36 results on '"H. . Ekberg"'
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2. Relationship of tacrolimus exposure and mycophenolate mofetil dose with renal function after renal transplantation.
- Author
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Ekberg H, van Gelder T, Kaplan B, and Bernasconi C
- Subjects
- Adult, Calcineurin Inhibitors, Female, Glomerular Filtration Rate drug effects, Humans, Immunosuppressive Agents blood, Kidney Transplantation adverse effects, Linear Models, Male, Middle Aged, Multivariate Analysis, Mycophenolic Acid administration & dosage, Tacrolimus blood, Immunosuppressive Agents administration & dosage, Immunosuppressive Agents adverse effects, Kidney Transplantation immunology, Kidney Transplantation physiology, Mycophenolic Acid analogs & derivatives, Tacrolimus administration & dosage, Tacrolimus adverse effects
- Abstract
Introduction: The most common immunosuppressive treatment in de novo renal transplantation is a triple regimen that includes tacrolimus, mycophenolate mofetil (MMF) and corticosteroids, and that may also include antibody induction. Whether nephrotoxicity is an issue with tacrolimus at the currently used dosages remains an open question., Methods: We pooled data from three large, randomized, de novo renal transplantation studies (Symphony, Fixed Dose Concentration Controlled [FDCC], and OptiCept) that used variations of the triple regimen with respect to tacrolimus target levels, MMF dosing, and antibody induction. We used multivariate linear regression to explore the relationship of renal function at 1 year after transplantation (estimated glomerular filtration rate) with tacrolimus levels and MMF dose measured over the previous 6 months. The model included also a series of possible confounders. RESULTS.: The analysis population consisted of 998 patients. On average, tacrolimus levels were in a range considered low (mean ± standard deviation 7.2 ± 2.54 ng/mL), and MMF dose was 1.5 ± 0.61 g/day. Lower tacrolimus levels and higher MMF doses were associated with significantly better renal function. There were other variables associated with renal function, most notably acute rejection, donor age, and delayed graft function. Subanalyses in each of the three studies gave a consistent picture. There was no overt difference in the effect sizes when patients with stage II (estimated glomerular filtration rate 60-89 mL/min) or stage III (30-59 mL/min) chronic kidney disease were assessed separately., Conclusion: Tacrolimus seems to have a moderate but consistent nephrotoxic effect even in modern efficient immunosuppressive regimens where it is used at lower doses than in previous years.
- Published
- 2011
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3. Renal transplant patients at high risk of acute rejection benefit from adequate exposure to mycophenolic acid.
- Author
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van Gelder T, Tedesco Silva H, de Fijter JW, Budde K, Kuypers D, Arns W, Soulillou JP, Kanellis J, Zelvys A, Ekberg H, Holzer H, Rostaing L, and Mamelok RD
- Subjects
- Antibiotics, Antineoplastic blood, Child, Drug Administration Schedule, Graft Rejection drug therapy, Graft Rejection epidemiology, Humans, Incidence, Kidney Transplantation pathology, Mycophenolic Acid blood, Prospective Studies, Risk Assessment, Risk Factors, Antibiotics, Antineoplastic therapeutic use, Graft Rejection prevention & control, Kidney Transplantation immunology, Mycophenolic Acid therapeutic use
- Abstract
Background: To better define subpopulations in which achieving adequate mycophenolic acid (MPA) concentrations quickly would be important, a post hoc exploratory analysis on the fixed-dose concentration-controlled database was performed, comparing high- versus low-risk renal transplant patients., Methods: Renal transplant patients were treated with mycophenolate mofetil, corticosteroids, and cyclosporine A or tacrolimus. Patients were defined as "high risk" if they had one or more of the following characteristics: delayed graft function, second or third transplantation, panel reactive antibodies >15%, four or more human leukocyte antigen mismatches, or were of black race., Results: A total of 549 patients (61%) were classified as high risk, of whom 284 were on cyclosporine A treatment and 265 on tacrolimus. In high-risk patients, the difference in rejection incidence was 14.3% in the MPA-area under the concentration (AUC) less than 30 mg hr/L vs. 7.8% in the MPA-AUC more than or equal to 30 mg hr/L groups (P=0.025) during the first month after transplantation; whereas, in low-risk patients, there were similar rejection rates (5.7% vs. 4.5%). In the subgroup of high-risk tacrolimus-treated patients, the difference in acute rejection incidence in the first month between patients with MPA-AUC0-12 less than or more than or equal to 30 mg hr/L was most pronounced: 16 of 67 patients (23.9%) vs. 18 of 173 patients (10.4%); P=0.012., Conclusions: The incidence of acute rejection is higher in high-risk patients if MPA-AUC0-12 is below 30 mg hr/L. In contrast, a difference in acute rejection incidence in low-risk patients with MPA-AUC0-12 less than or more than or equal to 30 mg hr/L was not observed. This supports the use of a higher mycophenolate mofetil starting dose in selected patient populations early after transplantation.
- Published
- 2010
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4. The challenge of achieving target drug concentrations in clinical trials: experience from the Symphony study.
- Author
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Ekberg H, Mamelok RD, Pearson TC, Vincenti F, Tedesco-Silva H, and Daloze P
- Subjects
- Adrenal Cortex Hormones therapeutic use, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized, Cadaver, Cyclosporine therapeutic use, Daclizumab, Dose-Response Relationship, Drug, Humans, Immunoglobulin G therapeutic use, Immunosuppressive Agents pharmacokinetics, Living Donors, Research Design, Sirolimus therapeutic use, Tacrolimus therapeutic use, Tissue Donors, Clinical Trials as Topic methods, Drug Therapy methods, Immunosuppressive Agents therapeutic use, Kidney Transplantation immunology
- Abstract
Background: The Symphony study compared four immunosuppressant regimens, defined by protocol-specified target drug concentrations. This subanalysis examines actual drug levels and the implications on the interpretation of results., Methods: De novo renal transplant patients (n=1645) were randomized to receive mycophenolate mofetil (2 g/day) and corticosteroids in combination with standard-dose cyclosporine A (CsA; 150-300 ng/mL for 3 months then 100-200 ng/mL), or daclizumab induction and low-dose CsA (50-100 ng/mL), low-dose tacrolimus (Tac; 3-7 ng/mL), or low-dose sirolimus (SRL; 4-8 ng/mL)., Results: Low-dose Tac was significantly superior for renal function, acute rejection, and graft survival at 12 months. Median trough levels of CsA, Tac, or SRL were toward the high end of target ranges in all groups, and 50% to 60% were within target. During weeks 1 to 8, only 6.5% to 11.0% of patients were consistently within target. At week 8, the range of concentrations encompassing 75% of patients on standard-dose CsA was 141 to 321 ng/mL; for low-dose CsA, 62 to 159 ng/mL; for low-dose Tac, 4.3 to 10.0 ng/mL, and for low-dose SRL, 4.4 to 11.2 ng/mL. The protocol-defined target levels were approximately, but not fully achieved., Conclusions: To replicate the Symphony study results in clinical practice, the protocol-defined drug concentration targets should be aimed for, but the concentrations actually achieved may be regarded as acceptable. Future clinical studies should include measures of how well target drug levels were achieved to better guide further attempts to develop new regimens designed to reduce or eliminate calcineurin inhibitors.
- Published
- 2009
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5. A randomized, doubleblind, placebo-controlled, study of single-dose rituximab as induction in renal transplantation.
- Author
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Tydén G, Genberg H, Tollemar J, Ekberg H, Persson NH, Tufveson G, Wadström J, Gäbel M, and Mjörnstedt L
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- Adult, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal, Murine-Derived, Antigens, CD analysis, Antigens, CD19 analysis, Antigens, CD20 analysis, Cadaver, Double-Blind Method, Female, Graft Rejection epidemiology, Humans, Immunologic Factors administration & dosage, Immunosuppressive Agents therapeutic use, Kidney Transplantation mortality, Living Donors, Lymphocyte Depletion, Male, Middle Aged, Mycophenolic Acid analogs & derivatives, Mycophenolic Acid therapeutic use, Placebos, Reoperation statistics & numerical data, Rituximab, Safety, Survival Analysis, Tissue Donors, Treatment Outcome, Antibodies, Monoclonal therapeutic use, Immunologic Factors therapeutic use, Kidney Transplantation immunology
- Abstract
Unlabelled: We performed a prospective, double blind, randomized, placebo-controlled multicenter study on the efficacy and safety of rituximab as induction therapy, together with tacrolimus, mycophenolate mofetil, and steroids. The primary endpoint was defined as acute rejection, graft loss, or death during the first 6 months. Secondary endpoints were creatinine clearance, incidence of infections, and incidence of rituximab-related adverse event., Results: We enrolled 140 patients (44 living donor and 96 deceased donor), and of those, 68 rituximab and 68 placebo patients fulfilled the study. In all the patients receiving rituximab, there was a complete depletion of CD19/CD20 cells, whereas there was no change in the number of CD19/CD20 cells in the placebo group. There were 10 treatment failures in the rituximab group versus 14 in the placebo group (P=0.348). There were eight rejection episodes in the rituximab group versus 12 in the placebo group (P=0.317) Creatinine clearance was 66+/-22 mL/min in the study group and 67+/-23 mL/min in the placebo group. There was no difference in the number of bacterial infections, cytomegalovirus infections, and BK virus infections or fungal infections., Conclusion: We performed a placebo-controlled study of rituximab induction in renal transplantation. There was a tendency toward fewer and milder rejections during the first 6 months in the rituximab group. Although induction with one dose of rituximab induced a complete depletion B cells, there was no increase in the incidence of infectious complications or leukopenia and it seems safe, therefore, to conduct further studies on the use of rituximab in transplantation.
- Published
- 2009
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6. Health-related quality of life of patients receiving low-toxicity immunosuppressive regimens: a substudy of the Symphony Study.
- Author
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Oppenheimer F, Rebollo P, Grinyo JM, Ortega F, Sanchez-Plumed J, Gonzalez-Molina M, Hernandez D, Anaya F, and Ekberg H
- Subjects
- Adrenal Cortex Hormones adverse effects, Adrenal Cortex Hormones therapeutic use, Adult, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized, Creatinine blood, Cyclosporine adverse effects, Cyclosporine therapeutic use, Daclizumab, Dose-Response Relationship, Drug, Female, Follow-Up Studies, Health Surveys, Humans, Immunoglobulin G adverse effects, Immunoglobulin G therapeutic use, Immunosuppressive Agents toxicity, Male, Middle Aged, Mycophenolic Acid adverse effects, Mycophenolic Acid analogs & derivatives, Mycophenolic Acid therapeutic use, Time Factors, Health Status, Immunosuppressive Agents therapeutic use, Kidney Transplantation physiology, Quality of Life
- Abstract
Objective: To evaluate health-related quality of life (HRQoL) in patients with different low-toxicity regimens posttransplantation., Methods: One hundred fifty-six patients were randomized to standard-dose cyclosporine A (CsA), mycophenolate mofetil, and corticosteroids or daclizumab induction, mycophenolate mofetil, and corticosteroids with a low dose of CsA, tacrolimus (Low-Tac), or sirolimus. SF-36 Health survey was completed at baseline, 3, 6, and 12 months., Results: There were no differences between groups in SF-36 at baseline or at month 12. Low-Tac showed higher scores at month 3 than standard-dose CsA and low dose of CsA. Patients with serum creatinine less than or equal to 1.5 mg/mL had better HRQoL at 6 and 12 months. Proportion of these patients was higher in Low-Tac at 6 months. Physical component summary of Patients increased during follow-up, but mental component summary did not. Patients with acute rejection showed lower mental component summary at 6 months., Conclusions: No HRQoL differences were identified among groups, but the low-dose Tac group showed the fastest improvement.
- Published
- 2009
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7. Operational tolerance in nonvascularized transplant models induced by AR-C117977, a monocarboxylate transporter inhibitor.
- Author
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Påhlman C, Malm H, Qi Z, Veress B, Ferguson D, Bundick R, Murray C, Donald D, and Ekberg H
- Subjects
- Animals, Cyclosporine pharmacology, Drug Therapy, Combination, Female, Graft Rejection immunology, Graft Rejection metabolism, Graft Survival immunology, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Models, Animal, Monocarboxylic Acid Transporters metabolism, Rats, Symporters metabolism, Time Factors, Transplantation, Homologous, Graft Rejection prevention & control, Graft Survival drug effects, Heterocyclic Compounds pharmacology, Immune Tolerance drug effects, Immunosuppressive Agents pharmacology, Islets of Langerhans Transplantation, Monocarboxylic Acid Transporters antagonists & inhibitors, Skin Transplantation, Symporters antagonists & inhibitors
- Abstract
AR-C117977, a monocarboxylate transporter inhibitor, reduces immune responses both in vitro and in vivo, maintains long-term graft survival, and induces operational tolerance. To evaluate the immunosuppressive limitations of AR-C117977, this study was performed in nonvascularized transplant models noted for their refractive response to standard immunosuppressive agents. Rat skin was transplanted from DA(RT1avl) into PVG(RT1c) and the reverse. Mouse islet allotransplantation was performed with BALB/c H2d donors and C57Bl/6J H2b recipients. In the skin graft model, AR-C117977 monotherapy was associated with long-term skin graft survival in one rat strain combination. AR-C117977 and cyclosporine A (CsA) in combination resulted in significant prolongation of graft survival in both rat strains. CsA monotherapy did not prevent acute rejection in either strain. Islet allograft survival was moderately prolonged with CsA or AR-C117977. AR-C117977 is an efficient immunosuppressive drug in stringent rodent transplant models and further studies are warranted.
- Published
- 2008
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8. Calcineurin inhibitor sparing in renal transplantation.
- Author
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Ekberg H
- Subjects
- Adrenal Cortex Hormones therapeutic use, Drug Therapy, Combination, Humans, Mycophenolic Acid analogs & derivatives, Mycophenolic Acid therapeutic use, Tacrolimus immunology, Calcineurin Inhibitors, Immunosuppressive Agents therapeutic use, Kidney Transplantation immunology, Sirolimus therapeutic use
- Abstract
Although calcineurin inhibitors (CNIs) are effective at preventing acute 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-dose 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-dose 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.
- Published
- 2008
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9. The specific monocarboxylate transporter-1 (MCT-1) inhibitor, AR-C117977, induces donor-specific suppression, reducing acute and chronic allograft rejection in the rat.
- Author
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Ekberg H, Qi Z, Pahlman C, Veress B, Bundick RV, Craggs RI, Holness E, Edwards S, Murray CM, Ferguson D, Kerry PJ, Wilson E, and Donald DK
- Subjects
- Acute Disease, Animals, Atherosclerosis pathology, Chronic Disease, Graft Survival drug effects, Graft Survival immunology, Heart Transplantation pathology, Lymphocyte Culture Test, Mixed, Postoperative Complications pathology, Rats, Rats, Inbred Lew, Transplantation, Homologous, Transplantation, Isogeneic, Graft Rejection prevention & control, Graft vs Host Reaction immunology, Heart Transplantation immunology, Heterocyclic Compounds therapeutic use, Immunosuppressive Agents therapeutic use, Monocarboxylic Acid Transporters antagonists & inhibitors, Symporters antagonists & inhibitors
- Abstract
Background: In a search for immunosuppressive drugs having novel mechanisms, monocarboxylate transporter (MCT-1) inhibitors were identified that markedly inhibited immune responses. Here, we report the effects of AR-C117977, a potent MCT-1 inhibitor, on alloimmune responses in the rat., Methods: In vitro activity was determined in a rat mixed lymphocyte response (MLR). In vivo activity was tested in a graft versus host response (GVHR) and in both high (DA to PVG) and low (PVG to DA) responder cardiac allograft models. To assess induction of donor-specific suppression recipients of allogeneic hearts surviving longer than 100 days received a second transplant either of the same donor strain or a third-party donor strain. Effects on chronic graft rejection were assessed histologically by evaluating vasculopathy in long-term surviving grafts and in an obliterative bronchiolitis (OB) model., Results: AR-C117977 inhibited the rat MLR and was more potent than cyclosporin A (CsA). In the rat GVHR model, AR-C117977 gave a dose-related inhibition. In the high responder cardiac allograft model, graft survival in excess of 100 days was achieved with AR-C117977 compared with 20 days with CsA and all the long-term survivors exhibited donor-specific suppression on retransplantation. In the low responder model, both AR-C117977 and CsA induced survival in excess of 100 days. Histology of the long-term surviving grafts suggested reduced vasculopathy associated with chronic rejection. Furthermore, AR-C117977 inhibited the occlusion of transplanted trachea in a OB model., Conclusion: This report describes a MCT-1 specific inhibitor having immunosuppressive activity on alloimmune responses and inducing donor-specific suppression.
- Published
- 2007
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10. Clinicians underestimate gastrointestinal symptoms and overestimate quality of life in renal transplant recipients: a multinational survey of nephrologists.
- Author
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Ekberg H, Kyllönen L, Madsen S, Grave G, Solbu D, and Holdaas H
- Subjects
- Data Collection, Female, Finland epidemiology, Gastrointestinal Diseases diagnosis, Gastrointestinal Diseases drug therapy, Humans, Immunosuppressive Agents therapeutic use, Male, Patients, Prevalence, Quality of Life, Scandinavian and Nordic Countries epidemiology, Attitude of Health Personnel, Gastrointestinal Diseases epidemiology, Kidney Transplantation adverse effects, Physicians psychology
- Abstract
Gastrointestinal (GI) symptoms are common in renal transplant recipients and are associated with impaired health-related quality of life (HRQoL). We investigated clinician attitudes to GI symptoms and HRQoL in these patients by surveying 145 nephrologists from Sweden, Denmark, Finland, and Norway. In total, 79 clinicians responded. They estimated that 20% of their patients experienced GI discomfort and that 36% had impaired HRQoL. We previously conducted a survey of the renal transplant recipients treated by these clinicians, in which 92% reported troublesome GI symptoms and 53% had impaired HRQoL compared with the general population. Nephrologists were more likely to manage GI symptoms by reducing immunosuppressant dose (87%) than by switching medication to one with fewer GI side effects (66%). We conclude that clinicians appear to underestimate the prevalence of GI symptoms and impaired HRQoL. Improving patient-clinician communication could lead to more informed management, resulting in better HRQoL and increased graft survival.
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- 2007
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11. Anti-LFA-1 improves pig islet xenograft function in diabetic mice when long-term acceptance is induced by CTLA4Ig/anti-CD40L.
- Author
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Kumagai-Braesch M, Ekberg H, Wang F, Osterholm C, Ehrnfelt C, Sharma A, Lindeborg E, Holgersson J, and Corbascio M
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- Abatacept, Animals, Blood Glucose metabolism, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes pathology, Cell Proliferation, Diabetes Mellitus, Experimental blood, Epitopes, Female, Glucose pharmacology, Immunoglobulin G biosynthesis, Immunoglobulin G immunology, Islets of Langerhans drug effects, Islets of Langerhans pathology, Leukocytes pathology, Male, Mice, Mice, Inbred C57BL, Mice, Nude, Swine, Time Factors, Antibodies pharmacology, CD40 Ligand immunology, Diabetes Mellitus, Experimental surgery, Immunoconjugates pharmacology, Islets of Langerhans physiopathology, Islets of Langerhans Transplantation, Lymphocyte Function-Associated Antigen-1 immunology, Transplantation, Heterologous
- Abstract
Background: It has been previously demonstrated that addition of anti-LFA-1 to a combination of CTLA4Ig and anti-CD40L induces the permanent acceptance of dopaminergic fetal pig xenografts when transplanted into the brain of wild-type mice. The purpose of this study was to test whether this costimulation blockade also can induce acceptance of adult pig islets transplanted to C57BL/6 mice with streptozotocin-induced diabetes., Methods: Recipients were treated with CTLA4Ig/anti-CD40L+/-anti-LFA-1 or isotype control antibodies during the first week after transplantation. Half of the costimulation blockade-treated recipients had their grafts removed after 8 weeks. The other half was observed up to 5 months., Results: Recipients treated with CTLA4Ig/anti-CD40L/anti-LFA-1 had significantly lower blood glucose and gained more weight than CTLA4Ig/anti-CD40L-treated recipients. CTLA4Ig/anti-CD40L-treated recipients exhibited unstable blood glucose. IPGTT of these recipients revealed a slow recovery to normal blood glucose levels at week 4. In comparison, CTLA4Ig/anti-CD40L/anti-LFA-1 treated recipients exhibited a significantly superior glucose clearance. CTLA4Ig/anti-CD40L+/-anti-LFA-1 treated recipients did not produce anti-pig IgG, whereas control antibody-treated mice did. CD4+ T cells from costimulation blockade-treated recipients proliferated less than CD4+ T cells from control antibody-treated mice when co-cultured with syngeneic antigen presenting cells loaded with pig islet antigens., Conclusions: CTLA4Ig/anti-CD40L/anti-LFA-1-treated recipients had superior islet function compared with CTLA4Ig/anti-CD40L-treated recipients. However, both costimulation blockade regimens led to islet graft acceptance up to 5 months after a 1-week treatment.
- Published
- 2007
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12. Interventional trials involving patients cannot be performed safely without a control group treated with the standard of care.
- Author
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Meier-Kriesche HU, Schold JD, and Ekberg H
- Subjects
- Controlled Clinical Trials as Topic methods, Controlled Clinical Trials as Topic standards, Humans, Clinical Trials as Topic methods, Clinical Trials as Topic standards, Control Groups, Patient Care standards
- Published
- 2007
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13. Increased prevalence of gastrointestinal symptoms associated with impaired quality of life in renal transplant recipients.
- Author
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Ekberg H, Kyllönen L, Madsen S, Grave G, Solbu D, and Holdaas H
- Subjects
- Adult, Female, Humans, Immunosuppression Therapy adverse effects, Male, Middle Aged, Prevalence, Surveys and Questionnaires, Gastrointestinal Diseases epidemiology, Immunosuppressive Agents adverse effects, Kidney Transplantation, Quality of Life
- Abstract
Background: Immunosuppressive therapies have been associated with gastrointestinal (GI) side effects, which may impair health-related quality of life (HRQoL)., Methods: In this survey, 4,232 renal transplant recipients from Denmark, Finland, Norway, and Sweden completed the Short-Form 36 (SF-36) questionnaire and the Gastrointestinal Symptom Rating Scale (GSRS). SF-36 scores were compared with country norm values. Multiple logistic regression analysis was used to identify immunosuppressants associated with GI symptoms., Results: The prevalence of troublesome GI symptoms (GSRS>1) was 83% for indigestion, 69% for abdominal pain, 58% for constipation, 53% for diarrhea, 47% for reflux, and 92% for any GI symptom. Compared with the general population, HRQoL was most commonly meaningfully impaired in the general health dimension (53% of patients). The presence and severity of GI symptoms were associated with worse HRQoL. Tacrolimus showed a significant association with diarrhea (odds ratio [OR]: 1.7; 95% confidence interval [CI]: 1.4-2.0) and constipation (OR: 1.3; 95% CI: 1.1-1.6), and sirolimus with indigestion (OR: 2.9; 95% CI: 1.0-8.1) and abdominal pain (OR: 2.2; 95% CI: 1.1-4.4)., Conclusions: GI symptoms are associated with impaired HRQoL in the renal transplant population. Managing GI symptoms by careful choice of immunosuppressants should be a focus for improving HRQoL in renal transplant recipients.
- Published
- 2007
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14. Costimulation blockade-induced cardiac allograft tolerance: inhibition of T cell expansion and accumulation of intragraft cD4(+)Foxp3(+) T cells.
- Author
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Oderup C, Malm H, Ekberg H, Qi Z, Veress B, Ivars F, and Corbascio M
- Subjects
- Animals, CD4 Antigens analysis, CD40 Ligand antagonists & inhibitors, CD40 Ligand immunology, CTLA-4 Antigen, Female, Forkhead Transcription Factors analysis, Forkhead Transcription Factors metabolism, Genes, RAG-1 genetics, Graft Survival immunology, Interleukin-10 genetics, Interleukin-2 Receptor alpha Subunit analysis, Lymphocyte Function-Associated Antigen-1 drug effects, Lymphocyte Function-Associated Antigen-1 immunology, Mice, Mice, Mutant Strains, Skin Transplantation, T-Lymphocytes, Regulatory immunology, Antigens, CD pharmacology, Antigens, Differentiation pharmacology, Graft Survival drug effects, Heart Transplantation immunology, Immunoglobulin G pharmacology, T-Lymphocytes, Regulatory drug effects, Transplantation Tolerance
- Abstract
Background: Previous studies have demonstrated that anti-CD40L or anti-B7 requires the presence of CD4(+)CD25(+) regulatory T cells (Treg) to induce antigen specific hyporesponsiveness. Other tolerance strategies involving Treg have shown a dependency on interleukin (IL)-10. The objective of this study was to investigate the role of CD4(+)CD25(+) Treg and IL-10 when treating transplant recipients with cytotoxic T lymphocyte-associated antigen (CTLA)-4 immunoglobulin (Ig), anti-CD40L, and anti-lymphocyte function-associated antigen (LFA)-1., Methods: Recombinase activating gene-deficient (Rag1(-/-) mice were transplanted with BALB/c hearts and adoptively transferred with IL-10(-/-) CD4(+) T cells, CD4(+)CD25(-) T cells or CD4(+)CD25(-)CD103(-) T cells and treated with costimulation blockade. Intragraft T cells from C57BL/6 recipients were analyzed for the expression of the Foxp3 protein after tolerance induction., Results: Mice reconstituted with IL-10(-/-) CD4(+) T cells, CD4(+)CD25(-) T cells or CD4(+)CD25(-) CD103(-) T cells and treated with costimulation blockade accepted allografts permanently. Analysis of cells from recipient mice adoptively transferred with CD4(+)CD25(-) T cells contained a population of CD4(low)CD25(+) T cells 100 days after transplantation. Costimulation blockade partially prevented the homeostatic proliferation of CD4(+)CD25(-)CD103(-) T cells in Rag-1(-/-) recipients. Accepted allografts contained an elevated number of CD4(+)Foxp3(+) T cells., Conclusions: These results indicate that T-cell derived IL-10 is not essential for induction of graft acceptance in mice treated with costimulation blockade, but that treatment limits T-cell expansion in the recipients. The results further indicate that tolerance is maintained by intragraft CD4(+)Foxp3(+) T cells.
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- 2006
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15. Induction of operational tolerance to discordant dopaminergic porcine xenografts.
- Author
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Larsson LC, Corbascio M, Pearson TC, Larsen CP, Ekberg H, and Widner H
- Subjects
- Abatacept, Animals, CD40 Ligand immunology, Fetal Tissue Transplantation, Graft Survival, Immunoconjugates therapeutic use, Lymphocyte Function-Associated Antigen-1 immunology, Mice, Mice, Inbred C57BL, Skin Transplantation, Swine, Brain Tissue Transplantation, Dopamine analysis, Immunosuppression Therapy methods, Mesencephalon transplantation, Transplantation, Heterologous immunology
- Abstract
Background: Porcine embryonic neural tissue transplanted intracerebrally could potentially relieve the symptoms of Parkinson's disease if the immune response toward the graft could be overcome. However, conventional immunosuppressive treatments have proven inefficient in preventing rejection. An alternative is blocking the costimulatory signals for lymphocyte activation. Treatment with cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA4Ig) and anti-CD40L has been successful in preventing rejection of xenografts in some experimental studies, but not all. Lymphocyte function antigen (LFA)-1 is an important costimulatory molecule for CD8+ T cells, and we hypothesize that blockade with anti-LFA-1 may enhance the efficacy of CTLA4Ig and anti-CD40L therapy., Methods: C57BL/6 mice received intracerebral transplants of ventral mesencephalic tissue from embryonic porcine donors. CTLA4Ig, anti-CD40L, and anti-LFA-1 were administered every other day on days 0 to 8, and the transplants were studied after 4 to 6 weeks. Grafts were histologically analyzed for size, survival of dopaminergic nerve cells, and immune responses. Recipients were challenged with cultured glia cells of donor origin or an allogeneic skin graft to evaluate tolerance induction., Results: Mice treated with all three substances had large grafts containing high amounts of dopamine cells but a low degree of immune response. Grafts in recipients challenged with glial cells showed an increased immunologic activity but were not rejected. Triple-treated mice showed a normal rejection process of the allogeneic skin grafts., Conclusion: After a short course of costimulation blocking therapy, discordant neural xenografts demonstrate long-term survival, withstand immunologic challenge, yet maintain host-versus-graft reactivity. Anti-LFA-1 complements CTLA4Ig and anti-CD40L in the induction of operational tolerance to these xenografts.
- Published
- 2003
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16. Fundamental and distinct roles of P-selectin and LFA-1 in ischemia/reperfusion-induced leukocyte-endothelium interactions in the mouse colon.
- Author
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Riaz AA, Wan MX, Schaefer T, Schramm R, Ekberg H, Menger MD, Jeppsson B, and Thorlacius H
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- Analysis of Variance, Animals, Base Sequence, Colonic Diseases physiopathology, Disease Models, Animal, Flow Cytometry, Intestinal Mucosa metabolism, Ischemia physiopathology, Leukocyte Count, Male, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Probability, Random Allocation, Reference Values, Reperfusion Injury metabolism, Reverse Transcriptase Polymerase Chain Reaction, Sensitivity and Specificity, Antibodies, Monoclonal pharmacology, Chemotaxis, Leukocyte physiology, Colonic Diseases metabolism, Ischemia metabolism, Lymphocyte Function-Associated Antigen-1 metabolism, P-Selectin metabolism, RNA, Messenger analysis, Reperfusion Injury physiopathology
- Abstract
Objective: To study the adhesive mechanisms underlying ischemia/reperfusion (I/R)-induced leukocyte-endothelium interactions in the colon., Summary Background Data: Leukocyte recruitment is a key feature in I/R-induced tissue injury, but the mechanisms regulating leukocyte rolling and adhesion in the colon are not known. The authors recently developed a new model to study the molecular mechanisms of I/R-provoked leukocyte-endothelium interactions in the colon microcirculation using inverted intravital fluorescence microscopy., Methods: The superior mesenteric artery was occluded for 30 minutes and leukocyte responses were analyzed after 120 minutes of reperfusion in colonic venules in mice. The adhesive mechanisms underlying I/R-induced leukocyte rolling and adhesion were investigated using monoclonal antibodies against L-, E- and P-selectin, and CD11a gene-targeted mice were used to examine the role of lymphocyte function antigen-1 (LFA-1, CD11a/CD18)., Results: Reperfusion provoked a clear-cut increase in leukocyte rolling and adhesion in colonic venules compared to negative controls. Both P- and E-selectin mRNA were expressed in the colon after this I/R insult. Pretreatment with an anti-P-selectin antibody reduced leukocyte rolling and adhesion by 88% and 85%, respectively, whereas antibodies against L- and E-selectin had no effect. Moreover, I/R-induced leukocyte adhesion in LFA-1-deficient mice was reduced by more than 95%., Conclusions: This study provides evidence that leukocyte rolling is exclusively and nonredundantly mediated by P-selectin and that firm adhesion is supported by LFA-1 in I/R-induced leukocyte recruitment in the colon. Taken together, both P-selectin and LFA-1 may be important targets to control pathologic inflammation in I/R-induced tissue injury in the colon.
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- 2002
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17. Anti-lymphocyte function-associated antigen-1 monoclonal antibody inhibits CD40 ligand-independent immune responses and prevents chronic vasculopathy in CD40 ligand-deficient mice.
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Corbascio M, Mahanty H, Osterholm C, Qi Z, Pearson TC, Larsen CP, Freise CE, and Ekberg H
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- Animals, CD40 Ligand genetics, Cell Division immunology, Chronic Disease, Graft Rejection immunology, Graft Survival immunology, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Knockout, Postoperative Complications immunology, Postoperative Complications prevention & control, T-Lymphocytes, Cytotoxic cytology, T-Lymphocytes, Cytotoxic immunology, Transplantation, Homologous, Vascular Diseases immunology, Vascular Diseases therapy, Antibodies, Monoclonal pharmacology, CD40 Ligand immunology, Graft Rejection therapy, Heart Transplantation, Skin Transplantation, Vascular Diseases prevention & control
- 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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- 2002
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18. CTLA4ig induces long-term graft survival of allogeneic skin grafts and totally inhibits T-cell proliferation in LFA-1-deficient mice.
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Malm H, Corbascio M, Osterholm C, Cowan S, Larsen CP, Pearson TC, and Ekberg H
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- Abatacept, Animals, Antigens, CD, CTLA-4 Antigen, Dose-Response Relationship, Drug, Graft Rejection, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Reoperation, Transplantation, Homologous, Antigens, Differentiation pharmacology, Graft Survival drug effects, Immunoconjugates, Immunosuppressive Agents pharmacology, Lymphocyte Activation drug effects, Lymphocyte Function-Associated Antigen-1 physiology, Skin Transplantation immunology, T-Lymphocytes immunology
- Abstract
Background: It was recently shown that some strains of mice are capable of rejecting transplants independently of B7 and CD40L signaling and that this rejection is mediated by CD8(+) T cells. LFA-1 is known to be important for CD8(+) T cell activation and cytotoxicity. Therefore, blockade of LFA-1 could be important in overcoming costimulation blockade, CD8(+) T-cell-mediated, resistant rejection. The purpose of this study was to define the effect of combined blockade of the LFA-1 and B7 costimulation pathways on the alloimmune response in mice., Methods: Allogeneic skin transplantation was performed using BALB/c mice as donors and C57BL/6J wild-type or LFA-1-deficient (CD11a(-/-)) mice as recipients. CTLA4Ig or anti-LFA-1 was administered either as an induction or a prolonged therapy. Mixed lymphocyte reactions were conducted to study the effect of CTLA4Ig on T-cell proliferation in CD11a(-/-) mice., Results and Conclusions: Administration of CTLA4Ig completely inhibits CD11a(-/-) T-cell proliferation in response to alloantigens and significantly improved skin allograft survival in CD11a(-/-) mice. Prolonged treatment of wild-type recipient mice with CTLA4Ig and anti-LFA-1 increased median survival time to 45.5 days compared with 16 days after induction therapy, but it was not sufficient to induce indefinite allograft survival in this model.
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- 2002
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19. Dose optimization of mycophenolate mofetil when administered with a low dose of tacrolimus in cadaveric renal transplant recipients.
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Squifflet JP, Bäckman L, Claesson K, Dietl KH, Ekberg H, Forsythe JL, Kunzendorf U, Heemann U, Land W, Morales JM, Mühlbacher F, Talbot D, Taube D, Tyden G, van Hooff J, Schleibner S, and Vanrenterghem Y
- Subjects
- Adrenal Cortex Hormones administration & dosage, Adrenal Cortex Hormones adverse effects, Adrenal Cortex Hormones therapeutic use, Adult, Cadaver, Dose-Response Relationship, Drug, Drug Therapy, Combination, Female, Gastrointestinal Diseases chemically induced, Graft Rejection prevention & control, Graft Survival drug effects, Humans, Immunosuppressive Agents adverse effects, Immunosuppressive Agents therapeutic use, Leukopenia chemically induced, Male, Middle Aged, Mycophenolic Acid adverse effects, Mycophenolic Acid analogs & derivatives, Mycophenolic Acid therapeutic use, Survival Analysis, Tacrolimus adverse effects, Tacrolimus therapeutic use, Time Factors, Treatment Outcome, Immunosuppressive Agents administration & dosage, Kidney Transplantation, Mycophenolic Acid administration & dosage, Tacrolimus administration & dosage
- Abstract
Background: Supplementation of immunosuppressive therapy with mycophenolate mofetil (MMF) has been found to reduce the rate of acute rejection in renal transplantation. We report a dose-finding study for MMF when administered in combination with low-dose tacrolimus and corticosteroid prophylaxis in cadaveric renal transplant recipients., Methods: Two hundred thirty-two patients at 16 centers were enrolled in this randomized, parallel-group study. The three treatment groups were tacrolimus and corticosteroids (MMF-0 group, n=82); tacrolimus, corticosteroids, and 1 g of MMF daily (MMF-1 g group, n=79); and tacrolimus, corticosteroids, and 2 g of MMF daily (MMF-2 g group, n=71). Study duration was 6 months, and patients were followed up for patient and graft survival for 12 months., Results: At 6 months posttransplantation, daily doses of 1 g and 2 g of MMF were associated with significantly lower rates of acute rejection compared with tacrolimus alone. The Kaplan-Meier rates were 48.5%, 24.9%, and 22.9%, respectively, for the three treatment groups when acute rejection was determined by clinical criteria (P=0.007). At month 12, patient survival rates were 100%, 97.5%, and 97.2% and graft survival rates were 90.2%, 92.4%, and 93.0% for the MMF-0 group, MMF-1 g group, and the MMF-2 g group, respectively. Gastrointestinal adverse events and leukopenia were higher in the MMF groups, especially in the MMF-2 g group (P<0.05)., Conclusions: Low-dose tacrolimus combined with a MMF dose of 1 g daily and corticosteroids provided an optimized efficacy and safety profile. A higher dose of MMF (2 g) was associated with greater toxicity without a significant improvement in efficacy.
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- 2001
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20. Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation.
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Vincenti F, Ramos E, Brattstrom C, Cho S, Ekberg H, Grinyo J, Johnson R, Kuypers D, Stuart F, Khanna A, Navarro M, and Nashan B
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- Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized, Biopsy, Daclizumab, Graft Rejection prevention & control, Graft Survival drug effects, Humans, Immunoglobulin G adverse effects, Immunoglobulin G pharmacology, Immunoglobulin G therapeutic use, Immunosuppressive Agents pharmacology, Immunosuppressive Agents therapeutic use, Kidney Transplantation pathology, Mycophenolic Acid analogs & derivatives, Mycophenolic Acid pharmacology, Mycophenolic Acid therapeutic use, Receptors, Interleukin-2 antagonists & inhibitors, Time Factors, Transplantation, Homologous pathology, Treatment Outcome, Calcineurin Inhibitors, Enzyme Inhibitors pharmacology, Kidney Transplantation immunology
- Abstract
Background: The adoption of calcineurin inhibitors (CNI) as the mainstay of immunosuppression has resuited in a significant decrease of acute rejection and improvement of short-term graft survival. However, because of the irreversible nephrotoxicity associated with the chronic use of the CNI, the magnitude of the improvement of long-term graft survival has been more modest. Therefore, an effective immunosuppression regimen that does not rely on CNI may result in improvement of long-term outcome and simplification of the management of transplant recipients., Methods: Ninety-eight patients of primary cadaver or living donor kidneys at low immunologic risk were enrolled in a CNI avoidance study. The immunosuppression regimen consisted of daclizumab, a humanized monoclonal antibody that binds to the alpha chain of the interleukin-2 receptor (IL-2Ralpha), administered for a total of five doses at biweekly intervals; 3 gm/day mycophenolate mofetil for the first 6 month and 2 gm thereafter; and conventional corticosteroid therapy. Patients who underwent rejection episodes could be started on CNI. The primary efficacy end-point was biopsy-proven rejection during the first 6 months posttransplant., Results: Biopsy-proven rejection was diagnosed in 48% of patients during the first 6 months after transplantation. The majority of rejection episodes were Banff grade I and IIA and were fully reversed with corticosteroid therapy. The median time to the first biopsy-proven rejection among patients who experienced this event during the first 6 months was 39 days. In 22 patients with delayed graft function, the proportion of patients with biopsy-proven rejection was 50% at 6 months. However in the first 2 weeks posttransplant, only 1 of 22 patients with delayed graft function developed biopsy-proven rejection. At 1 year, patient survival was 97% and graft survival was 96%. Only two grafts were lost secondary to rejection. At 1-year posttransplant, 62% of patients had received CNI for more than 7 days. At 1-year posttransplant, the mean serum creatinine in the nonrejectors with no CNI use was 113 micromol/L (95%, confidence interval [CI], 100.7 to 125.3 micromol/L) and in the rejectors or patients with CNI use (more than 7 days) was 154 micromol/L (95% CI, 135.0 to 173.0 micromol/L). In selected patients with rejection, analysis of circulating and intragraft lymphocytes revealed complete IL-2Ralpha saturation., Conclusions: This CNI avoidance study in immunologic low-risk patients, while only partially successful in preventing acute rejection, provided benefits to a sizable minority of patients who have not required chronic CNI therapy. However, wide acceptance of a CNI-sparing immunosuppression regimen may require a lower rate of acute rejection, possibly through the addition of a non-nephrotoxic dose of CNI. However, because complete IL-2Ralpha blockade was present during rejection, it can be assumed that alternative pathways, such as IL-15, may be responsible for the rejection; thus, the incorporation of non-nephrotoxic immunosuppressive agents, such as sirolimus, may provide a more strategic approach.
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- 2001
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21. The use of pretransplant erythropoietin to normalize hemoglobin levels has no deleterious effects on renal transplantation outcome.
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Linde T, Ekberg H, Forslund T, Furuland H, Holdaas H, Nyberg G, Tydén G, Wahlberg J, and Danielson BG
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- Adult, Aged, Female, Humans, Male, Middle Aged, Time Factors, Treatment Outcome, Erythropoietin pharmacology, Hemoglobins metabolism, Kidney Transplantation physiology
- Abstract
Background: The aim of this study was to establish the outcome of renal transplantation in patients given pretransplant erythropoietin (EPO) treatment targeted at reaching a normal hemoglobin concentration (Hb), compared to those given EPO-treatment aimed at maintaining subnormal Hb., Methods: A total of 416 patients from Scandinavian countries and with renal anaemia were enrolled to examine the effects of increasing Hb from a subnormal level (90-120 g/liter) to a normal level (135-160 g/liter) by EPO treatment. Half of the patients were randomized to have their Hb increased, with the other half randomized to maintain a subnormal Hb. Thirty-two patients from the normal Hb group and 24 patients from the subnormal group received a renal graft during the study period. The outcomes of these transplantations were examined prospectively for 6 months., Results: Preoperative Hb levels were 143+/-17 and 121+/-14 g/liter in the two groups, respectively (P<0.0001). The Hb remained higher in the normal Hb group during the first 2 weeks after transplantation. The percentage of patients requiring postoperative blood transfusions in the normal Hb group was 16%, compared with 50% in the subnormal group (P<0.01). No statistically significant difference in the proportion of functioning grafts or in the serum creatinine levels could be detected. No correlation between EPO treatment and creatinine levels after transplantation was found. The frequency of adverse events was similar in the two groups., Conclusions: EPO treatment aimed at reaching a normal Hb in renal transplant recipients reduces the postoperative requirement for blood transfusions and has no deleterious effects on kidney graft function.
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- 2001
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22. Double-blind comparison of two corticosteroid regimens plus mycophenolate mofetil and cyclosporine for prevention of acute renal allograft rejection.
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Vanrenterghem Y, Lebranchu Y, Hené R, Oppenheimer F, and Ekberg H
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- Adolescent, Adult, Double-Blind Method, Drug Therapy, Combination, Female, Graft Rejection prevention & control, Humans, Male, Middle Aged, Adrenal Cortex Hormones therapeutic use, Cyclosporine therapeutic use, Immunosuppressive Agents therapeutic use, Kidney Transplantation immunology, Mycophenolic Acid analogs & derivatives, Mycophenolic Acid therapeutic use
- Abstract
Background: Renal transplant recipients experience adverse events attributed to corticosteroid therapy., Methods: This was a multicenter, randomized, double-blind, 6-month, controlled steroid dose-reduction study in renal transplant recipients with an unblinded 6-month follow-up. In the low/stop arm, corticoste. roids were given at half the dosage of control for 3 months from the date of transplantation, and then withdrawn. Both arms received mycophenolate mofetil and cyclosporine. The primary endpoint was the incidence of biopsy-proven acute rejection at 6 months posttransplantation., Results: There were 248 patients in the control group and 252 in the low/stop group. At 6 months the low/stop group had more biopsy-proven acute rejection episodes than the control (23% vs. 14%; P=0.008). At 12 months this increased to 25% vs. 15%. Most rejections were Banff grade I. Twelve-month graft loss was 5% in the low/stop group vs. 4% in the control. At 6 and 12 months serum cholesterol (P<0.01, P<0.01), triglycer. ides (P<0.01, P<0.01), and systolic blood pressure (P<0.001, P<0.001) were lower in the low/stop group. Diastolic pressure was lower (P<0.01) and lumbar spine bone density was greater (P<0.01) in the low/ stop group at 12 months., Conclusions: In renal transplant recipients treated with mycophenolate mofetil and cyclosporine, reduction and early withdrawal of the prophylactic corticosteroid dose is feasible without an unacceptable increase in serious rejection episodes. This is accompanied by a significant reduction of steroid-related adverse events.
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- 2000
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23. Factor V R506Q mutation (activated protein C resistance) is an additional risk factor for early renal graft loss associated with acute vascular rejection.
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Ekberg H, Svensson PJ, Simanaitis M, and Dahlbäck B
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- Acute Disease, Adult, Drug Resistance genetics, Female, Genotype, Graft Rejection epidemiology, Humans, Male, Middle Aged, Prevalence, Prognosis, Protein C physiology, Renal Circulation, Risk Factors, Thrombosis epidemiology, Vascular Diseases complications, Factor V genetics, Graft Rejection etiology, Kidney Transplantation
- Abstract
Background: The factor V R506Q mutation (FV R506Q, FV:Q506, or FV Leiden) resulting in activated protein C (APC) resistance is the most common inherited risk factor for venous thrombosis, including in renal transplant recipients. We investigated a possible association between the FV mutation and early renal graft loss, and the prevalence of macro- and microvascular thrombosis, endothelialitis, and fibrinoid vascular necrosis by FV genotype., Method: One hundred and nine renal allograft recipients were genotyped for FV mutation. A vascular rejection subgroup of patients (n=29) had experienced at least one episode of vascular rejection, or graft thrombosis. A second group of patients (n=80) had experienced no acute rejection and retained a well-functioning graft., Results: The prevalence of APC resistance was numerically but not statistically significantly higher in the vascular rejection group (17.2%) compared with the group without rejection episodes (7.5%) (P=0.16). There was a significant association between the presence or absence of FV mutation and graft survival, with a 55.6% 1-year graft survival rate versus a 76.4% rate, respectively (P=0.02). The prevalence of vascular rejection, as evidenced by endothelialitis or fibrinoid vascular necrosis, was significantly associated with APC resistance but macro- or microvascular thrombosis were not., Conclusion: Renal transplant recipients who are carriers of the FV:Q506 allele have an increased risk of early graft loss. Vascular rejection changes including endothelialitis and fibrinoid vascular necrosis were more common in this group, and therefore an association between the hypercoagulable state, which entails an up-regulation of the mitogenic and proinflammatory enzyme thrombin, and the immunological challenge to the endothelium may be the cause of inferior prognosis in these patients.
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- 2000
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24. Proportion of glomerulosclerosis in procurement wedge renal biopsy cannot alone discriminate for acceptance of marginal donors.
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Pokorná E, Vítko S, Chadimová M, Schück O, and Ekberg H
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- Adolescent, Adult, Aged, Aging physiology, Biopsy, Child, Cryopreservation, Female, Graft Survival, Histocompatibility Testing, Humans, Ischemia physiopathology, Kidney blood supply, Male, Middle Aged, Prospective Studies, Time Factors, Glomerulosclerosis, Focal Segmental pathology, Kidney pathology, Kidney Transplantation, Personnel Selection, Tissue Donors
- Abstract
Background: The shortage of available kidneys for renal transplantation could be addressed, to some extent, by expanding the criteria for acceptance of marginal donors. The study of these criteria is limited by the selection of grafts actually retrieved and transplanted, therefore reduced to a study of risk factors. We have evaluated the potential of procurement renal biopies as an instrument for acceptance or refusal of donor kidneys for transplantation., Methods: This was a prospective study of a consecutive series of 200 donors. Biopsies were performed by wedge technique at the donor operation and were evaluated for proportion of glomerulosclerosis, vascular and tubular changes, and interstitial fibrosis. The study included 387 renal grafts with a representative biopsy, transplanted, and followed-up for survival and functional evaluation; 24 hr creatinine clearance at 1 and 3 weeks, and 3, 6, 12, 18, and 24 months., Results: Factors associated with initial graft function included cold ischemia time, number of DR mismatches, tubular changes, although donor age showed the strongest correlation with short- and long-term level of graft function. DR mismatches and retransplantation appeared to be the only significant risk factors for graft loss. The proportion of glomerulosclerosis (mean 8%, range 0-48%) correlated with graft function in the simple regression analysis. However, when age was taken into account glomerulosclerosis did not correlate significantly with graft function. Furthermore, glomerulosclerosis as high as 25% or more had an acceptable 3-year graft survival rate of 74.7%., Conclusion: Procurement biopsy provides only limited information for the decision whether or not to accept a kidney donor.
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- 2000
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25. A randomized multicenter trial of the anti-ICAM-1 monoclonal antibody (enlimomab) for the prevention of acute rejection and delayed onset of graft function in cadaveric renal transplantation: a report of the European Anti-ICAM-1 Renal Transplant Study Group.
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Salmela K, Wramner L, Ekberg H, Hauser I, Bentdal O, Lins LE, Isoniemi H, Bäckman L, Persson N, Neumayer HH, Jørgensen PF, Spieker C, Hendry B, Nicholls A, Kirste G, and Hasche G
- Subjects
- Acute Disease, Adolescent, Adult, Aged, Animals, Cadaver, Female, Graft Survival, Humans, Immunization, Passive, Male, Mice, Middle Aged, Antibodies, Monoclonal therapeutic use, Graft Rejection prevention & control, Intercellular Adhesion Molecule-1 immunology, Kidney physiopathology, Kidney Transplantation
- Abstract
Background: T-cell activation through T-cell receptor engagement requires co-stimulatory molecules and also adhesion molecules such as ICAM-1. Moreover ICAM-1 mediates leukocyte invasion from the blood into tissue during inflammatory processes. In animal studies using mouse monoclonal antibodies against ICAM-1 (enlimomab), renal allograft survival has been improved and reperfusion damage from ischemia reduced. The European Anti-ICAM-1 Renal Transplant Study (EARTS) was a randomized, double-blind, parallel-group, placebo-controlled study lastingl year and performed in 10 transplant centers in Europe., Methods: A total of 262 recipients of cadaveric kidneys were given either enlimomab or a placebo for 6 days and were given triple immunosuppressive therapy of cyclosporine, azathioprine, and prednisolone. The primary efficacy endpoint was the incidence of the first acute rejection within 3 months, and each event was assessed by a committee including investigators and independent pathologists., Results: There was no significant difference in the incidences of first acute rejection at 3 months between the placebo and enlimomab groups (39% vs. 45%), and enlimomab did not reduce the risk of delayed onset of graft function (DGF) (26% vs. 31%). Neither was there a difference in patient survival (95% vs. 91%) or graft survival (89% vs. 84%) at 1 year. Fatal events occurred in 19 (7%) patients (7 placebo, 12 enlimomab). Clinically, the most important non-fatal adverse events were infections; however, there was no statistically significant difference between the incidences in the two groups (70% vs. 79%)., Conclusion: Short term enlimomab induction therapy after renal transplantation did not reduce the rate of acute rejection or DGF.
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- 1999
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26. Long-term duct-occluded segmental pancreatic autografts: absence of microvascular diabetic complications.
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Hawthorne WJ, Wilson TG, Williamson P, Stewart GJ, Allen RD, Little JM, Deane SA, and Ekberg H
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- Animals, Diabetic Angiopathies physiopathology, Diabetic Nephropathies prevention & control, Diabetic Retinopathy physiopathology, Dogs, Fluorescein Angiography, Glycated Hemoglobin analysis, Kidney pathology, Microcirculation pathology, Neural Conduction, Pancreas blood supply, Pancreas Transplantation mortality, Pancreas Transplantation pathology, Pancreatectomy, Survival Rate, Time Factors, Transplantation, Autologous, Diabetes Mellitus, Type 1 physiopathology, Diabetes Mellitus, Type 1 surgery, Diabetic Angiopathies prevention & control, Diabetic Retinopathy prevention & control, Graft Survival, Pancreas Transplantation physiology, Pancreatic Ducts physiology
- Abstract
Background: Current insulin therapies for control of glucose metabolism in patients with type I diabetes mellitus prevent major metabolic consequences of insulin deficiency, but none prevents or arrests long-term complications. In experimental models of canine diabetes, retinopathy, neuropathy, and nephropathy have been shown to develop within 5 years. The aim of this study was to determine in a canine model whether glucose control provided by segmental duct-occluded pancreas autografts could prevent the long-term complications of diabetes., Methods: Thirty-five outbred mongrel dogs underwent segmental pancreas autotransplantation with residual pancreatectomy. Follow-up over 5 years included endocrine, retinal fundus photography, fluorescein angiography, and nerve conduction studies. At endpoint, analysis of organ specific changes was undertaken., Results: Long-term survival was achieved in 14 dogs for 4 to 5 years and in 3 dogs for 3 to 5 years. Glycosylated hemoglobin levels remained within normal limits, although response to glucose challenge was suboptimal. Fundus photography and fluorescein angiography demonstrated the absence of retinal vascular aneurisms, capillary leakage, and obliteration. Retinal digest showed no vascular changes and normal endothelial/pericyte ratios. Nerve conduction was normal, and histology of nerves revealed normal density of myelinated fibers and absence of intrafascicular vessels and glycogen deposits, with no change in spectrum of fiber diameters and ovoids. Renal histology revealed no evidence of nephropathy with normal glomerular basement membranes., Conclusions: We have demonstrated that duct-occluded segmental pancreatic autografts are capable of providing satisfactory metabolic control for up to 5 years, thereby preventing development of the long-term microvascular complications of diabetes.
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- 1997
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27. Activation of alloreactive natural killer cells is resistant to cyclosporine.
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Petersson E, Qi Z, Ekberg H, Ostraat O, Dohlsten M, and Hedlund G
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- Animals, CD3 Complex analysis, Drug Resistance immunology, Female, Graft Survival drug effects, Heart Transplantation immunology, Interleukin-2 pharmacology, Lymphocyte Activation drug effects, Male, Rats, Rats, Inbred BN, Rats, Inbred WF, T-Lymphocytes, Cytotoxic drug effects, T-Lymphocytes, Cytotoxic immunology, Cyclosporine pharmacology, Killer Cells, Natural immunology
- Abstract
Background: We have previously shown that cytotoxic T lymphocytes (CTL) with alloreactivity were induced when Wistar Furth (WF; RT1u) rats were immunized with allogeneic Brown Norway (BN; RT1n) cells. In contrast, when BN rats were immunized with WF cells, the allospecific response was confined to alloreactive natural killer (NK) cells, and no CTL activity was observed. In this study, the effect of cyclosporine (CsA) on the activation of alloreactive NK cells in vivo was analyzed., Methods: Distinct peritoneal effector cells from rats immunized with allogenic cells with or without concomitant CsA and/or interleukin (IL) 2 treatment were tested for specific cytolytic activity. Furthermore, the presumptive role of NK cells in rejection immunity was addressed in a cardiac graft model., Results: The results showed that doses of CsA that completely inhibited the activation of alloreactive CTL, only marginally affected the activation of alloreactive NK cells. We also showed that CsA treatment failed to prolong graft survival in BN recipients of WF hearts. Treatment of BN rats with CsA/IL-2 during immunization with allogeneic WF cells resulted in concomitant induction of alloreactive NK cells and alloreactive CTL., Conclusions: We have demonstrated that CsA failed to suppress the activation of alloreactive NK cells. Consequently, the cardiac graft survival in the donor-recipient combination known to activate alloreactive NK cells was not significantly prolonged by CsA treatment, emphasizing the involvement of NK cells as effectors in organ rejection. Furthermore, the parallel emergence of alloreactive NK cells and CTL only in the presence of CsA/IL-2 indicated that CsA interfered with alloreactive NK cell-associated suppression of CTL activated by allogeneic tissue.
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- 1997
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28. Simultaneous pancreas and kidney transplant rejection: separate or synchronous events?
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Hawthorne WJ, Allen RD, Greenberg ML, Grierson JM, Earl MJ, Yung T, Chapman J, Ekberg H, and Wilson TG
- Subjects
- Animals, Biomarkers analysis, Disease Models, Animal, Dogs, Graft Rejection metabolism, Graft Rejection pathology, Graft Survival, Kidney Transplantation pathology, Pancreas Transplantation pathology, Time Factors, Graft Rejection diagnosis, Kidney Transplantation immunology, Pancreas Transplantation immunology
- Abstract
The results of simultaneous pancreas and kidney transplantation (SPK) cannot be matched by pancreas transplantation alone (PTA), in part because an independent diagnosis of pancreas graft rejection remains difficult. The relationship between rejection of the pancreas and rejection of the kidney is poorly understood, and it is not known whether simultaneous transplantation of both organs confers true protection to either graft. To study these questions, reliable canine allotransplant models of kidney transplantation alone (KTA), PTA, and SPK were established. Sixty-seven mongrel dogs received KTA (n=21), PTA (n=23), or SPK (n=23) with either no immunosuppression, low-dose cyclosporine (CsA)-based immunosuppression, or high-dose CsA-based immunosuppression. Needle core biopsy (NCB) and fine needle aspiration biopsy (FNAB) were performed at 0, 2, 4, 7, 9, 11, 14, 21, and 30 days or at the time of graft failure. Pancreas and kidney graft survival after SPK was significantly shorter in dogs given low-dose CsA than in dogs given high-dose CsA (pancreas, P<0.04; kidney, P<0.03). Concurrent NCBs and FNABs were performed on 227 occasions in pancreas grafts and 229 occasions in kidney grafts. The time to initial evidence of rejection by NCB was not different in any immunosuppressed group. Synchronous rejection occurred in 73% of immunosuppressed SPK biopsies. Kidney-only rejection occurred in 23% of biopsies and pancreas-only rejection occurred in only 3% after SPK. All markers of pancreas graft rejection were poor, with the most sensitive being NCB of the simultaneously transplanted kidney. In summary, recipients of SPK required more immunosuppression than recipients of PTA, and improved PTA survival should be achievable with more sensitive markers of rejection. Markers of kidney rejection were the most sensitive indicators of pancreas rejection, and independent pancreas rejection was uncommon after SPK.
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- 1997
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29. The effect of venous drainage on glucose homeostasis after experimental pancreas transplantation.
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Hawthorne WJ, Griffin AD, Lau H, Ekberg H, and Allen RD
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- Animals, Body Weight, Dogs, Graft Survival, Homeostasis, Immunosuppressive Agents therapeutic use, Pancreas blood supply, Portal System surgery, Glucose metabolism, Insulin metabolism, Pancreas Transplantation methods
- Abstract
In this canine study, glucose homeostasis after clinical pancreas transplantation is complex, with the relative effect of systemic versus portal delivery of insulin remaining unresolved. Thirty-two pancreatectomized dogs received either systemic venous drainage (SVD) with bladder exocrine drainage (n = 16), or portal venous drainage (PVD) with gastric exocrine drainage (n = 16). Cyclosporine (CsA) based immunosuppression was commenced on day -7. The effect of immunosuppression was a significant increase in fasting blood glucose (FBGL) (P = 0.002), fasting insulin (P = 0.024), AUC for insulin (P = 0.009), and K values decreased (P = 0.009). FBGL and K values remained abnormal after transplantation with no significant difference seen between SVD and PVD. However, fasting insulin became significantly lower after PVD and AUC insulin fell in both groups. CsA levels fell in both groups after transplantation, mirroring the fall in AUC insulin, and implicating CsA as a major cause of peripheral resistance to insulin. In conclusion, PVD did not demonstrate a significant advantage over SVD in handling an intravenous glucose challenge. The need for pancreatectomy in large animals may make them an unsatisfactory experimental model to evaluate the glucoregulatory effects of pancreas allotransplantation.
- Published
- 1996
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30. Experimental hyperacute rejection in pancreas allotransplants.
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Hawthorne WJ, Griffin AD, Lau H, Hibbins M, Grierson JM, Ekberg H, Chapman JR, and Allen RD
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- Acute Disease, Animals, Antilymphocyte Serum analysis, Blood Cell Count, Dogs, Female, Histocompatibility Testing, Male, Pancreas pathology, Transplantation, Homologous, Graft Rejection blood, Pancreas Transplantation
- Abstract
A model of sensitization by intraperitoneal lymph node inoculation was developed to test the hypothesis that hyperacute rejection (HAR) could occur in sensitized recipients of vascularized pancreas allografts. Ten pairs of outbred mongrel dogs that were lymphocytotoxic cross-match assay negative were inoculated with homogenized lymph nodes on either three or four occasions at fortnightly intervals before renal transplantation. A renal allograft from the same donor was used to test the HAR response and to further enhance sensitization by rejection of a vascularized organ. Pancreas transplants were performed 2 weeks later, with biopsies of the graft and blood samples taken at 0, 10, 20, and 30 min and then at 30-min intervals until the grafts were no longer viable. All renal and pancreas grafts were rejected in a classical hyperacute pattern. Within 4 min of revascularization of the pancreas, central lobular hemorrhage and vascular congestion appeared, followed by general edema. Histology demonstrated parallel changes of edema, vascular congestion, necrosis, hemorrhage, and leukocytic infiltrate, which all preceded graft infarction. A sharp decline in both arterial and venous white blood cell count and platelets occurred within 10 min of revascularization with initial sequestration and subsequent release of platelets from the graft (P=0.02). In summary, HAR of the allografted pancreas can be observed by the surgeon within minutes of revascularization, with predictable macroscopic and microscopic changes. This study supports the use of routine lymphocytotoxic cross-match tests for all recipients of pancreas transplants and implies that particular care is warranted in regraft pancreas allograft recipients.
- Published
- 1996
- Full Text
- View/download PDF
31. Canine pancreas and kidney transplantation following total-lymphoid irradiation.
- Author
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Williamson P, Allen RD, Deane SA, Ekberg H, Grierson JM, Hawthorne WJ, Mears DC, Tiver K, Little JM, and Stewart GJ
- Subjects
- Animals, Antilymphocyte Serum pharmacology, Dogs, Graft Survival drug effects, Histocompatibility Testing, Transplantation, Homologous, Immunosuppression Therapy, Kidney Transplantation, Lymphoid Tissue radiation effects, Pancreas Transplantation
- Abstract
The effect of total-lymphoid irradiation on survival of canine pancreas and kidney allografts was studied. TLI had a marked immunosuppressive effect as measured by in vitro immune responses and reduced circulating leukocytes. Despite the changes, median graft survival times for animals treated with 800 cGy (9 days) or 1800 cGy (9.5 days) were not significantly different from untreated control animals (7 days). The addition of low-dose antithymocyte globulin (10 mg/kg/day) on post-transplant days 0, 2, 4, 6, 8, and 10 had no measurable synergistic effect. Similarly, median segmental pancreas allograft survival times after 1700-2200 cGy of TLI treatment (16.5 days) were only marginally longer than those of untreated controls (9 days). The only animal to maintain a graft for greater than 200 days was matched to the donor in mixed lymphocyte culture (MLC). This animal was able to reject a third-party skin graft after 8 days while a graft from the original donor was still surviving after 21 days when the pancreas graft failed from a chronic-type rejection. These results indicate that TLI alone or in combination with ATG will not be predictably effective as a method of prolonging allograft survival. The role of matching major histocompatibility complex antigens in TLI treatment requires clarification.
- Published
- 1990
- Full Text
- View/download PDF
32. Early diagnosis of rejection of canine pancreas allografts by fine-needle aspiration biopsy.
- Author
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Ekberg H, Allen RD, Greenberg ML, Hawthorne WJ, Earl M, Grierson JM, Williamson P, Deane SA, Stewart GJ, and Little JM
- Subjects
- Amylases urine, Animals, Biopsy, Needle, Dogs, Pancreas pathology, Transplantation, Homologous mortality, Graft Rejection, Pancreas Transplantation
- Abstract
In pancreatic allograft transplantation with bladder exocrine drainage, falls in urinary amylase (UA) levels have been shown to be an earlier marker of rejection than rises in fasting blood glucose levels. Nevertheless, this is often too late for reversal of the rejection process. In an attempt to diagnose rejection earlier, fine-needle aspiration biopsy was correlated with UA and graft histology. Sixteen dogs were given total pancreatic allografts, 10 without immunosuppression and 6 with triple therapy. FNAB and needle-core biopsies were performed on days 0, 2, 4, 7, 9, 24, and 30 and/or at functional rejection, defined as a fasting UA level of less than 5000 IU/L. Cytocentrifuge preparations of the FNABs were evaluated by total corrected increment (TCI) scores. These increased significantly from 1.0 (+/- 0.4; mean +/- SEM) 6 days, to 3.0 (+/- 1.2) 4 days before functional rejection. The increase was due to the presence of blast cells and macrophages. The TCI of healthy immunosuppressed grafts remained below 1.6 for 30 days after transplantation and was greater than 5.0 when pancreatitis or acute rejection was seen on conventional histology. Minimal histologic change had significantly lower TCI scores than both acute rejection (P less than 0.01) and pancreatitis (P less than 0.001). Acute rejection and pancreatitis were distinguished by a significant difference in increments of monocytes/lymphocytes and macrophages. In contrast to FNAB, UA levels did not differentiate minimal change from acute rejection but were a reliable marker of end-stage rejection.
- Published
- 1988
- Full Text
- View/download PDF
33. Estrogen receptor immunocytochemical assay on cytologic material from primary and metastatic breast cancer.
- Author
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Greenberg ML, Earl MJ, Bilous AM, Ekberg H, Milliken J, and Pacey NF
- Subjects
- Adenofibroma analysis, Adenofibroma secondary, Adult, Aged, Aged, 80 and over, Biopsy, Needle, Body Fluids analysis, Carcinoma analysis, Carcinoma secondary, Cytosol analysis, Female, Humans, Image Processing, Computer-Assisted, Immunohistochemistry, Menopause, Middle Aged, Predictive Value of Tests, Video Recording, Breast Neoplasms analysis, Receptors, Estrogen analysis
- Abstract
The determination of estrogen receptor (ER) status in primary and metastatic breast tumours has been facilitated by the recent advent of monoclonal antibodies to ER. The aim of this study was to determine the feasibility of estrogen receptor immunocytochemical assay (ER-ICA) applied to cytologic specimens from primary and metastatic breast tumours. One hundred and sixty specimens from 133 patients were evaluated by cytologic ER-ICA. Comparison with histologic ER-ICA was available for 28 of the specimens and with cytosol assay for 27 specimens. Some 101 of the 160 samples were breast lesions of which 87 had a definitive diagnosis of breast carcinoma. Of these, 68% were considered positive for ER. Metastatic breast cancers comprised 59 of the 160 specimens of which 37% were found to be positive for ER. The predominant staining intensity (SI) of the nuclei of the tumour cells added to the percentage of cells (PC) stained gave an estrogen receptor score (ERS) in both cytologic and histologic specimens. A positive threshold was determined for an ERS greater than 2, equivalent to ER levels greater than 10 fmol/mg of protein. We observed very good correlation between cytologic ERS and the corresponding cytosol assay values (r = 0.74; p less than 0.001; n = 27). The sensitivity was 95% and the specificity 88%. Correlation with histologic ER-ICA was also very high (r = 0.83; p less than 0.001; n = 28). We assessed the role of video image analysis (VIA) and did not find any additional advantages in evaluating cytologic ER-ICA.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1989
- Full Text
- View/download PDF
34. Major liver resection for hilar cholangiocarcinoma.
- Author
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Bengmark S, Ekberg H, Evander A, Klofver-Stahl B, and Tranberg KG
- Subjects
- Adenoma, Bile Duct mortality, Adult, Aged, Common Bile Duct surgery, Common Bile Duct Neoplasms classification, Common Bile Duct Neoplasms mortality, Female, Humans, Jejunum surgery, Male, Middle Aged, Neoplasm Recurrence, Local mortality, Postoperative Complications mortality, Adenoma, Bile Duct surgery, Common Bile Duct Neoplasms surgery, Hepatectomy methods
- Abstract
Between 1968 and 1984 liver resection with curative attempt was performed in 22 patients with hilar cholangiocarcinoma. Right lobectomy was performed in 4 patients, extended right lobectomy in 7, left lobectomy in 8, and excision of the median segment segment of the left lobe (segment IV) in 3. Bilio-enteric continuity was restored by hepatocholedochostomy in 17 patients and hepatojejunostomy in 4. (One patient had external transhepatic catheter drainage and no internal bile drainage.) Operative mortality rate was 27% and caused by excessive intraoperative bleeding, sepsis, or liver insufficiency. Postoperative complications occurred in 57% of patients surviving the operation and were due mainly to leakage from the hepatocholedochostomy. Median survival was 6 months, and one third of the patients survived 1 year. Three patients survived 10 years and were among the four patients in whom a tumor-free resection margin was obtained (one of them died in the postoperative phase). It is concluded that resection of hilar cholangiocarcinoma may give long-term survival if a free resection margin is obtained. The importance of a free resection margin indicates that surgery should be aggressive and include liver resection.
- Published
- 1988
- Full Text
- View/download PDF
35. Long-term duct-occluded segmental pancreatic autografts. Does fibrosis lead to graft loss?
- Author
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Ekberg H, Deane SA, Williamson P, Hawthorne WJ, Grierson JM, Eastman CJ, Stewart GJ, and Little JM
- Subjects
- Animals, Blood Glucose metabolism, Dogs, Fibrosis complications, Graft Survival, Islets of Langerhans physiology, Pancreatic Diseases pathology, Pancreatic Ducts pathology, Time Factors, Pancreas Transplantation, Pancreatic Diseases complications
- Abstract
In clinical pancreas transplantation, duct-occluded segmental allografts are often used. There is concern that fibrosis following duct-occlusion may lead to progressive graft failure. In this study, sequential histology and endocrine function in long-term (up to 5 years) canine autografts were assessed. Segmental pancreatic autografts with residual pancreatectomy were performed, and the pancreatic duct was occluded with cyanoacrylate glue. Serial i.v. glucose tolerance tests (IVGTT) and percutaneous needle-core biopsies of the grafts were performed as long as grafts functioned. Ten dogs were long-term (greater than 18 months) survivors: 8 dogs had functioning grafts for a median of 48 months (range 18-60) after transplantation, and 3 dogs had graft failure at 21, 27, and 60 months. The mean 40-min blood glucose concentration (BGL-40') after i.v. glucose injection did not increase with time up to 5 years after grafting. Graft biopsies showed a universal picture of aggregated islet cells and fibrous replacement of acinar tissue. The total amount of fibrosis did not change with time, but the existing fibrosis became less cellular and more dense. This long-term study showed that in autografted animals, adequate endocrine function was maintained in the majority of cases, and progressive replacement of islet tissue by fibrosis could not be demonstrated in serial biopsies taken between 18 months and 5 years after autotransplantation. We therefore conclude, that while duct-occlusion results in extensive fibrosis, the process is not progressive, and although fibrosis may contribute to late graft failure this is not inevitable.
- Published
- 1988
- Full Text
- View/download PDF
36. Long-term canine duct-occluded segmental pancreatic autografts: endocrine function.
- Author
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Williamson P, Deane SA, Ekberg H, Hawthorne WJ, Garvey JF, Stewart GJ, Eastman CJ, and Little JM
- Subjects
- Animals, Blood Glucose analysis, Dogs, Female, Glucose Tolerance Test, Insulin blood, Male, Pancreas Transplantation, Pancreatic Ducts physiology, Transplantation, Autologous, Pancreas physiology
- Abstract
This study examines the endocrine function of duct-obliterated canine segmental autografts for periods up to 5 years posttransplant. Overall the response profile of autografted animals was subnormal. After intravenous glucose tolerance tests K-values in transplanted animals (2.8 +/- 0.9%/min) were significantly lower than normal (4.6 +/- 1.2% min, p less than 0.001). After oral glucose stimulation, blood glucose in the autografted dogs reached a mean peak of 10.6 +/- 2.8 mmol/L whereas in normal dogs the peak value was 6.0 +/- 1.0 mmol/L (p less than 0.002). The mean insulin response in autografted dogs showed lower insulin concentrations in the early stages of the test, whereas insulin secretion after glucagon stimulation was significantly reduced in autografted dogs. Intravenous glucose tolerance tests were analyzed by calculating K value or measuring a single blood glucose concentration 40 min after glucose injection. This value had a high correlation with the K value (r = 0.967). No progressive deterioration of graft function up to 5 years was found. Glycosylated hemoglobin levels were measured in autografted (646 +/- 59 pmol/mg) and normal dogs (620 +/- 85 pmol/mg) and no significant difference was found. In conclusion, duct-occluded segmental pancreatic autografts were shown to have a reduced functional capacity but there was no deterioration of function up to 5 years after duct-occlusion and grafting. The degree of metabolic control may be sufficient to prevent diabetic complications.
- Published
- 1988
- Full Text
- View/download PDF
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