significantly with AZA+everolimus, whereas MMF+everolimus patients demonstrated a significant increase in levels of C-reactive protein, vascular cell adhesion molecule-1, and von Willebrand factor. Conclusions. Conversion to everolimus and reduced CNI does not influence CAV progression among maintenance HTx recipients. However, background immunosuppressive therapy is important as AZA+everolimus patients demonstrated attenuated CAV progression and a decline in inflammatory markers, whereas the opposite pattern was seen with everolimus +MMF. The different effect of everolimus when combined with AZA versus MMF could potentially reflect hitherto unknown interactions.
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| 2. |
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| 3. |
- Biglarnia, Ali-Reza, et al.
(författare)
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Desensitization With Antigen-Specific Immunoadsorption Interferes With Complement in ABO-Incompatible Kidney Transplantation
- 2012
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 93:1, s. 87-92
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Complement activation was characterized during and after desensitization treatment in 19 consecutive patients receiving ABO-incompatible (ABOi) living donor kidney transplants to assess the effect of desensitization protocol including antigen-specific immunoadsorption (IA) on complement activation.METHODS:All patients received rituximab- and tacrolimus-based triple treatment. Anti-A/B antibodies were removed by IA. Serial determinations of C3, C3a, the C3a/C3 ratio, and sC5b-9 were carried out between day -30 and postoperative day 30. C1q was measured on day -30 and the day before the transplantation. In two recipients, eluates from immunoadsorbent columns were analyzed for C3a, C1q, and immunoglobulins by western blotting. Same complement analysis was performed in eluate from a control column after in vitro perfusion of AB-plasma.RESULTS:Patient and graft survival were 100% for a median follow-up of 40 months (range, 12-60 months). There were no humoral rejections based on ABO-antigen-antibody interactions. C3a and the C3a/C3 ratio declined with the start of IA treatment, and this decline was maintained postoperatively. C1q declined from day -30 to a lower value on the day before transplantation (P<0.05). In eluates from both patient and control, immunoadsorbent column immunoglobulins together with C3a and C1q were detected.CONCLUSIONS:The current protocol including antigen-specific IA interferes with the complement system; this effect may be partially responsible for the absence of humoral rejection resulting from ABO-antigen-antibody interactions and the excellent outcomes obtained after ABO-incompatible kidney transplantation.
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| 4. |
- Brandhorst, Heide, 1962-, et al.
(författare)
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A new oxygen carrier for improved long-term storage of human pancreata before islet isolation
- 2010
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 89:2, s. 155-60
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Pancreas oxygenation during cold storage has been established in islet isolation and transplantation to prevent ischemic tissue damage using perfluorodecalin (PFD) as hyperoxygen carrier. However, studies in humans and pigs provided conflicting results about the efficiency of PFD for pancreas oxygenation. The aim of this study was to compare PFD with a newly developed oxygen carrier composed of perfluorohexyloctane and polydimethylsiloxane 5 (F6H8S5) for long-term storage of human pancreata.METHODS: After 24-hr storage in preoxygenated PFD or F6H8S5, pancreata were processed using Liberase HI for pancreas dissociation and a Ficoll gradient for islet purification. Islet quality assessment was performed measuring glucose-stimulated insulin release, viability, islet ATP content, and posttransplant function in diabetic nude mice.RESULTS: Compared with PFD, F6H8S5 significantly increased the intrapancreatic partial oxygen pressure and islet ATP content. This corresponded to an increase of islet yield, recovery after culture, glucose stimulation index, viability, and improved graft function in diabetic nude mice.CONCLUSIONS: The present findings indicate clearly that F6H8S5 improves isolation outcome after prolonged ischemia compared with PFD. This observation seems to be related to the significant lipophilicity and almost pancreas-specific density of F6H8S5. Moreover, these characteristics facilitate pancreas shipment without using custom-made transport vessels as required for PFD.
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| 9. |
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| 11. |
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| 12. |
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| 13. |
- Friberg, Andrew S., et al.
(författare)
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Quantification of the Islet Product : Presentation of a Standardized Current Good Manufacturing Practices Compliant System With Minimal Variability
- 2011
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 91:6, s. 677-683
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Tidskriftsartikel (refereegranskat)abstract
- Background. Accurate islet quantification has proven difficult to standardize in a good manufacturing practices (GMP) approved manner. Methods. The influence of assessment variables from both manual and computer-assisted digital image analysis (DIA) methods were compared using calibrated, standardized microspheres or islets alone. Additionally, a mixture of microspheres and exocrine tissue was used to evaluate the variability of both the current, internationally recognized, manual method and a novel GMP-friendly purity-and volume-based method (PV) evaluated by DIA in a semiclosed, culture bag system. Results. Computer-assisted DIA recorded known microsphere size distribution and quantities accurately. By using DIA to evaluate islets, the interindividual manually evaluated percent coefficients of variation (CV%; n = 14) were reduced by almost half for both islet equivalents (IEs; 31% vs. 17%, P = 0.002) and purity (20% vs. 13%, P = 0.033). The microsphere pool mixed with exocrine tissue did not differ from expected IE with either method. However, manual IE resulted in a total CV% of 44.3% and a range spanning 258 kIE, whereas PV resulted in CV% of 10.7% and range of 60 k IE. Purity CV% for each method were similar approximating 10.5% and differed from expected by +7% for the manual method and +3% for PV. Conclusion. The variability of standard counting methods for islet samples and clinical quantities of microspheres mixed with exocrine tissue were reduced with DIA. They were reduced even further by use of a semiclosed bag system compared with standard manual counting, thereby facilitating the standardization of islet evaluation according to GMP standards.
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| 14. |
- Friberg, Andrew S., et al.
(författare)
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Transplanted functional islet mass : donor islet preparation, and recipitent factors influence early graft function in islet-after-kidney patients
- 2012
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 93:6, s. 632-638
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Tidskriftsartikel (refereegranskat)abstract
- Background.The ability to predict clinical function of a specific islet batch released for clinical transplantation using standardized variables remains an elusive goal.Methods. Analysis of 10 donor, 7 islet isolation, 3 quality control, and 6 recipient variables was undertaken in 110 islet-after-kidney transplants and correlated to the pre- to 28-day posttransplant change in C-peptide to glucose and creatinine ratio ([DELTA]CP/GCr).Results.Univariate analysis yielded islet volume transplanted (Spearman r=0.360, P<0.001) and increment of insulin secretion (r=0.377, P<0.001) as variables positively associated to [DELTA]CP/GCr. A negative association to [DELTA]CP/GCr was cold ischemia time (r=-0.330, P<0.001). A linear, backward-selection multiple regression was used to obtain a model for the transplanted functional islet mass (TFIM). The TFIM model, composed of islet volume transplanted, increment of insulin secretion, cold ischemia time, and exocrine tissue volume transplanted, accounted for 43% of the variance of the clinical outcome in the islet-after-kidney data set.Conclusion.The TFIM provides a straightforward and potent tool to guide the decision to use a specific islet preparation for clinical transplantation.
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| 15. |
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| 16. |
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| 17. |
- Gullestad, Lars, et al.
(författare)
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Everolimus With Reduced Calcineurin Inhibitor in Thoracic Transplant Recipients With Renal Dysfunction: A Multicenter, Randomized Trial
- 2010
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Ingår i: Transplantation. - : Williams and Wilkins. - 0041-1337 .- 1534-6080. ; 89:7, s. 864-872
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Tidskriftsartikel (refereegranskat)abstract
- Background. The proliferation signal inhibitor everolimus offers the potential to reduce calcineurin inhibitor (CNI) exposure and alleviate CNI-related nephrotoxicity. Randomized trials in maintenance thoracic transplant patients are lacking. Methods. In a 12-month, open-labeled, multicenter study, maintenance thoracic transplant patients (glomerular filtration rate greater than= 20 mL/min/1.73m(2) and less than90 mL/min/1.73 m(2)) greater than1 year posttransplant were randomized to continue their current CNI-based immunosuppression or start everolimus with predefined CNI exposure reduction. Results. Two hundred eighty-two patients were randomized (140 everolimus, 142 controls; 190 heart, 92 lung transplants). From baseline to month 12, mean cyclosporine and tacrolimus trough levels in the everolimus cohort decreased by 57% and 56%, respectively. The primary endpoint, mean change in measured glomerular filtration rate from baseline to month 12, was 4.6 mL/min with everolimus and -0.5 mL/min in controls (Pless than0.0001). Everolimus-treated heart and lung transplant patients in the lowest tertile for time posttransplant exhibited mean increases of 7.8 mL/min and 4.9 mL/min, respectively. Biopsy-proven treated acute rejection occurred in six everolimus and four control heart transplant patients (P=0.54). In total, 138 everolimus patients (98.6%) and 127 control patients (89.4%) experienced one or more adverse event (P=0.002). Serious adverse events occurred in 66 everolimus patients (46.8%) and 44 controls (31.0%) (P=0.02). Conclusion. Introduction of everolimus with CNI reduction offers a significant improvement in renal function in maintenance heart and lung transplant recipients. The greatest benefit is observed in patients with a shorter time since transplantation.
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| 18. |
- Gullestad, Lars, et al.
(författare)
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Two-Year Outcomes in Thoracic Transplant Recipients After Conversion to Everolimus With Reduced Calcineurin Inhibitor Within a Multicenter, Open-Label, Randomized Trial.
- 2010
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Ingår i: Transplantation. - : Williams and Wilkins. - 1534-6080 .- 0041-1337. ; 90:12, s. 1581-1589
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND.: Use of the mammalian target of rapamycin inhibitor everolimus with an accompanying reduction in calcineurin inhibitor (CNI) exposure has shown promise in preserving renal function in maintenance thoracic transplant patients, but robust, long-term data are required. METHODS.: In a prospective, open-label, multicenter study, thoracic transplant recipients more than or equal to 1 year posttransplant with mild-to-moderate renal insufficiency were randomized to continue their current CNI-based immunosuppression or convert to everolimus with predefined CNI exposure reduction. After a 12-month core trial, patients were followed up to month 24 after randomization. RESULTS.: Of 245 patients who completed the month 12 visit, 235 patients (108 everolimus and 127 controls) entered the 12-month extension phase. At month 24, mean measured glomerular filtration rate had increased by 3.2±12.3 mL/min from the point of randomization in everolimus-treated patients and decreased by 2.4±9.0 mL/min in controls (P<0.001), a difference that was significant within both the heart and lung transplant subpopulations. During months 12 to 24, 5.6% of everolimus patients and 3.1% of controls experienced biopsy-proven acute rejection (P=0.76). There were no significant differences in the rate of adverse events or serious adverse events (including pneumonia) between groups during months 12 to 24. CONCLUSIONS.: Converting maintenance thoracic transplant recipients to everolimus with low-exposure CNI results in a renal benefit that is sustained to 2 years postconversion, with significantly improved measured glomerular filtration rate in both heart and lung transplant patients. Despite reductions of more than 50% in CNI exposure, there was no marked loss of efficacy. The safety profile of the everolimus-based regimen was acceptable.
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| 19. |
- Gustafson, Elisabet K., et al.
(författare)
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The Instant Blood-Mediated Inflammatory Reaction Characterized in Hepatocyte Transplantation
- 2011
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 91:6, s. 632-638
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Tidskriftsartikel (refereegranskat)abstract
- Background. Hepatocyte transplantation (HcTx) has proven to be a safe procedure, although the functional results have been unsatisfactory, probably due to insufficient engraftment or a loss of transplanted mass or function. In this study, we investigate whether hepatocytes in contact with blood induce an inflammatory reaction leading to, similar to what happens in clinical islet transplantation, an instant blood-mediated inflammatory reaction (IBMIR) resulting in an early loss of transplanted cells. Methods. By using an experimental model that mimics the portal vein blood flow, we could study different parameters reflecting the effects on the innate immunity elicited by hepatocytes in contact with ABO-matched human blood. Results. We report that all aspects of the IBMIR such as platelet and granulocyte consumption, coagulation, and complement activation were demonstrated. Addition of various specific inhibitors of coagulation allowed us to clearly delineate the various stages of the hepatocyte-triggered IBMIR and show that the reaction was triggered by tissue factor. Analysis of a case of clinical HcTx showed that hepatocyte-induced IBMIR also occurs in vivo. Both the inflammatory and the coagulation aspects were controlled by low-molecular-weight dextran sulfate. Conclusion. Isolated hepatocytes in contact with blood induce the IBMIR in vitro, and there are indications that these events are also relevant in vivo. According to these findings, HcTx would benefit from controlling a wider range of signals from the innate immune system.
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| 20. |
- Gustafsson, Sandra, et al.
(författare)
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Amyloid Fibril Composition as a Predictor of Development of Cardiomyopathy After Liver Transplantation for Hereditary Transthyretin Amyloidosis
- 2012
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 93:10, s. 1017-1023
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Tidskriftsartikel (refereegranskat)abstract
- Background. Liver transplantation (LTx) is an accepted treatment for hereditary transthyretin (TTR) amyloidosis (ATTR). However, unforeseen heart complications, especially a rapid development of cardiomyopathy after LTx has affected mortality and morbidity. Recently, a relationship between ATTR-fibril composition and cardiomyopathy has been noted. The aim of this study was to investigate whether development of cardiomyopathy and heart failure in LTx ATTR amyloid patients is related to amyloid fibril composition.Methods. Twenty-four patients with hereditary ATTR amyloidosis who had undergone LTx and have had their amyloid fibril type tested were available for the study. They had been examined by echocardiography including tissue Doppler and speckle tracking echocardiography before and after LTx. Patients were divided into two groups according to fibril composition, 10 patients with type A fibrils (a mixture of truncated and full-length TTR) and 14 patients with type B fibrils (full-length TTR fibrils only). There was no difference in time to the follow-up echocardiography between the two groups.Results. After LTx, the group consisting of type A patients developed symptoms of heart failure and with reduced systolic and diastolic ventricular function as shown by echocardiography, whereas no similar deterioration was noted for the group of patients with type B fibrils.Conclusion. Patients with type A fibrils deteriorate an already existing cardiomyopathy and heart failure after LTx, in contrast to patients with type B fibrils. These results might have significant clinical implications in optimizing best patients selection criteria for LTx.
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| 21. |
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| 22. |
- Holdaas, Hallvard, et al.
(författare)
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Conversion of Long-Term Kidney Transplant Recipients From Calcineurin Inhibitor Therapy to Everolimus : A Randomized, Multicenter, 24-Month Study
- 2011
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 92:4, s. 410-418
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Tidskriftsartikel (refereegranskat)abstract
- Background. Benefits of conversion from calcineurin inhibitor (CNI) to mammalian target of rapamycin inhibitor-based immunosuppression in long-term kidney transplant patients remain uncertain. Methods. ASCERTAIN was a 24-month, open-label, multicenter study. Kidney transplant patients more than 6 months posttransplant receiving CNI (baseline glomerular filtration rate [GFR] 30-70 mL/min/1.73 m(2)) were randomized to everolimus with CNI elimination (n = 127) or CNI minimization (n = 144), or continued CNI unchanged (controls, n = 123) to assess the effect on measured GFR at month 24 after randomization. Results. Renal function was stable in all groups to month 24. Mean measured GFR at month 24, the primary endpoint, was 48.0 +/- 22.0 mL/min/1.73 m(2), 46.6 +/- 21.1 mL/min/1.73 m(2), and 46.0 +/- 20.4 mL/min/1.73 m(2) in the CNI elimination, CNI minimization, and control groups, respectively. Differences between CNI elimination (1.12 mL/min/1.73 m(2), 95% confidence interval [CI] -3.51 to 5.76, P=0.63) and CNI minimization (0.59 mL/min/1.73 m(2), 95% CI -3.88 to 5.07, P=0.79) versus controls at month 24 were nonsignificant that is, the primary endpoint was not met. No efficacy endpoint differed significantly between groups. Post hoc analyses showed that patients with baseline creatinine clearance (CrCl) more than 50 mL/min had a significantly greater increase in measured GFR after CNI elimination versus controls (difference 11.4 mL/min/1.73 m(2), 95% CI 2.1 to 20.8 mL/min/1.73 m(2), P=0.017). Adverse events resulted in discontinuation in 36 (28.3%) CNI elimination patients, 24 (16.7%) CNI minimization patients, and 5 (4.1%) controls (P<0.001 vs. CNI elimination; P=0.020 vs. CNI minimization). Conclusion. Conversion to everolimus with CNI elimination or minimization a mean of 5.6 years after kidney transplantation had no overall renal benefit and was associated with more frequent adverse events and discontinuations. Patients with CrCl more than 50 mL/min may benefit from a change in therapy more than 6 months after renal transplantation.
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| 23. |
- Ingelsten, Madeleine, 1978, et al.
(författare)
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Postischemic Inflammatory Response in an Auxiliary Liver Graft Predicts Renal Graft Outcome in Sensitized Patients
- 2011
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 91:8, s. 888-894
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Tidskriftsartikel (refereegranskat)abstract
- Background. The liver is considered a tolerogenic organ that favors the induction of peripheral tolerance and protects other organs from the same donor from rejection. This has been exploited in combined auxiliary liver-kidney transplantation, where a renal graft is transplanted against a positive crossmatch under the protection of a liver transplanted from the same donor. Methods. To elucidate mechanisms behind the liver protective effect, we studied early transcriptional changes of inflammatory mediators in the grafts during combined auxiliary liver-kidney transplantation using microarrays and real-time polymerase chain reaction. The results were correlated to clinical data. Results. Liver and kidney grafts both exhibited an upregulation of the leukocyte-recruiting chemokines CCL2, CCL3, and CCL4. Notably, liver grafts strongly upregulated CCL20, a dendritic cell, and T-cell recruiting chemokine. By comparing the gene expression in liver grafts with the clinical outcome, we found that 14 of 45 investigated inflammatory genes were expressed significantly higher in patients without early rejection when compared with those with early rejections. This included the above-mentioned chemokines and the T-cell-recruiting CX3CL1, NFKB1, and the tolerance-inducing gene indoleamine 2,3-dioxygenase. Conclusions. In this study, the protective role of the liver was associated with a proinflammatory reaction within this organ after ischemia-reperfusion. In particular, we found an increased expression of leukocyte-recruiting chemokines in patients without rejection, indicating a protective role of host inflammatory cells infiltrating the auxiliary liver graft in presensitized patients. Second, gene expression profiling of transplant biopsies shortly after reperfusion predicted the risk of early rejection in these patients.
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| 24. |
- Ingelsten, Madeleine, et al.
(författare)
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Rapid Increase of Interleukin-10 Plasma Levels After Combined Auxiliary Liver-Kidney Transplantation in Presensitized Patients
- 2014
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 98:2, s. 208-215
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Tidskriftsartikel (refereegranskat)abstract
- Background. After transplantation, donor dendritic cells (DCs) in the grafted organ are activated by an ischemia/reperfusion-induced inflammatory process that induces their migration to the recipient's secondary lymphoid tissues. The subsequent interaction between migrated and mature donor DCs, recipient T cells, and natural killer (NK) cells is proposed to be crucial in directing host immune reactions toward allograft rejection. A liver transplant is less prone to induce rejection compared with most other solid organ transplants, and simultaneous transplantation of liver and kidney is known to improve the clinical outcome of kidney transplantation. Methods and Results. Here we show that liver as well as combined auxiliary liver-kidney transplantation in patients induces a rapid increase in plasma interleukin-10 (IL-10) to levels that are significantly higher than those seen after standard kidney transplantation. Addition of IL-10 during in vitro maturation of human monocyte-derived DCs with ischemia/reperfusion-associated factors was found to affect phenotypic DC maturation significantly. Addition of IL-10 inhibited DC production of the NK cell- and T cell-recruiting chemokines CXCL9, CXCL10 and CXCL11. Conclusion. Our findings indicate that liver transplantation induces a substantial systemic release of IL-10, which may inhibit T cell- and NK cell- mediated rejection processes toward the transplanted liver and concurrently transplanted kidney.
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| 25. |
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| 26. |
- Koh, Angela, et al.
(författare)
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Insulin-heparin infusions peritransplant substantially improve single-donor clinical islet transplant success
- 2010
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 89:4, s. 465-471
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Successful islet transplantation can result in insulin independence in many patients with type 1 diabetes mellitus, but it often requires more than one islet infusion. The ability to achieve insulin independence with a single donor is an important goal in clinical islet transplantation due to the limited organ supply. METHODS: We examined factors that may be associated with insulin independence after islet transplantation with islets from a single donor, using univariate and multivariate analysis. RESULTS: Thirteen of 85 (15.3%) achieved insulin independence after single-donor islet transplantation. Using multivariate analysis, only the use of insulin and heparin infusions peritransplant was a significant factor associated with insulin independence, with an adjusted odds ratio of 8.6 (95% confidence interval 2.0-37.0). Patients who had received insulin and heparin infusions peritransplant had greater indices of islet engraftment and a greater reduction in insulin use (80.1% + or - 4.3% vs. 54.2% + or - 2.8%, P<0.001) even if insulin independence was not achieved. CONCLUSIONS: Peritransplant intensive insulin and heparin enhances islet transplantation outcomes likely related in part to mitigation of the effects of the instant blood-mediated inflammatory reaction, combined with islet rest and avoidance of inflammation. It would be important to further investigate the effects of peritransplant insulin and heparin infusions on islet engraftment.
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| 27. |
- Kraemer, Bernhard K., et al.
(författare)
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Tacrolimus-Based, Steroid-Free Regimens in Renal Transplantation : 3-Year Follow-Up of the ATLAS Trial
- 2012
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 94:5, s. 492-498
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Tidskriftsartikel (refereegranskat)abstract
- Background. Long-term use of corticosteroids is associated with considerable morbidity, including cardiovascular and metabolic adverse effects. Methods. This study evaluated the long-term efficacy and safety of two steroid-free regimens compared with a triple immunosuppressive therapy in renal transplant recipients. This was a 3-year follow-up to a 6-month, open-label, randomized, multicenter study. Results. Data from 3 years were available for 421 (93.3%) of 451 patients in the original intent-to-treat population (143 tacrolimus/basiliximab [Tac/Bas], 139 tacrolimus/mycophenolate mofetil [Tac/MMF], and 139 tacrolimus/MMF/steroids [triple therapy]). In the time interval from 6 months to 3 years after transplantation, the incidence of biopsy-proven acute rejection was low and similar (Tac/Bas, 2.1%; Tac/MMF, 2.2%; triple therapy, 2.2%); Most rejection episodes occurred during the first 6 months of the study. Graft survival was high (Kaplan-Meier estimates: 92.7%, 92.5%, and 92.5%), as was patient survival (93.1%, 96.4%, and 97.0%). There were 10 graft losses (n=2, 4, and 4) and 12 patient deaths (n=5, 2, and 5). Renal function was well preserved throughout the study and similar between groups. There was a trend toward improved cardiovascular risk factors in the Tac/Bas group, including reduced total and low-density lipoprotein cholesterol and lower new-onset insulin use. There were no between-group differences in the incidence or type of adverse events. Conclusion. Higher rates of acute rejection early in treatment were seen with the steroid-free regimens, but this did not translate into poorer long-term outcomes, such as graft and patient survival and renal function. A trend for a more favorable cardiovascular risk profile was observed for steroid-free immunosuppression with Tac/Bas.
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| 28. |
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| 29. |
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| 30. |
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| 31. |
- Pihlstrom, Hege, et al.
(författare)
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Symmetric Dimethylarginine as Predictor of Graft loss and All-Cause Mortality in Renal Transplant Recipients
- 2014
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 98:11, s. 1219-1225
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Elevated symmetric dimethylarginine (SDMA) has been shown to predict cardiovascular events and all cause mortality in diverse populations. The potential role of SDMA as a risk marker in renal transplant recipients (RTR) has not been investigated. METHODS: We analyzed SDMA in the placebo arm of the Assessment of Lescol in Renal Transplantation study, a randomized controlled trial of fluvastatin in RTR. Mean follow-up was 5.1 years. Patients were grouped into quartiles based on SDMA levels at study inclusion. Relationships between SDMA and traditional risk factors for graft function and all-cause mortality were analyzed in 925 RTR using univariate and multivariate survival analyses. RESULTS: In univariate analysis, SDMA was significantly associated with renal graft loss, all-cause death, and major cardiovascular events. After adjustment for established risk factors including estimated glomerular filtration rate, an elevated SDMA-level (4th quartile, >1.38 mumol/L) was associated with renal graft loss; hazard ratio (HR), 5.51; 95% confidence interval (CI), 1.95-15.57; P=0.001, compared to the 1st quartile. Similarly, SDMA in the 4th quartile was independently associated with all-cause mortality (HR, 4.56; 95% CI, 2.15-9.71; P<0.001), and there was a strong borderline significant trend for an association with cardiovascular mortality (HR, 2.86; 95% CI, 0.99-8.21; P=0.051). CONCLUSION: In stable RTR, an elevated SDMA level is independently associated with increased risk of all-cause mortality and renal graft loss.
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| 32. |
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| 36. |
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| 37. |
- Soveri, Inga, et al.
(författare)
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A Cardiovascular Risk Calculator for Renal Transplant Recipients
- 2012
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 94:1, s. 57-62
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Renal transplant recipients (RTRs) have increased cardiovascular disease (CVD) risk. Standard CVD risk calculators are poorly predictive in RTRs; we therefore aimed to develop and validate an equation for CVD risk prediction in this population.METHODS: We used data from the Assessment of Lescol in Renal Transplantation trial, which are randomly divided into an assessment sample and a test sample (67% and 33%, respectively, of the total population). For variable selection in the assessment sample, backward stepwise Cox regression was used. Using the regression coefficients and centralized prognostic index, risk was calculated for individual patients. The equation was then validated for calibration and discrimination using the test sample.RESULTS:Major adverse cardiac events could be predicted using a seven-variable model including age, previous coronary heart disease, diabetes, low-density lipoprotein, creatinine, number of transplants, and smoking. The calibration of the model was good in the test sample with a Hosmer-Lemeshow chi-square value of 11.47 and a P value of 0.245. The areas under the receiver operating characteristic curve were 0.738 in the assessment sample and 0.740 in the test sample. Total mortality could be predicted using a six-variable model including age, coronary heart disease, diabetes, creatinine, total time on renal replacement therapy, and smoking. The calibration of the model was acceptable in the test sample with a Hosmer-Lemeshow chi-square value of 13.08 and a P value of 0.109. The areas under the receiver operating characteristic curve were 0.734 in the assessment sample and 0.720 in the test sample.CONCLUSIONS:Using the Assessment of Lescol in Renal Transplantation trial population, a formula for 7-year CVD and mortality risk calculation for prevalent RTRs has been developed.
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| 38. |
- Soveri, Inga, et al.
(författare)
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The External Validation of the Cardiovascular Risk Equation for Renal Transplant Recipients : Applications to BENEFIT and BENEFIT-EXT Trials
- 2013
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 95:1, s. 142-147
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Tidskriftsartikel (refereegranskat)abstract
- Background. Renal transplant recipients (RTRs) have increased cardiovascular disease risk. Recently, major adverse cardiac event (MACE) and mortality risk calculators for prevalent RTRs were developed. We aimed to externally validate these risk equations in an international transplant database and subsequently demonstrate application to 2 clinical trials: Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT) and Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial-EXTended criteria donors (BENEFIT-EXT). Methods. The 7-year risk calculators were developed using data from the ALERT trial and validated for discrimination and calibration in the Patient Outcomes in Renal Transplantation (PORT) study cohort. The outlier laboratory readings were trimmed to the 99th percentile observed in the PORT database. Diabetes mellitus, LDL-cholesterol, and serum creatinine values 3 years posttransplantation were used when applying the calculators to BENEFIT and BENEFIT-EXT trial treatment arms. Results. MACE could be predicted using a 7-variable model. The area under the ROC curve was 0.738 in ALERT and 0.740 in PORT, indicating preserved discrimination. In PORT, the calibration of the model indicated significant underestimation of risk in decile 5 and 9. Total mortality could be predicted using a 6-variable model. The area under the ROC curve was 0.734 in ALERT and 0.721 in PORT, indicating preserved discrimination. In PORT, the calibration of the model indicated significant underestimation of risk in decile 7 and significant overestimation in the highest risk decile. In BENEFIT and BENEFIT-EXT trial, the calculator estimated that belatacept use may result in reduction in MACE (>20%) and mortality (similar to 18%-30%). Conclusion. The MACE and mortality risk calculators for prevalent RTRs have been externally validated and found suitable for generic risk stratification.
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- Takemoto, Naohiro, et al.
(författare)
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Transplantation of Co-aggregates of Sertoli Cells and Islet Cells Into Liver Without Immunosuppression
- 2014
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 97:3, s. 287-293
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Tidskriftsartikel (refereegranskat)abstract
- Background Transplantation of islets of Langerhans (islets) was used to treat insulin-dependent diabetes mellitus. However, islet grafts must be maintained by administration of immunosuppressive drugs, which can lead to complications in the long term. An approach that avoids immunosuppressive drug use is desirable. Methods Co-aggregates of Sertoli cells and islet cells from BALB/c mice that were prepared by the hanging drop method were transplanted into C57BL/6 mouse liver through the portal vein as in human clinical islet transplantation. Results The core part of the aggregates contained mainly Sertoli cells, and these cells were surrounded by islet cells. The co-aggregates retained the functions of both Sertoli and islet cells. When 800 co-aggregates were transplanted into seven C57BL/6 mice via the portal vein, six of seven recipient mice demonstrated quasi-normoglycemia for more than 100 days. Conclusions The hanging drop method is suitable for preparing aggregates of Sertoli and islet cells for transplantation. Notably, transplantation of these allogeneic co-aggregates into mice with chemically induced diabetes via the portal vein resulted in long-term graft survival without systemic immunosuppression.
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- Tokodai, Kazuaki, et al.
(författare)
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Attenuation of Cross-Talk Between the Complement and Coagulation Cascades by C5a Blockade Improves Early Outcomes After Intraportal Islet Transplantation
- 2010
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 90:12, s. 1358-1365
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Tidskriftsartikel (refereegranskat)abstract
- Background. Complement 5a factor (C5a) elicits a broad range of proinflammatory effects, including chemotaxis of inflammatory cells and cytokine release. C5a is also linked to the coagulant activity in autoimmune diseases. Therefore, C5a most likely plays a crucial role in the instant blood-mediated inflammatory reaction. Methods. Intraportal transplantation of 2.5 islet equivalents/g of syngeneic rat islet grafts was performed in two groups of streptozotocin-induced diabetic rats: controls and C5a inhibitory peptide (C5aIP)-treated group. Results. The thrombin-antithrombin complex was significantly suppressed in the C5aIP group (P = 0.003), and both the curative rate and the glucose tolerance were significantly improved in the C5aIP group (P < 0.05 and P < 0.005, respectively). Expression of tissue factor on granulocytes in recipient livers was up-regulated 1 h after islet infusion (P < 0.0001), which was significantly suppressed by C5aIP (P < 0.005). However, C5aIP was unable to regulate tissue factor expression on isolated islets. Furthermore, no differences were detected between the groups, regarding infiltration of CD11b-positive cells and deposition of C5b-9 on the islet grafts. Conclusions. These data suggest that C5aIP attenuates cross-talk between the complement and coagulation cascades through suppressing up-regulation of tissue factor expression on leukocytes in recipient livers but not on islet grafts, a process leading to improvement in islet engraftment. Therefore, C5aIP in combination with conventional anticoagulants could be a strong candidate strategy to control the instant blood-mediated inflammatory reaction induced in clinical islet transplantation.
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