| 1. |
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| 2. |
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| 3. |
- Abedini, Sadollah, et al.
(author)
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Cerebrovascular events in renal transplant recipients
- 2009
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In: Transplantation. - 0041-1337 .- 1534-6080. ; 87:1, s. 112-7
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Journal article (peer-reviewed)abstract
- BACKGROUND: The incidence of stroke and risk factors for different subtypes of cerebrovascular (CBV) events in renal transplant recipients have not been examined in any large prospective controlled trial. METHODS: The Assessment of Lescol in Renal Transplantation was a randomized, double-blind, placebo-controlled study of the effect of fluvastatin (40-80 mg) daily on cardiovascular, and renal outcomes in renal transplant recipients. Patients initially randomized to fluvastatin or placebo in the 5 to 6 year trial was offered open-label fluvastatin in a 2-year extension to the original study. We investigated the incidence of stroke and risk factors for ischemic and hemorrhagic CBV events in 2102 renal graft recipients participating in the Assessment of Lescol in Renal Transplantation core and extension trial with a mean follow-up of 6.7 years. RESULTS: The incidence and type of CBV events did not differ between the lipid lowering arm and the placebo arm. A total of 184 (8.8%, 95% confidence interval 4.6-12.9) of 2102 patients experienced a CBV event during follow-up, corresponding to an incidence of 1.3% CBV event per year. The mortality for patients experiencing a hemorrhagic stroke was 48% (13 of 27), whereas the mortality for ischemic strokes was 6.0% (8 of 133). Diabetes mellitus, previous CBV event, age, and serum creatinine were independent risk factors for cerebral ischemic events. The risk of a hemorrhagic cerebral event was increased by diabetes mellitus, polycystic kidney disease, left ventricular hypertrophy, and systolic blood pressure. INTERPRETATION: Risk factors for CBV events in renal transplant recipients differ according to subtype.
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| 4. |
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| 5. |
- Ahrens, Norbert, et al.
(author)
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Mesenchymal stem cell content of human vertebral bone marrow
- 2004
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In: Transplantation. - 1534-6080. ; 78:6, s. 925-929
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Journal article (peer-reviewed)abstract
- Mesenchymal stem cells (MSCs) are capable of down-regulating alloimmune responses and promoting the engraftment of hematopoietic stem cells. MSCs may therefore be suitable for improving donor-specific tolerance induction in solid-organ transplantation. Cells from cadaveric vertebral bone marrow (V-BM), aspirated iliac crest-BM, and peripheral blood progenitor cells were compared. Cells were characterized by flow cytometry and colony assays. MSCs generated from V-BM were assayed for differentiation capacity and immunomodulatory function. A median 5.7 x 10(8) nucleated cells (NCs) were recovered per vertebral body. The mesenchymal progenitor, colony-forming unit-fibroblast, frequency in V-BM (11.6/10(5) NC, range: 6.0-20.0) was considerably higher than in iliac crest-BM (1.4/10(5) NC, range: 0.4-2.6) and peripheral blood progenitor cells (not detectable). MSC generated from V-BM had the typical MSC phenotype (CD105(pos)CD73(pos)CD45(neg)CD34(neg)), displayed multilineage differentiation potential, and suppressed alloreactivity in mixed lymphocyte reactions. V-BM may be an excellent source for MSC cotransplantation approaches.
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| 6. |
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| 7. |
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| 8. |
- Alves, Fabio de Abreu, et al.
(author)
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Immunohistopathology of the Newly Discovered Giant Papillae Tongue Disorder in Organ-Transplanted Children
- 2017
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In: Transplantation. - : Lippincott Williams & Wilkins. - 0041-1337 .- 1534-6080. ; 101:6, s. 1441-1448
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Journal article (peer-reviewed)abstract
- Background. Giant papillae tongue disorder (GRID) is a newly discovered, long-lasting clinical disorder that may develop in organ-transplanted pediatric recipients. The key feature of this disorder is the unique tongue lesion, which comprises swollen fungiform papillae. The aim of this study was to characterize the immunohistopathology of this novel inflammatory condition. Methods. Six organ transplanted children with GRID were included in the study. Routine histopathology and immunohistochemical stainings for CD3, CD4, CD8, CD25, FOXP3, CD20, CD138, CD68, CD1a, CD15, CD23, and mast cell tryptase were performed. Results. Immunohistochemical analyses of the oral lesions revealed a subepithelial infiltrate that was primarily composed of CD3- and CD4-positive T cells, CD20-expressing B cells, macrophages, and CD138-positive plasma cells. The CD20-positive cells did not display the typical B cell morphology, having in general a more dendritic cell-like appearance. The CD138-expressing plasma cells were distinctly localized as a dense infiltrate beneath the accumulation of T cells and B cells. Increased numbers of CD1a-expressing Langerhans cells were detected both in the epithelium and connective tissue. Because no granulomas were observed and only single lesional eosinophils were detected, GPTD does not resemble a granulomatous or eosinophilic condition. Conclusions. We describe for the first time the immunopathological characteristics of a novel inflammatory disorder of the oral cavity, which may develop after solid organ transplantation in children.
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| 9. |
- Anan, Intissar, et al.
(author)
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Liver transplantation restores endocrine cells in patients with familial amyloidotic polyneuropathy.
- 2000
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In: Transplantation. - 0041-1337 .- 1534-6080. ; 70:5, s. 794-9
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Journal article (peer-reviewed)abstract
- BACKGROUND: The aim of this study was to investigate familial amyloidotic polyneuropathy, Portuguese type patients' endocrine cell content in the stomach and duodenum before and after liver transplantation, and to relate the findings to the patients' gastrointestinal disturbances.METHODS: Ten liver-transplanted familial amyloidotic polyneuropathy, Portuguese type patients and 10 healthy controls were seen. Endocrine cells were identified by immunohistochemistry and quantified with computerized image analysis. The activity of the cells was appraised by measurements of the cell secretory index and nuclear area. Clinical symptoms were obtained from the patients' medical records.RESULTS: After transplantation, a significant increase of several endocrine cell types were noted, and the pretransplant depletion of several types of endocrine cells disappeared. For no type of endocrine cell was any difference compared with controls noted after transplantation. There was no significant decrease of the amount of amyloid in the biopsies after liver transplantation. The patients' symptoms remained generally unchanged after transplantation, although a substantial time lapse between pretransplant evaluation and transplantation was present.CONCLUSIONS: Liver transplantation restores the endocrine cells in the upper part of the gastrointestinal tract. The restoration was not correlated with an improvement of the patients' symptoms. No decrease of the amyloid deposits was noted.
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| 10. |
- Arnadottir, Margret, et al.
(author)
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Hyperhomocysteinemia in cyclosporine-treated renal transplant recipients
- 1996
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In: Transplantation. - 1534-6080. ; 61:3, s. 509-512
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Journal article (peer-reviewed)abstract
- Moderate hyperhomocysteinemia, an independent cardiovascular risk factor, has been reported in renal transplant recipients. In the present study, plasma concentrations of total homocysteine were significantly increased in 120 renal transplant recipients as compared with 60 healthy controls (19.0 +/- 6.9 vs. 11.6 +/- 2.8 mumol/L, P < 0.0001) and as compared with 53 patients without a transplant but with a comparable degree of renal failure (19.0 +/- 6.9 vs. 16.0 4.9 mumol/L, P < 0.01). There was a significant inverse correlation between glomerular filtration rates and plasma homocysteine concentrations in the renal transplant recipients (r = -0.52, P < 0.0001). Groups of renal transplant recipients, with and without cyclosporine, and renal patients without a transplant were studied; these groups were comparable regarding age, sex distribution, glomerular filtration rate, and folate and vitamin B12 concentrations. Renal transplant recipients on cyclosporine had significantly higher plasma homocysteine concentrations than those not on cyclosporine (19.5 +/- 7.6 vs. 16.2 +/- 4.8 mumol/L, P < 0.05), and the patients without a transplant (19.5 +/- 7.6 vs. 16.0 +/- 4.9 mumol/L, P < 0.01). Thus, the hyperhomocysteinemia of renal transplant recipients not treated with cyclosporine, and that of renal patients without a transplant probably is explained by the same mechanism: renal insufficiency. An additional mechanism seems to operate in renal transplant recipients treated with cyclosporine. The lack of correlation between the concentrations of plasma homocysteine and red cell folate in these patients suggests that cyclosporine interferes with folate-assisted remethylation of homocysteine. Plasma homocysteine concentrations were significantly increased in 24 patients with a history of atherosclerotic complications as compared with the remaining 96 renal transplant recipients (20.8 +/- 4.4 vs. 18.5 +/- 7.3 mumol/L, P < 0.01).
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| 11. |
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| 12. |
- Arora, Satish, et al.
(author)
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Effect of Everolimus Introduction on Cardiac Allograft Vasculopathy-Results of a Randomized, Multicenter Trial
- 2011
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In: Transplantation. - : Williams and Wilkins. - 0041-1337 .- 1534-6080. ; 92:2, s. 235-243
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Journal article (peer-reviewed)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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| 13. |
- Auråen, Henrik, et al.
(author)
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Effect of Donor Age on Outcome of Lung Transplantation Stratified by Recipient Diagnosis : A Nordic Multicenter Study
- 2019
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In: Transplantation. - 1534-6080. ; 103:4, s. 807-814
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Journal article (peer-reviewed)abstract
- BACKGROUND: Organs from older donors are increasingly used in lung transplantation, and studies have demonstrated that this could be safe in selected recipients. However, which recipient groups that have the largest benefit of older organs are unclear. This multicenter study reviews all bilateral lung transplantations (BLTx) from donors 55 years or older stratified by recipient diagnosis and compares outcomes with transplantations from younger donors. METHODS: All BLTx recipients (excluding retransplantation) at 5 Scandiatransplant centers between 2000 and 2013 were included (n = 913). Recipients were stratified to diagnosis groups including cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), and "other." Intensive care unit (ICU) length of stay (LOS) and survival were assessed. RESULTS: Overall, there was no difference in survival among patients transplanted from donors 55 years or older compared with younger donors. However, in CF recipients, donor age 55 years or older was associated with inferior survival (P = 0.014), and this remained significant in a multivariate model (hazard ratio, 5.0; 95% confidence interval, 1.8-14.1; P = 0.002). There was no significant effect of donor age on survival in recipients with COPD, ILD, or in the "other" group in multivariate models. Utilization of older donors was associated with increased ICU LOS for recipients with CF and ILD, but not in the COPD or "other" group. CONCLUSIONS: The BLTx recipients with CF had inferior survival and longer ICU LOS when receiving organs from donors 55 years or older. Recipients with COPD, ILD, or in the "other" group did not have inferior survival in multivariate models.
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| 14. |
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| 15. |
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| 16. |
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| 17. |
- Berglund, David, et al.
(author)
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Expression of Intratumoral Forkhead Box Protein 3 in Posttransplant Lymphoproliferative Disorders : Clinical Features and Survival Outcomes
- 2015
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In: Transplantation. - : Lippincott Williams & Wilkins. - 0041-1337 .- 1534-6080. ; 99:5, s. 1036-1042
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Journal article (peer-reviewed)abstract
- Background. The infiltration of regulatory T cells (Tregs) in lymphomas is associated with better prognosis for some types of lymphomas, but knowledge of their role in posttransplant lymphoproliferative disorders (PTLDs) is limited. We therefore investigated the association between the expression of the Treg marker forkhead box protein 3 (FoxP3) in biopsies of PTLDs and survival, PTLD subtype, and clinical characteristics.Methods. Seventy-four cases of PTLD after solid organ transplantation with sufficient material for further analysis were included from a population-based study of PTLDs in Sweden. The PTLD biopsies were reevaluated and stained with the 236A/E7 antibody to detect FoxP3 in lymphoma tissue. Detailed clinical data were collected retrospectively from medical records.Results. Based on a cutoff level of 29 FoxP3+ cells per mm2, most (80%) of the PTLDs were FoxP3-. Forty-seven of 74 PTLDs displayed no FoxP3+ cells at all. The frequency of FoxP3+ cells did not influence median overall survival. The FoxP3- PTLDs were more frequently of T-cell phenotype (P=0.04), located at the graft (P=0.03), occurred earlier after transplantation (P=0.04), were more likely to develop in lung recipients (P=0.04), and in patients that had received anti T-cell globulin as induction therapy (P=0.02). The FoxP3+ PTLDs were associated with hepatitis C seropositivity (P=0.03). In multivariate analysis, B-cell PTLD and hepatitis C infection were independent predictors of FoxP3 positivity.Conclusion. Our findings suggest that intratumoral FoxP3+ Tregs do not influence survival in patients with PTLD. FoxP3+ Tregs are rare in PTLD, possibly because of heavy immunosuppression.
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| 18. |
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| 19. |
- Berglund, Erik, et al.
(author)
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Clinical Significance of Alloantibodies in Hand Transplantation : A Multicenter Study
- 2019
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In: Transplantation. - : LIPPINCOTT WILLIAMS & WILKINS. - 0041-1337 .- 1534-6080. ; 103:10, s. 2173-2182
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Journal article (peer-reviewed)abstract
- Background. Donor-specific antibodies (DSAs) have a strong negative correlation with long-term survival in solid organ transplantation. Although the clinical significance of DSA and antibody-mediated rejection (AMR) in upper extremity transplantation (UET) remains to be established, a growing number of single-center reports indicate their presence and potential clinical impact. Methods. We present a multicenter study assessing the occurrence and significance of alloantibodies in UET in reference to immunological parameters and functional outcome. Results. Our study revealed a high prevalence and early development of de novo DSA and non-DSA (43%, the majority detected within the first 3 postoperative y). HLA class II mismatch correlated with antibody development, which in turn significantly correlated with the incidence of acute cellular rejection. Cellular rejections preceded antibody development in almost all cases. A strong correlation between DSA and graft survival or function cannot be statistically established at this early stage but a correlation with a lesser outcome seems to emerge. Conclusions. While the phenotype and true clinical effect of AMR remain to be better defined, the high prevalence of DSA and the correlation with acute rejection highlight the need for optimizing immunosuppression, close monitoring, and the relevance of an HLA class II match in UET recipients.
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| 20. |
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| 21. |
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| 22. |
- Biglarnia, Ali-Reza, et al.
(author)
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Desensitization With Antigen-Specific Immunoadsorption Interferes With Complement in ABO-Incompatible Kidney Transplantation
- 2012
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In: Transplantation. - 0041-1337 .- 1534-6080. ; 93:1, s. 87-92
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Journal article (peer-reviewed)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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| 23. |
- Biglarnia, Alireza, et al.
(author)
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Venous thromboembolism in live kidney donors : a prospective study
- 2008
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In: Transplantation. - 0041-1337 .- 1534-6080. ; 86:5, s. 659-661
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Journal article (peer-reviewed)abstract
- AIM:The aim of this study was to evaluate risk factors for venous thromboembolism (VTE) and deep vein thrombosis after living donor nephrectomy in a center using extensive preoperative screening and perioperative venous duplex scan.MATERIAL AND METHODS: Thrombophilia screening and pre- and postoperative ultrasonographies were performed in 130 consecutive living kidney donors (laparoscopic 105, open 25). Donors were followed prospectively for at least 3 months. All donors received prophylaxis with the low molecular weight heparin enoxaparin and compression stockings. Donors with increased risk received a double dose of enoxaparin and the prophylaxis was continued for 6 weeks. Donors with venous thrombosis at discharge duplex also received prolonged prophylaxis.RESULTS:The frequency of thrombophilia was similar to what can be expected in the Swedish population (four with factor V Leiden and one each with protein S deficiency, prothrombin gene mutation, and anticardiolipin antibodies). Preoperative duplex was normal. Three donors had small postoperative deep vein thrombosis. Twelve donors (9.2%) received an intensified and prolonged prophylaxis. No further thromboembolic complications developed in 3 postoperative months.CONCLUSION:With the present protocol for preoperative evaluation, perioperative duplex screening, and prophylaxis, the risk of postoperative VTE is low after living donor nephrectomy. Given that 9.2% had risk factors or developed deep vein thrombosis, the extraordinary situation of an operation being performed on a healthy person who has no therapeutic benefit and the low incidence of VTE in the present study, we recommend the presented approach to be implemented more broadly and that further studies are performed in larger cohorts.
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| 24. |
- Biró, Péter, et al.
(author)
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Building Kindey Exchange Programmes in Europe - An Overview of Exchange Practice and Activities
- 2019
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In: Transplantation. - 1534-6080. ; 103:7, s. 1514-1522
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Journal article (peer-reviewed)abstract
- Bakgrund: Considerable differences exist among the living donor Kidney Exchange Programmes (KEPs) that are in use and being built in Europe, contributing to a variation in the number of living donor transplants [6]. Efforts of European KEPs to exchange (best) practices and share approaches to address challenges have, however, been limited.Methods: Experts from 23 European countries, collaborating on the ENCKEP COST Action, developed a questionnaire to collect detailed information on the functioning of all existing KEPs in Europe, as well as their opportunities and challenges. Following a comparative analysis, results were synthesised and interpreted by the same experts.Results: The practices, opportunities and challenges reported by 17 European countries reveal that some of the 10 operating programmes are mature, while others are in earlier stages of development. Over 1300 transplants were performed through existing KEPs up to the end of 2016, providing approximately 8% of their countries’ living kidney donations in 2015. All countries report challenges to either initiating KEPs or increasing volumes. Some challenges are shared, whilst others differ because of differences in context (eg, country size, effectiveness of deceased donor programme) and ethical and legal considerations (eg, regarding living donation as such, nonrelated donors, and altruistic donation). Transnational initiatives have started in Central Europe, Scandinavia, and Southern Europe.Conclusions: Exchange of best practices and shared advancement of national programmes to address existing challenges, aided by transnational exchanges, may substantially improve access to the most (cost) effective treatment for the increasing number of patients suffering from kidney disease.
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| 25. |
- Bockermann, Robert, et al.
(author)
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Imlifidase-generated Single-cleaved IgG : Implications for Transplantation
- 2022
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In: Transplantation. - : Ovid Technologies (Wolters Kluwer Health). - 0041-1337 .- 1534-6080. ; 106:7, s. 1485-1496
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Journal article (peer-reviewed)abstract
- Background. Imlifidase is an immunoglobulin G (IgG)-specific protease conditionally approved in the EU for desensitization in highly sensitized crossmatch positive kidney transplant patients. Imlifidase efficiently cleaves both heavy chains of IgG in a 2-step process. However, low levels of the intermediate cleavage product, single-cleaved IgG (scIgG), may persist in the circulation. The study objective was to investigate Fc-mediated effector functions of scIgG and its potential impact on common clinical immunologic assays used to assess transplant eligibility.Methods. Imlifidase-generated scIgG, obtained by in vitro cleavage of HLA-sensitized patient serum or selected antibodies, was investigated in different complement- and Fc gamma R-dependent assays and models, including clinical tests used to evaluate HLA-specific antibodies.Results. ScIgG had significantly reduced Fc-mediated effector function compared with intact IgG, although some degree of activity in complement- and Fc gamma R-dependent models was still detectable. A preparation of concentrated scIgG generated from a highly HLA-sensitized individual gave rise to a positive signal in the anti-HLA IgG LABScreen, which uses anti-Fc detection, but was entirely negative in the C1qScreen. The same high-concentration HLA-binding scIgG preparation also generated positive complement-dependent cytotoxicity responses against 80%-100% of donor T and B cells, although follow-up titrations demonstrated a much lower intrinsic activity than for intact anti-HLA IgG.Conclusions. ScIgG has a significantly reduced capacity to mediate Fc-dependent effector functions. However, remaining HLA-reactive scIgG in plasma after imlifidase treatment can cause positive assay results equivalent to intact IgG in clinical assays. Therefore, complete IgG cleavage after imlifidase treatment is essential to allow correct decision-making in relation to transplant eligibility.
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| 26. |
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| 29. |
- Brandhorst, Heide, 1962-, et al.
(author)
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A new oxygen carrier for improved long-term storage of human pancreata before islet isolation
- 2010
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In: Transplantation. - 0041-1337 .- 1534-6080. ; 89:2, s. 155-60
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Journal article (peer-reviewed)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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| 30. |
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| 31. |
- Brandhorst, Heide, 1962-, et al.
(author)
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The importance of tryptic-like activity in purified enzyme blends for efficient islet isolation
- 2009
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In: Transplantation. - 0041-1337 .- 1534-6080. ; 87:3, s. 370-5
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Journal article (peer-reviewed)abstract
- BACKGROUND: The isolation of islets from the human pancreas critically depends on an efficient enzyme blend. Previous studies have solely focused on the presence of collagenase and neutral protease/thermolysin. Despite improved characterization of these components, the lot-related variability in efficacy still persists suggesting that additional so far disregarded enzymes are required for efficient islet cleavage. METHODS: Varying activities of a tryptic-like enzyme were identified within collagenase NB1 lots, which were selected according to a matched ratio between tryptic-like and collagenase activity (TLA-ratio). Rat and human pancreata were processed with current standard procedures. RESULTS: Increasing the TLA-ratio from 1.3% to 10% reduced pancreas dissociation time in rats by 50% without affecting islet yield, viability, or posttransplant function in diabetic nude mice. Enhancing the TLA-ratio from 1.3% to 12.6% for human pancreas processing resulted in a significant reduction of recirculation time and increased incrementally human islet yield without affecting purity, in vitro function or recovery after culture. Optimized pancreas digestion correlated with a higher percentage of islet preparations fulfilling quality criteria for clinical transplantation. CONCLUSIONS: We conclude that TLA is an effective component that should be included in moderate amounts in enzyme blends for human islet isolation to optimize the efficiency and minimize the lot-related variability.
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| 32. |
- Brandhorst, Heide, et al.
(author)
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The ratio between collagenase class I and class II influences the efficient islet release from the rat pancreas
- 2008
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In: Transplantation. - 0041-1337 .- 1534-6080. ; 85:3, s. 456-61
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Journal article (peer-reviewed)abstract
- BACKGROUND: Previous studies indicated different roles of collagenase class I, class II and neutral protease in the enzymatic islet release from pancreatic tissue. Because no information has been available, this study was aimed to investigate the isolation efficiency of different ratios between collagenase class II and I (C-ratio) in the rat pancreas serving as model for the human pancreas without being restricted by the large variability observed in human donors. METHODS: Rat pancreata were digested using a marginal neutral protease activity and 20 PZ-U of purified collagenase classes recombined to create a C-ratio of 0.5, 1.0, or 1.5. Collagenase efficiency was evaluated in terms of isolation outcome and posttransplantation function in diabetic nude mice. RESULTS: The highest yield of freshly isolated islets was obtained using a C-ratio of 1.0. Purity and fragmentation of freshly isolated islets were not influenced by the C-ratio. After 24-hr culture performed for quality assessment, a marginal but significant reduction of viability was observed in islets isolated by means of a C-ratio of 0.5 and 1.5. Islet in vitro and posttransplantation function revealed no negative effect mediated by different C-ratios. CONCLUSIONS: The present study demonstrates that the C-ratio is of significant relevance for the outcome after enzymatic rat islet isolation. The data indicate further that purified collagenase class I or class II does not damage islet tissue even if used in excess. The present study can serve as a start for subsequent experiments in the human pancreas.
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| 33. |
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| 34. |
- Breimer, Michael, 1951, et al.
(author)
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Multicenter evaluation of a novel endothelial cell crossmatch test in kidney transplantation.
- 2009
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In: Transplantation. - 1534-6080. ; 87:4, s. 549-56
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Journal article (peer-reviewed)abstract
- BACKGROUND: Despite their clinical importance, clinical routine tests to detect anti-endothelial cell antibodies (AECA) in organ transplantation have not been readily available. This multicenter prospective kidney transplantation trial evaluates the efficacy of a novel endothelial cell crossmatch (ECXM) test to detect donor-reactive AECA associated with kidney allograft rejection. METHODS: Pretransplant serum samples from 147 patients were tested for AECA by a novel flow cytometric crossmatch technique (XM-ONE) using peripheral blood endothelial progenitor cells as targets. Patient enrolment was based on acceptance for transplantation determined by donor lymphocyte crossmatch results. RESULTS: Donor-reactive AECA were found in 35 of 147 (24%) patients. A significantly higher proportion of patients with a positive ECXM had rejections (16 of 35, 46%) during the follow-up of at least 3 months compared with those without AECA (13 of 112, 12%; P<0.00005). Both IgG and IgM AECAs were associated with graft rejections. Mean serum creatinine levels were significantly higher in patients with a positive ECXM test at 3 and 6 months posttransplant. CONCLUSIONS: XM-ONE is quick, easy to perform on whole blood samples and identifies patients at risk for rejection and reduced graft function not identified by conventional lymphocyte crossmatches.
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| 35. |
- Broecker, Verena, et al.
(author)
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Reproducibility of Rejection Grading in Uterus Transplantation: A Multicenter Study.
- 2023
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In: Transplantation Direct. - 0041-1337 .- 1534-6080. ; 9:10
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Journal article (peer-reviewed)abstract
- Diagnosis of rejection after uterus transplantation is based on histopathological examination of ectocervical biopsies. Inflammation at the stromal-epithelial interface is the backbone of the histopathological classification proposed by our group in 2017. However, the reproducibility of this grading scheme has not been tested, and it is unclear whether it covers the full morphological spectrum of rejection.We present a multicenter study in which 5 pathologists from 4 uterus transplantation centers performed 2 rounds of grading on 145 and 48 cervical biopsies, respectively. Three of the centers provided biopsies. Additionally, the presence of perivascular stromal inflammation was recorded. During discussions after the first round, further histological lesions (venous endothelial inflammation and apoptosis) were identified for closer evaluation and added to the panel of lesions to score in the second round. All participants completed a questionnaire to explore current practices in handling and reporting uterus transplant biopsies.Cervical biopsies were commonly performed in all centers to monitor rejection. Intraobserver reproducibility of rejection grading (performed by 1 rater) was excellent, whereas interobserver reproducibility was moderate and did not improve in the second round. Reproducibility of perivascular stromal inflammation was moderate but unsatisfactory for venous endothelial inflammation and apoptosis. All lesions were more frequent in, but not restricted to, biopsies with rejection patterns.Grading of rejection in cervical biopsies is reproducible and applicable to biopsies from different centers. Diagnosis of rejection may be improved by adding further histological lesions to the grading system; however, lesions require rigorous consensus definition.
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| 36. |
- Brännström, Mats, 1958, et al.
(author)
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Uterus transplantation: A Rapidly Expanding Field
- 2018
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In: Transplantation. - 0041-1337 .- 1534-6080. ; 102:4, s. 569-577
-
Research review (peer-reviewed)abstract
- Uterus transplantation (UTx) has been successfully introduced as a treatment option for women with absolute uterine factor infertility (AUFI). AUFI representing approximately 3% to 5% of the female general population is linked to either congenital uterine agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome), major congenital uterine malformation (hypoplastic uterus, fraction of bicornuate/unicornuate uterus), a surgically absent uterus, or an acquired condition (intrauterine adhesions, leiomyoma) linked to uterine malfunction that causes implantation failure or defect placentation. The world's first clinical uterus transplant was performed in 2000. However, a hysterectomy became necessary shortly after the surgery due to uterine necrosis. In 2011, a group in Turkey reported on a surgically successful deceased donor transplant; however, this procedure has, to date, not resulted in a healthy live birth, the ultimate goal of UTx. Building on an extensive experimental background in various animal models, including primates, the Gothenburg group led by Brannstrom reported on the first delivery of a healthy baby in a recipient of a live donor UTx in 2014. This event did not only show the feasibility of UTx, it also helped defining relevant areas of clinical and basic research. Use of a gestational surrogate carrier, is, at least in theory, an alternative for a woman with AUFI seeking genetic motherhood. However, in the clear majority of countries worldwide, gestational surrogacy is not practiced based on legal, ethical, or religious concerns. Of note, the overwhelming majority of surveyed women in the United Kingdom, a country which permits surrogacy, preferred UTx over gestational surrogacy and adoption. Moreover, randomly selected women of fertile age in Sweden preferred UTx over gestational surrogacy. A recent large survey in Japan with more than 3000 participants revealed that UTx had a twofold higher acceptance rate compared with gestational surrogacy. In a recent US survey exploring the potential of donating vascularized composite allografts, uterus donation achieved the highest priority. Thus, the acceptance of UTx as infertility treatment for women with AUFI is high, although the procedure remains in its infancy. Here, we provide an update of clinical activities, summarize achievements and challenges, and submit areas of research interests.
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| 37. |
- Bućin, Dragan, et al.
(author)
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Desensitization and Heart Transplantation of a Patient With High Levels of Donor-Reactive Anti-Human Leukocyte Antigen Antibodies.
- 2010
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In: Transplantation. - 1534-6080. ; 90, s. 1220-1225
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Journal article (peer-reviewed)abstract
- BACKGROUND.: To prepare a highly immunized recipient for heart transplantation, reduction of high levels of cytotoxic antibodies against human leukocyte antigen (HLA) was deemed essential to prevent antibody-mediated graft failure. METHODS.: Antibodies were analyzed by lymphocytotoxic and solid-phase assays. The pretransplant desensitization treatment protocol included daily tacrolimus and mycophenolate mofetil, weekly protein-A immunoadsorption (IA), intravenous immunoglobulin, and daclizumab. Posttransplant treatment consisted of tacrolimus, mycophenolate mofetil, prednisolone, IA, and daclizumab. RESULTS.: During pretransplant desensitization, each of the weekly immunoadsorption treatments reduced anti-HLA antibody levels by 50% to 70%, but they returned to the pretreatment level within 1 week as measured by flow cytometry. Cytotoxic antibodies remained reduced. After perioperative immunoadsorption, the donor-reactive antibodies (DRAs) were reduced to low levels. The patient underwent successful heart transplantation after 6 weeks on a waiting list. During the first week posttransplant, DRAs remained low. However, after the first week, anti-HLA DRAs reappeared and increased slightly over a 3-week period and then decreased slowly. Cytotoxic crossmatches were negative before and 3 week after transplantation. No clinical rejection was encountered. The patient was doing well 3 years after transplantation, and yearly clinical cardiac investigations were all normal. Three hyperimmunized patients have now undergone successful heart transplantation at our center using this desensitization protocol. CONCLUSIONS.: IA in combination with pretransplant immunosuppressive drug treatment temporarily reduces antibody levels. The therapeutic levels of drug treatment at the time of transplantation may be of crucial importance. The treatment protocol resulted in freedom from rejection and other clinical adverse events.
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| 38. |
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| 39. |
- Caballero-Corbalán, José, et al.
(author)
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No beneficial effect of two-layer storage compared with UW-storage on human islet isolation and transplantation
- 2007
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In: Transplantation. - : Ovid Technologies (Wolters Kluwer Health). - 0041-1337 .- 1534-6080. ; 84:7, s. 864-869
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Journal article (peer-reviewed)abstract
- Background. Shipment of pancreata between distant centers is frequently associated with prolonged cold ischemia time (CIT) that leads to poorer outcomes for islet transplantation. Clinical pilot trials have indicated that oxygenation of explanted human pancreata utilizing the two-layer method (TLM) allows the use of marginal donor pancreata for islet transplantation. The present study aimed to clarify whether TLM enhances the ischemic tolerance of human pancreata. Methods. We analyzed retrospectively the outcome of 200 human islet isolations performed after TLM preservation or storage in University of Wisconsin solution (UWS). Results. Donor characteristics and digestion parameters did not vary significantly between TLM-preserved and UWS-stored pancreata. No differences were observed between experimental groups with regard to islet yield, purity, or dynamic glucose stimulation index after either short or prolonged CIT. However, CIT and stimulation index were negatively correlated in each experimental group. The isolation outcome in donors aged ≥60 years was not increased after TLM preservation when compared to UWS storage. No effect was observed regarding islet posttransplant function in recipients with established kidney grafts. Conclusions. The present study suggests that the ischemic tolerance of human pancreata cannot be extended by TLM preservation. In addition, TLM does not seem to improve the isolation outcome for pancreata from elderly donors.
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| 40. |
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| 41. |
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| 42. |
- Carlsson, Per-Ola, et al.
(author)
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Chronically decreased oxygen tension in rat pancreatic islets transplantedunder the kidney capsule
- 2000
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In: Transplantation. - 0041-1337 .- 1534-6080. ; 69:5, s. 761-766
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Journal article (peer-reviewed)abstract
- BACKGROUND: A factor of potential importance in the failure of islet grafts is poor or inadequate engraftment of the islets in the implantation organ. This study measured the oxygen tension and blood perfusion in 1-, 2-, and 9-month-old islet grafts. METHODS: The partial pressure of oxygen was measured in pancreatic islets transplanted beneath the renal capsule of diabetic and nondiabetic recipient rats with a modified Clark electrode (outer tip diameter 2-6 microm). The size of the graft (250 islets) was by purpose not large enough to cure the diabetic recipients. The oxygen tension in islets within the pancreas was also recorded. Blood perfusion was measured with the laser-Doppler technique. RESULTS: Within native pancreatic islets, the partial pressure of oxygen was approximately 40 mm Hg (n=8). In islets transplanted to nondiabetic animals, the oxygen tension was approximately 6-7 mm Hg 1, 2, and 9 months posttransplantation. No differences could be seen between the different time points after transplantation. In the diabetic recipients, an even more pronounced decrease in graft tissue oxygen tension was recorded. The mean oxygen tension in the superficial renal cortex surrounding the implanted islets was similar in all groups (approximately 15 mm Hg). Intravenous administration of glucose (0.1 gxkg(-1)x min(-1)) did not affect the oxygen tension in any of the investigated tissues. The islet graft blood flow was similar in all groups, measuring approximately 50% of the blood flow in the kidney cortex. CONCLUSION: The oxygen tension in islets implanted beneath the kidney capsule is markedly lower than in native islets up to 9 months after transplantation. Moreover, persistent hyperglycemia in the recipient causes an even further decrease in graft oxygen tension, despite similar blood perfusion. To what extent this may contribute to islet graft failure remains to be determined.
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| 43. |
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| 44. |
- Corbascio, Matthias, et al.
(author)
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Anti-lymphocyte function-associated antigen-1 monoclonal antibody inhibits CD40 ligand-independent immune responses and prevents chronic vasculopathy in CD40 ligand-deficient mice.
- 2002
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In: Transplantation. - 1534-6080. ; 74:1, s. 35-41
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Journal article (peer-reviewed)abstract
- BACKGROUND: Blockade of CD40 ligand (CD40L; CD154, gp39) is a potential treatment for autoimmune disease and allograft rejection. However, CD40L-/- mice are capable of mobilizing cellular immune responses to viral, parasitic, and intracellular bacterial infections as well as rejecting skin grafts with nearly the same efficiency as wild-type mice. CD40L-deficient mice (CD40L-/-) or wild-type mice treated with anti-CD40L develop chronic vasculopathy only 8 weeks after allogeneic heart transplantation. To overcome CD40L-independent immune responses, we used anti-lymphocyte function-associated antigen monoclonal antibody (LFA)-1, which has previously been shown to inhibit CD8+ immune responses. METHODS: We conducted mixed lymphocyte reactions, cytotoxicity assays, skin transplantation, and vascularized heterotopic heart transplantation in wild-type B6 and CD40L-deficient mice in the presence and absence of anti-LFA-1 to study the effects of anti-LFA-1 in the absence of CD40L signaling. RESULTS: Anti-LFA-1 inhibited proliferation of naïve CD40L-/- mixed leukocyte reactions and the lysis of donor targets by CD40L-/- cytotoxic T lymphocytes. Anti-LFA-1-treated CD40L-/- mice that received fully MHC-mismatched skin grafts showed significant prolongation of graft survival, with a median survival time of 55 days (mean 66 days) compared with 13 and 21 days in wild-type and CD40L-/- controls, respectively. CD40L-/- mice that received fully MHC-mismatched vascularized heart transplants treated with four doses of 200 microg of anti-LFA-1 at the time of transplantation did not develop any signs of chronic vasculopathy 150 days after transplantation. CONCLUSION: These results indicate that anti-LFA-1 can complement CD40L inhibition in the prevention of undesirable immune responses.
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| 45. |
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| 46. |
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| 47. |
- Dor, Frank J M F, et al.
(author)
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New classification of ELPAT for living organ donation.
- 2011
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In: Transplantation. - 1534-6080. ; 91:9, s. 935-8
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Journal article (peer-reviewed)abstract
- In the literature, varying terminology for living organ donation can be found. However, there seems to be a need for a new classification to avoid confusion. Therefore, we assessed existing terminology in the light of current living organ donation practices and suggest a more straightforward classification. We propose to concentrate on the degree of specificity with which donors identify intended recipients and to subsequently verify whether the donation to these recipients occurs directly or indirectly. According to this approach, one could distinguish between "specified" and "unspecified" donation. Within specified donation, a distinction can be made between "direct" and "indirect" donation.
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| 48. |
- Drechsler, Christiane, et al.
(author)
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Homoarginine and Clinical Outcomes in Renal Transplant Recipients : Results From the Assessment of Lescol in Renal Transplantation Study
- 2015
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In: Transplantation. - 0041-1337 .- 1534-6080. ; 99:7, s. 1470-1476
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Journal article (peer-reviewed)abstract
- Background: Despite improvements in kidney transplantation, complications, including cardiovascular morbidity and graft loss, contribute to reduced graft and patient survival. The amino acid homoarginine exerts a variety of beneficial effects that may be relevant for cardiovascular and graft outcomes, which is investigated in the present study.Methods: Homoarginine was measured in 829 renal transplant recipients participating in the placebo group of the Assessment of Lescol in Renal Transplantation study. Mean follow-up was 6.7 years. By Cox regression analyses, we determined hazard ratios (HRs) to reach prespecified, adjudicated endpoints according to baseline homoarginine levels: major adverse cardiovascular events (n = 103), cerebrovascular events (n = 53), graft failure or doubling of serum creatinine (n = 140), noncardiovascular mortality (n = 51), and all-cause mortality (n = 107).Results: Patients mean age was 50 ± 11 years, homoarginine concentration was 1.96 ± 0.76 µmol/L, and 65% were men. Patients in the lowest homoarginine quartile (<1.40 µmol/L) had an adjusted 2.6-fold higher risk of cerebrovascular events compared to those in the highest quartile (>2.34 µmol/L) (HR, 2.56; 95% confidence interval [95% CI], 1.13–5.82). Similarly, the renal endpoint occurred at a significantly increased rate in the lowest homoarginine quartile (HR, 2.34; 95% CI, 1.36–4.02). For noncardiovascular and all-cause mortality, there was also increased risk associated with the lowest levels of homoarginine, with HRs of 4.34 (95% CI, 1.63–10.69) and 2.50 (95% CI, 1.38–4.55), respectively.Conclusions: Low homoarginine is strongly associated with cerebrovascular events, graft loss and progression of kidney failure and mortality in renal transplant recipients. Whether interventions with homoarginine supplementation improve clinical outcomes requires further evaluation.
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| 49. |
- Eich, Torsten, et al.
(author)
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Positron emission tomography : A real-time tool to quantify early islet engraftment in a preclinical large animal model
- 2007
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In: Transplantation. - : Ovid Technologies (Wolters Kluwer Health). - 0041-1337 .- 1534-6080. ; 84:7, s. 893-898
-
Journal article (peer-reviewed)abstract
- Background. Clinical islet transplantation is currently being explored as a therapeutic option for persons with type I diabetes and hypoglycemic unawareness. Techniques to monitor graft survival are urgently needed to optimize the procedure. Therefore, the objective of the present study was to develop a technique for imaging survival of transplanted islets in the peritransplant and early posttransplant phase.Methods. Isolated porcine islets were labeled in vitro with 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG) and infused intraportally into anesthetized pigs (n=10). Dynamic examination was performed on a positron emission tomography/computed tomography hybrid system.Results. More than 95% of the radioactivity was confined to the islets at the time of transplantation. The peak percentage of infused radioactivity within the liver, quantified at the end of the islet infusion, was only 54±5.1%. The distribution of the radioactivity in the liver was found to be heterogeneous. A whole-body examination showed no accumulation in the lungs or brain; extrahepatic radioactivity was, except urinary excretion, evenly distributed in the pig body.Conclusions. Our results imply that almost 50% of the islets were damaged to the extent that the FDG contained was release within minutes after intraportal transplantation. The distribution of radioactivity without accumulation in the brain indicates that the activity is released from lysed islet cells in the form of [18F]FDG-6P rather than native [18F]FDG. The presented technique shows promise to become a powerful and quantitative tool, readily available in the clinic, to evaluate initial islet engraftment and survival.
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| 50. |
- Ekberg, Henrik
(author)
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Calcineurin inhibitor sparing in renal transplantation
- 2008
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In: Transplantation. - 1534-6080. ; 86:6, s. 761-767
-
Research review (peer-reviewed)abstract
- Although calcineurin inhibitors (CNIs) are effective at preventing a cute rejection, their long-term use is associated with nephrotoxicity that may compromise long-term renal allograft Survival. Consequently, there is considerable interest in identifying immunosuppressive regimens that permit reduced exposure to CNIs while maintaining adequate immunosuppression. Introducing such strategies early after transplantation may mean that the development of CNI-associated nephrotoxicity could be minimized or prevented. Several CNI-sparing regimens have shown at least comparable efficacy with standard-dos CNI regimens. In particular, a regimen of mycophenolate mofetil (MMF), corticosteroids, interleukin-2 receptor antagonist induction, and low-dose tacrolimus from the time of transplantation provided superior renal function and a lower acute rejection rate than the same regimen but with low-dose cyclosporine or low-close sirolimus, or standard-dose cyclosporine, MMF, and corticosteroids. The use of low-dose cyclosporine does not seem to eliminate nephrotoxicity in de novo renal transplant recipients. The early withdrawal of CNIs from MMF-based regimens generally improves renal function but has been associated with an increased risk of acute rejection, in particular when the levels of mycophenolic acid were not adjusted to maintain the same total level Of immunosuppression. Research aiming to achieve the "best" balance of efficacy and toxicity of available immunosuppressive regimens continues.
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