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  • 1.
    Andreassen, A. K.
    et al.
    Oslo University Hospital, Norway.
    Andersson, B.
    Sahlgrens University Hospital, Sweden.
    Gustafsson, F.
    Rigshosp, Denmark.
    Eiskjaer, H.
    Aarhus University Hospital, Denmark.
    Radegran, G.
    Lund University, Sweden; Lund University, Sweden.
    Gude, E.
    Oslo University Hospital, Norway.
    Jansson, Kjell
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Solbu, D.
    Novartis Norge AS, Norway.
    Karason, K.
    Sahlgrens University Hospital, Sweden.
    Arora, S.
    Oslo University Hospital, Norway.
    Dellgren, G.
    Sahlgrens University Hospital, Sweden.
    Gullestad, L.
    Oslo University Hospital, Norway; University of Oslo, Norway; University of Oslo, Norway.
    Everolimus Initiation With Early Calcineurin Inhibitor Withdrawal in De Novo Heart Transplant Recipients: Three-Year Results From the Randomized SCHEDULE Study2016In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 16, no 4, p. 1238-1247Article in journal (Refereed)
    Abstract [en]

    In a randomized, open-label trial, de novo heart transplant recipients were randomized to everolimus (3-6ng/mL) with reduced-exposure calcineurin inhibitor (CNI; cyclosporine) to weeks 7-11 after transplant, followed by increased everolimus exposure (target 6-10ng/mL) with cyclosporine withdrawal or standard-exposure cyclosporine. All patients received mycophenolate mofetil and corticosteroids. A total of 110 of 115 patients completed the 12-month study, and 102 attended a follow-up visit at month 36. Mean measured GFR (mGFR) at month 36 was 77.4mL/min (standard deviation [SD] 20.2mL/min) versus 59.2mL/min (SD 17.4mL/min) in the everolimus and CNI groups, respectively, a difference of 18.3mL/min (95% CI 11.1-25.6mL/min; p < 0.001) in the intention to treat population. Multivariate analysis showed treatment to be an independent determinant of mGFR at month 36. Coronary intravascular ultrasound at 36 months revealed significantly reduced progression of allograft vasculopathy in the everolimus group compared with the CNI group. Biopsy-proven acute rejection grade 2R occurred in 10.2% and 5.9% of everolimus- and CNI-treated patients, respectively, during months 12-36. Serious adverse events occurred in 37.3% and 19.6% of everolimus- and CNI-treated patients, respectively (p=0.078). These results suggest that early CNI withdrawal after heart transplantation supported by everolimus, mycophenolic acid and steroids with lymphocyte-depleting induction is safe at intermediate follow-up. This regimen, used selectively, may offer adequate immunosuppressive potency with a sustained renal advantage. A follow-up study of the SCHEDULE trial, which randomized de novo heart transplant recipients to everolimus with cyclosporine discontinuation or to standard-exposure cyclosporine, shows that measured glomerular filtration rate remains significantly higher in the everolimus group at three years posttransplant, with significantly reduced progression of allograft vasculopathy compared to cyclosporine therapy.

  • 2.
    Andreassen, A.K.
    et al.
    University of Oslo, Norway .
    Andersson, B.
    Sahlgrens University Hospital, Sweden .
    Gustafsson, F.
    Rigshosp, Denmark .
    Eiskjaer, H.
    Aarhus University Hospital, Denmark .
    Rdegran, G.
    Skåne University Hospital, Sweden Lund University, Sweden .
    Gude, E.
    University of Oslo, Norway .
    Jansson, Kjell
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Solbu, D.
    Novartis Norge AS, Norway .
    Sigurdardottir, V.
    Sahlgrens University Hospital, Sweden .
    Arora, S.
    University of Oslo, Norway .
    Dellgren, G.
    Sahlgrens University Hospital, Sweden .
    Gullestad, L.
    University of Oslo, Norway University of Oslo, Norway University of Oslo, Norway .
    Everolimus Initiation and Early Calcineurin Inhibitor Withdrawal in Heart Transplant Recipients: A Randomized Trial2014In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 14, no 8, p. 1828-1838Article in journal (Refereed)
    Abstract [en]

    In a randomized, open-label trial, everolimus was compared to cyclosporine in 115 de novo heart transplant recipients. Patients were assigned within 5 days posttransplant to low-exposure everolimus (3-6 ng/mL) with reduced-exposure cyclosporine (n 56), or standard-exposure cyclosporine (n = 59), with both mycophenolate mofetil and corticosteroids. In the everolimus group, cyclosporine was withdrawn after 7-11 weeks and everolimus exposure increased (6-10 ng/mL). The primary efficacy end point, measured GFR at 12 months posttransplant, was significantly higher with everolimus versus cyclosporine (mean +/- SD: 79.8 +/- 17.7 mL/min/1.73m 2 vs. 61.5 +/- 19.6 mL/min/1.73m 2; pless than0.001). Coronary intravascular ultrasound showed that the mean increase in maximal intimal thickness was smaller (0.03 mm [95% CI 0.01, 0.05 mm] vs. 0.08 mm [95% CI 0.05, 0.12 mm], p = 0.03), and the incidence of cardiac allograft vasculopathy (CAV) was lower (50.0% vs. 64.6%, p = 0.003), with everolimus versus cyclosporine at month 12. Biopsy-proven acute rejection after weeks 7-11 was more frequent with everolimus (p = 0.03). Left ventricular function was not inferior with everolimus versus cyclosporine. Cytomegalovirus infection was less common with everolimus (5.4% vs. 30.5%, pless than0.001); the incidence of bacterial infection was similar. In conclusion, everolimus-based immunosuppression with early elimination of cyclosporine markedly improved renal function after heart transplantation. Since postoperative safety was not jeopardized and development of CAV was attenuated, this strategy may benefit long-term outcome.

  • 3.
    Arora, Satish
    et al.
    Oslo University Hospital Rikshospitalet, Norway.
    Erikstad, I.
    Oslo University Hospital Rikshospitalet, Norway.
    Ueland, T.
    Oslo University Hospital Rikshospitalet, Norway.
    Sigurdardottir, V.
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Ekmehag, B.
    Skåne University Hospital and Lund University, Lund, Sweden.
    Jansson, Kjell
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Cardiology UHL.
    Eiskjaer, H.
    Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Cardiology UHL.
    Bøtker, H. E.
    Skejby University Hospital, Denmark .
    Mortensen, S.-A.
    Rigshospitalet, Copenhagen, Denmark.
    Saunamaki, K.
    Rigshospitalet, Copenhagen, Denmark.
    Gude, E.
    Oslo University Hospital Rikshospitalet, Norway.
    Ragnarsson, A.
    Oslo University Hospital Rikshospitalet, Norway.
    Solbu, D.
    Medical Department, Novartis, Norway .
    Gullestad, L
    Oslo University Hospital Rikshospitalet, Norway.
    Virtual Histology Assessment of Cardiac Allograft Vasculopathy Following Introduction of Everolimus—Results of a Multicenter Trial2012In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 12, no 10, p. 2700-2709Article in journal (Refereed)
    Abstract [en]

    In this 12-month multicenter Scandinavian study, 78 maintenance heart transplant (HTx) recipients randomized to everolimus with reduced calcineurin inhibitor (CNI) exposure or continued standard CNI-therapy underwent matched virtual histology (VH) examination to evaluate morphological progression of cardiac allograft vasculopathy (CAV). Parallel measurement of a range of inflammatory markers was also performed. A similar rate of quantitative CAV progression was observed in the everolimus (n = 30) and standard CNI group (n = 48) (plaque index 1.9 +/- 3.8% and 1.6 +/- 3.9%, respectively; p = 0.65). However, VH analysis revealed a significant increase in calcified (2.4 +/- 4.0 vs. 0.3 +/- 3.1%; p = 0.02) and necrotic component (6.5 +/- 8.5 vs. 1.1 +/- 8.6%; p = 0.01) among everolimus patients compared to controls. The increase in necrotic and calcified components was most prominent in everolimus patients with time since HTx andgt;5.1 years and was accompanied by a significant increase in levels of von Willebrand (vWF) factor (p = 0.04) and vascular cell adhesion molecule (VCAM) (p = 0.03). Conversion to everolimus and reduced CNI is associated with a significant increase in calcified and necrotic intimal components and is more prominent in patients with a longer time since HTx. A significant increase in vWF and VCAM accompanied these qualitative changes and the prognostic implication of these findings requires further investigation.

  • 4.
    Berglund, E.
    et al.
    Karolinsk Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Ljungdahl, M. Andersen
    Karolinsk Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Bogdanovic, D.
    Karolinsk Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Wadström, J.
    Karolinsk Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Weissenbacher, A.
    Innsbruck Med Univ, Ctr Operat Med, Innsbruck, Austria..
    Petruzzo, P.
    Hop Edouard Herriot, Dept Transplantat, Lyon, France..
    Schneeberger, S.
    Innsbruck Med Univ, Ctr Operat Med, Innsbruck, Austria..
    Clinical Significance of Alloantibodies in Hand Transplantation: Impact on Rejection and Functional Outcome2017In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 17, no S3, p. 240-240, article id 96Article in journal (Other academic)
  • 5.
    Biglarnia, Ali-Reza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Lorant, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Lennmyr, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wadström, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Efficacy and safety of continuous local infusion of ropivacaine after retroperitoneoscopic live donor nephrectomy2011In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 11, no 1, p. 93-100Article in journal (Refereed)
    Abstract [en]

    Morphine-based analgesia is effective but can compromise donor safety. We investigated whether continuous infusion of local anesthetics (CILA) can provide sufficient pain control and reduce morbidity related to opiate analgesics after hand-assisted retroperitoneoscopic (HARS) live donor nephrectomy. Forty consecutive live kidney donors underwent HARS and were treated with the ON-Q system providing CILA with 0.5% ropivacaine through two SilvaGard® catheters placed in the retroperitoneal cavity and the rectus sheath, respectively. The case control group consisted of 40 donors matched with regard to sex, age, BMI and surgical technique. All donors were maintained on standardized multimodal analgesia combining nurse-controlled oxycodone treatment and acetaminophen. CILA donors had lower median cumulative consumption of morphine equivalents (CCME) (7 mg [0-56] vs. 42 mg [15-127]; p < 0.0000001), lower incidence of nausea (18 [45%] vs. 35 [87.5%] donors; p < 0.001), shorter time in postoperative care unit (160 vs. 242.5 min; p < 0.001) and shorter hospital stay (4 [4-7] vs. 6 [4-11] days; p < 0.001). In 32.5% of CILA donors the CCME was 0 mg (0% in matched control group, p < 0.001). CILA with 0.5% ropivacaine provides effective postoperative pain relief, reduces the need for opioid treatment and promotes postoperative recovery. Continuous local infusion of ropivacaine provides sufficient analgesia and opioid-sparing effect as well as reduces the incidence of nausea and vomiting after hand-assisted retroperitoneoscopic live donor nephrectomy.

  • 6.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Espes, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sedigh, Amir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Rotem, Avi
    Zimermann, Baruch
    Grinberg, Helena
    Goldman, Tali
    Barkai, Uriel
    Avni, Yuval
    Westermark, Gunilla T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlbom, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Antaros Medical AB, Mölndal, Sweden.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Olerud, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Transplantation of macroencapsulated human islets within the bioartificial pancreas βAir to patients with type 1 diabetes mellitus2018In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 18, no 7, p. 1735-1744Article in journal (Refereed)
    Abstract [en]

    Macroencapsulation devices provide the dual possibility to immunoprotect transplanted cells while also being retrievable; the latter bearing importance for safety in future trials with stem-cell derived cells. However, macroencapsulation entails a problem with oxygen supply to the encapsulated cells. The βAir device solves this with an incorporated refillable oxygen tank. This phase 1 study evaluated the safety and efficacy of implanting the βAir device containing allogeneic human pancreatic islets to patients with type 1 diabetes. Four patients were transplanted with 1-2 βAir devices, each containing 155000-180000 IEQ (i.e. 1800-4600 IEQ per kg body weight), and monitored for 3-6 months, followed by the recovery of devices. Implantation of the βAir device was safe and successfully prevented immunization and rejection of the transplanted tissue. However, although beta cells survived in the device, only minute levels of circulating C-peptide were observed with no impact on metabolic control. Fibrotic tissue with immune cells was formed in capsule surroundings. Recovered devices displayed a blunted glucose-stimulated insulin response, and amyloid formation in the endocrine tissue. We conclude that the βAir device is safe and can support survival of allogeneic islets for several months, although the function of the transplanted cells was limited.

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  • 7.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Eich, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Tibell, Annika
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Andersson, H.
    Felldin, M.
    Foss, A.
    Kyllönen, L.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Lundgren, Torbjörn
    Positron emission tomography in clinical islet transplantation2009In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 9, no 12, p. 2816-2824Article in journal (Refereed)
    Abstract [en]

    The fate of islets in clinical transplantation is unclear. To elude on this positron emission tomography combined with computed tomography (PET/CT) was performed for 60 min during islet transplantation in five patients receiving six transplants. A fraction of the islets (23%) were labeled with 18F-fluorodeoxyglucose ([(18)F]FDG) and carefully mixed with unlabeled islets just prior to intraportal transplantation. The peak radioactivity concentration in the liver was found at 19 min after start of islet infusion and corresponded to only 75% of what was expected, indicating that islets are lost during the transplantation procedure. No accumulation of radioactivity was found in the lungs. A nonphysiological peak of C-peptide was found in plasma during and immediately after transplantation in all subjects. Distribution in the liver was heterogeneous with wide variations in location and concentration. Islets found in areas with concentrations of >400 IEQ/cc liver tissue varied between 1% and 32% of the graft in different subjects. No side effects attributed to the PET/CT procedure were found. Clinical outcome in all patients was comparable to that previously observed indicating that the [(18)F]FDG labeling procedure did not harm the islets. The technique has potential to be used to assess approaches to enhance islet survival and engraftment in clinical transplantation.

  • 8.
    Espes, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lau, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Quach, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ullsten, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Christoffersson, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. La Jolla Inst Allergy & Immunol, La Jolla, CA USA..
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rapid Restoration of Vascularity and Oxygenation in Mouse and Human Islets Transplanted to Omentum May Contribute to Their Superior Function Compared to Intraportally Transplanted Islets2016In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 16, no 11, p. 3246-3254Article in journal (Refereed)
    Abstract [en]

    Transplantation of islets into the liver confers several site-specific challenges, including a delayed vascularization and prevailing hypoxia. The greater omentum has in several experimental studies been suggested as an alternative implantation site for clinical use, but there has been no direct functional comparison to the liver. In this experimental study in mice, we characterized the engraftment of mouse and human islets in the omentum and compared engraftment and functional outcome with those in the intraportal site. The vascularization and innervation of the islets transplanted into the omentum were restored within the first month by paralleled ingrowth of capillaries and nerves. The hypoxic conditions in the islets early posttransplantation were transient and restricted to the first days. Newly formed blood vessels were fully functional, and the blood perfusion and oxygenation of the islets became similar to that of endogenous islets. Furthermore, islet grafts in the omentum showed at 1 month posttransplantation functional superiority to intraportally transplanted grafts. We conclude that in contrast to the liver the omentum provides excellent engraftment conditions for transplanted islets. Future studies in humans will be of great interest to investigate the capability of this site to also harbor larger grafts without interfering with islet functionality.

  • 9.
    Espes, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Lau, Joey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Quach, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Christoffersson, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Restoration of Islet Vascularity and Oxygenation in Mouse and Human Islets Experimentally Transplanted to the Omentum: A Basis for Superior Function when Compared to Intraportally Transplanted Islets2016In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143Article in journal (Refereed)
  • 10.
    Felldin, M.
    et al.
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Ekberg, J.
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Polanska‐Tamborek, D.
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Hansson, U.
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Sender, M.
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Rizell, M.
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Svanvik, Joar
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Mölne, J.
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Donor monoclonal gammopathy may cause lymphoproliferative disorders in solid organ transplant recipients2016In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, American Journal of transplantation, Vol. 16, no 9, p. 2676-2683Article in journal (Refereed)
    Abstract [en]

    Prior research on donor monoclonal gammopathy of undetermined significance (MGUS) has been inadequate regarding the risk for lymphoproliferative disease in solid organ transplantation recipients. Seven organ recipients from two different donors developed lymphoproliferative disease. The origin of the malignancy was determined by use of microsatellite analysis, and the plasma of the two donors was analyzed with the use of electrophoresis. The clinical courses of the seven recipients were followed for 36–60 months. One donor transmitted lymphoplasmacytic lymphoma to two kidney recipients and MGUS to a liver recipient, all IgMκ. A second donor caused IgGλ myeloma in two kidney and one liver recipient, and IgGλ gammopathy in a heart recipient. Transplant nephrectomy was performed in three kidney recipients and remission was achieved. The fourth kidney recipient has kept the graft and the disease has progressed. The liver recipient died from myeloma. There were no clinical signs of lymphoproliferative disease in the donors, but retrospective serum analyses showed M‐components, IgMκ (37 g/L) and IgGλ (8 g/L). Donors with MGUS may cause donor‐transmitted malignancies via passenger lymphocytes/plasma cells in solid organ recipients. The results call for a large register study of the incidence of donor MGUS and lymphoproliferative disease in their recipients.

  • 11.
    Fellström, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jardine, Alan G.
    Soveri, Inga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Cole, E.
    Neumayer, Hans-Helmutt
    Maes, Bart
    Gimpelewicz, Claudio
    Holdaas, Hallvard
    Renal dysfunction is a strong and independent risk factor for mortality and cardiovascular complications in renal transplantation2005In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 5, no 8, p. 1986-1991Article in journal (Refereed)
    Abstract [en]

    Renal transplant recipients (RTR) have shortened life expectancy, primarily due to premature cardiovascular disease (CVD). Traditional CVD risk factors are highly prevalent. In addition, several non-traditional risk factors may contribute to the high risk. The aim of the study was to evaluate the effects of renal dysfunction on mortality and cardiovascular complications in 1052 placebo-treated patients of the Assessment of LEscol in Renal Transplantation (ALERT) trial. Follow-up was 5-6 years and endpoints included cardiac death, non-cardiovascular death, all-cause mortality, major adverse cardiac event (MACE), non-fatal myocardial infarction (MI) and stroke. The effects of serum creatinine at baseline on these endpoints were evaluated. Elevated serum creatinine in RTR was a strong and independent risk factor for MACE, cardiac, non-cardiovascular, and all-cause mortality, but not for stroke or non-fatal MI alone. Serum creatinine was associated with increased mortality and MACE, independent of established CVD risk factors. Graft loss resulted in increased incidences of non-cardiovascular death, all-cause mortality, MACE and non-fatal MI. In conclusion, elevated serum creatinine is a strong risk factor for all-cause, non-cardiovascular and cardiac mortality, and MACE, independent of traditional risk factors, but not for stroke or non-fatal MI alone.

  • 12. Fernberg, P.
    et al.
    Edgren, G.
    Adami, J.
    Ingvar, Å.
    Bellocco, R.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Höglund, P.
    Kinch, Amelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Simard, J. F.
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Lindelöf, B.
    Pawitan, Y.
    Smedby, K. E.
    Time Trends in Risk and Risk Determinants of Non-Hodgkin Lymphoma in Solid Organ Transplant Recipients2011In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 11, no 11, p. 2472-2482Article in journal (Refereed)
    Abstract [en]

    Organ transplantation increases risk of non-Hodgkin lymphoma (NHL), but long-term risk and time trends have seldom been evaluated. Immunosuppressive drug load is an important risk determinant, but the details are unclear. We studied NHL risk in a nationwide Swedish cohort of 11 081 graft recipients transplanted 1970-2008. Relative risks (RRs) were estimated within the cohort and versus the general population by age, sex, follow-up time and calendar period. NHL risk was also assessed by cumulative and average doses of immunosuppressive treatments in a nested case-control design throughout 1997 using conditional logistic regression. We observed 153 NHL cases during 97 853 years of follow-up. Compared with the general population, NHL risk was eightfold increased (RR 7.9; 95% confidence interval [CI] 6.6-9.4), and increased risks persisted after >= 15 years of follow-up among kidney (6.1; 95% CI 3.5-10) and nonkidney recipients (44; 14-103). Among nonkidney recipients, NHL risk was lower in the 2000s compared with the 1990s (0.5; 95% CI 0.3-1.0; p = 0.04). A high average dose of antithymocyte immunoglobulin (ATG) conferred an eightfold increased risk of NHL (OR 8.5; 95% CI 1.9-38). To conclude, posttransplant NHL risk decreased during the last decade among nonkidney recipients, possibly because of a more careful use of ATG, the introduction of new drugs, or both.

  • 13. Friman, S.
    et al.
    Arns, W.
    Nashan, B.
    Vincenti, F.
    Banas, B.
    Budde, K.
    Cibrik, D.
    Chan, L.
    Klempnauer, J.
    Mulgaonkar, S.
    Nicholson, M.
    Wahlberg, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Wissing, K. -M
    Abrams, K.
    Witte, S.
    Woodle, E. S.
    Sotrastaurin, a Novel Small Molecule Inhibiting Protein-Kinase C: Randomized Phase II Study in Renal Transplant Recipients2011In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 11, no 7, p. 1444-1455Article in journal (Refereed)
    Abstract [en]

    Sotrastaurin, a selective protein-kinase-C inhibitor, blocks early T-cell activation through a calcineurin-independent mechanism. In this study, de novo renal transplant recipients with immediate graft function were randomized 1: 2 to tacrolimus (control, n = 44) or sotrastaurin (300 mg b.i.d.; n = 81). All patients received basiliximab, mycophenolic acid (MPA) and steroids. The primary endpoint was the composite of treated biopsy-proven acute rejection (BPAR), graft loss, death or lost to follow-up at month 3. The main safety assessment was estimated glomerular filtration rate (eGFR); modification of diet in renal disease (MDRD) at month 3. Composite efficacy failure at month 3 was higher for the sotrastaurin versus control regimen (25.7% vs. 4.5%, p = 0.001), driven by higher BPAR rates (23.6% vs. 4.5%, p = 0.003), which led to early study termination. Median (+/- standard deviation [SD]) eGFR was higher for sotrastaurin versus control at all timepoints from day 7 (month 3: 59.0 +/- 22.3 vs. 49.5 +/- 17.7 mL/min/1.73 m(2), p = 0.006). The most common adverse events were gastrointestinal disorders (control: 63.6%; sotrastaurin: 88.9%) which led to study-medication discontinuation in two sotrastaurin patients. This study demonstrated a lower degree of efficacy but better renal function with the calcineurin-inhibitor-free regimen of sotrastaurin+MPA versus the tacrolimus-based control. Ongoing studies are evaluating alternative sotrastaurin regimens.

  • 14. Gao, R.
    et al.
    Ustinov, J.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Otonkoski, Timo
    Effects of immunosuppressive drugs on in vitro neogenesis of human islets: mycophenolate mofetil inhibits the proliferation of ductal cells2007In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 7, no 4, p. 1021-1026Article in journal (Refereed)
    Abstract [en]

    Assuming that neogenesis contributes to long-term function of islet grafts, it is important to study the effects of immunosuppressive drugs on precursor cell proliferation and differentiation. We examined the effects of low-dose immunosuppressive drugs on these processes in vitro. Immunosuppressive drugs, including sirolimus, tacrolimus, mycophenolate mofetil (MMF), daclizumab and their combinations were tested in parallel culture wells through either the expansion phase (5-7 days) or the entire culture period (4-5 weeks). MMF, alone or in combination with sirolimus or tacrolimus, severely hampered duct-cell proliferation by 8-fold during the expansion period, and significantly reduced the total DNA content by about 40% after 5-week culture. After 4-5 week exposure to different drugs, only sirolimus and daclizumab showed no adverse effects on insulin content, whereas significant reductions of 30-60% in insulin content were seen in all other experimental groups. Only tacrolimus decreased the insulin content per DNA, as well as the proportion of insulin-positive cells. In conclusion, MMF has a potent inhibitory effect on neogenesis primarily through an antiproliferative effect on the precursors, whereas tacrolimus mainly affects beta-cell differentiation. Sirolimus and daclizumab have no adverse effects on these parameters. The immunosuppressive protocol may be an important determinant of long-term clinical islet graft function.

  • 15.
    Glotz, Denis
    et al.
    INSERM, Paris Translat Res Ctr Organ Transplantat, Unite Mixte Rech S970, Paris, France;St Louis Hosp, AP HP, INSERM, Dept Nephrol & Organ Transplantat,Unite U1160, Paris, France.
    Russ, Graeme
    Royal Adelaide Hosp, Cent & Northern Adelaide Renal & Transplantat Ser, Adelaide, SA, Australia;Univ Adelaide, Adelaide, SA, Australia.
    Rostaing, Lionel
    Rangueil Univ Hosp Ctr, Dept Nephrol & Organ Transplantat, Toulouse, France;Grenoble Alpes Univ Hosp Ctr, Dept Nephrol Hemodialysis Apheresis & Transplanta, Ave Maquis du Gresivaudan, La Tronche, France.
    Legendre, Christophe
    Univ Paris 05, Hop Necker Enfants Malad, Sorbonne Paris Cite, Adult Nephrol Transplantat Serv, Paris, France;Hop Necker Enfants Malad, INSERM, Inst Necker Enfants Malad, U1151, Paris, France.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Chadban, Steve
    Univ Sydney, Royal Prince Alfred Hosp, Dept Renal Med, Sydney, NSW, Australia.
    Grinyo, Josep
    Univ Barcelona, Hosp Univ Bellvitge, Dept Nephrol, Barcelona, Spain.
    Mamode, Nizam
    Guys & St Thomas Evelina London Childrens & Great, Dept Transplant Surg, London, England.
    Rigotti, Paolo
    Univ Hosp Padua, Kidney & Pancreas Transplant Unit, Padua, Italy.
    Couzi, Lionel
    Bordeaux Univ, ImmunoConcEpT, UMR CNRS 5164, Bordeaux, France;CHU, Dept Nephrol Transplantat Dialysis Apheresis, Bordeaux, France.
    Buchler, Matthias
    Tours Univ Hosp, Dept Nephrol, Tours, France.
    Sandrini, Silvio
    Univ Brescia, Div Nephrol, Brescia, Italy;Spedali Civili Gen Hosp, Brescia, Italy.
    Dain, Bradley
    Alexion Pharmaceut, Boston, MA USA.
    Garfield, Mary
    Alexion Pharmaceut, Boston, MA USA;Arvinas, New Haven, CT USA.
    Ogawa, Masayo
    Alexion Pharmaceut, Boston, MA USA.
    Richard, Tristan
    Alexion Pharmaceut, Boston, MA USA.
    Marks, William H.
    Alexion Pharmaceut, Boston, MA USA.
    Safety and efficacy of eculizumab for the prevention of antibody-mediated rejection after deceased-donor kidney transplantation in patients with preformed donor-specific antibodies2019In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 19, no 10, p. 2865-2875Article in journal (Refereed)
    Abstract [en]

    The presence of preformed donor-specific antibodies in transplant recipients increases the risk of acute antibody-mediated rejection (AMR). Results of an open-label single-arm trial to evaluate the safety and efficacy of eculizumab in preventing acute AMR in recipients of deceased-donor kidney transplants with preformed donor-specific antibodies are reported. Participants received eculizumab as follows: 1200 mg immediately before reperfusion; 900 mg on posttransplant days 1, 7, 14, 21, and 28; and 1200 mg at weeks 5, 7, and 9. All patients received thymoglobulin induction therapy and standard maintenance immunosuppression including steroids. The primary end point was treatment failure rate, a composite of biopsy-proved grade II/III AMR (Banff 2007 criteria), graft loss, death, or loss to follow-up, within 9 weeks posttransplant. Eighty patients received transplants (48 women); the median age was 52 years (range 24-70 years). Observed treatment failure rate (8.8%) was significantly lower than expected for standard care (40%; P < .001). By 9 weeks, 3 of 80 patients had experienced AMR, and 4 of 80 had experienced graft loss. At 36 months, graft and patient survival rates were 83.4% and 91.5%, respectively. Eculizumab was well tolerated and no new safety concerns were identified. Eculizumab has the potential to provide prophylaxis against injury caused by acute AMR in such patients (EudraCT 2010-019631-35).

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  • 16. Goto, Masafumi
    et al.
    Holgersson, Jan
    Kumagai-Braesch, M.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    The ADP/ATP ratio: A novel predictive assay for quality assessment of isolated pancreatic islets2006In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 6, no 10, p. 2483-2487Article in journal (Refereed)
    Abstract [en]

    The current standard assays for islet product release criteria are unable to predict the outcome after clinical islet transplantation. Therefore, establishment of reliable and rapid assays enabling pre-transplantation prediction of islet potency is warranted. In the present study, we have evaluated the adenosine diphosphate (ADP)/adenosine triphosphate (ATP) test, the glucose-stimulated insulin release, the loss of islets during the first 24 h in culture, and the insulin/deoxyribonucleic acid as predictive assays for the ability of isolated porcine islets to cure athymic mice with streptozotocin-induced diabetes. From the results presented, it is concluded that the measurement of the ADP/ATP ratio was the only test that correlated with transplantation outcome. In summary, we propose that the ADP/ATP assay is worthwhile as applied to human islet transplantation and seek to validate it as a rapid and potent predictor of transplant outcome.

  • 17. Hagness, M.
    et al.
    Guren, T.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Pfeiffer, P.
    Line, P.
    Solheim, J.
    Tveitt, K.
    Dueland, S.
    Foss, A.
    Liver Transplantation or Chemotherapy for Non-Resectable Colorectal Liver Metastases?2014In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 14, p. 166-166Article in journal (Other academic)
  • 18. Heller, T.
    et al.
    van Gelder, T.
    Budde, K.
    de Fijter, J. W.
    Kuypers, D.
    Arns, W.
    Schmidt, J.
    Rostaing, L.
    Powis, S. H.
    Claesson, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Macphee, I. A .M.
    Pohanka, E.
    Engelmayer, J.
    Brandhorst, G.
    Oellerich, M.
    Armstrong, V. W.
    Plasma concentrations of mycophenolic acid acyl glucuronide are not associated with diarrhea in renal transplant recipients2007In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 7, no 7, p. 1822-1831Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to determine whether plasma concentrations of the acyl (AcMPAG) and phenolic (MPAG) glucuronide metabolites of mycophenolic acid (MPA) were related to diarrhoea in renal transplant patients on mycophenolate mofetil (MMF) with cyclosporine (CsA) or tacrolimus (TCL). Blood samples (0, 30, 120 min) were taken at days 3, 10, week 4, months 3, 6 and 12 for determination of MPA, MPAG and AcMPAG. MPA-AUC was estimated using validated algorithms. Two hour AUCs were calculated for MPAG and AcMPAG. Immunosuppressive therapy consisted of CsA/MMF (n= 110) and of TCL/MMF (n= 180). In 70/290 (24%) patients 86 episodes of diarrhoea were recorded during 12 months. Significantly more patients on TCL (31.1%) suffered from diarrhea compared to CsA (12.7%). MMF dose, MPA-AUC and the 2 h AUCs of MPAG and AcMPAG did not differ between patients with and without diarrhoea. Plasma AcMPAG and MPAG concentrations were substantially higher in patients on CsA compared with TCL, while MPA-AUC was lower in the former group. These data support the concept that CsA inhibits the biliary excretion of MPAG and AcMPAG, thereby potentially reducing the risk of intestinal injury through enterohepatic recycling of MPA and its metabolites.

  • 19.
    Hellström, Vivan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Wallgren, AnnaCarin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Tötterman, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Bengtsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Laurell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Lundberg, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Holmström, B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Lorant, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Donor Derived and BK Virus Positive Urologic Cancers After Renal Transplantation2017In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 17, no S3, p. 472-472, article id A188Article in journal (Other academic)
  • 20.
    Holdaas, H.
    et al.
    Rikshospitalet, Oslo, Norway.
    Fellstrom, B.
    Fellström, B., University Hospital, Uppsala, Sweden.
    Cole, E.
    University Health Network, Toronto, Canada.
    Nyberg, G.
    Sahlgrenska Academy, Göteborg, Sweden.
    Olsson, Anders G.
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Pedersen, T.R.
    Ulleval University Hospital, Oslo, Norway.
    Madsen, S.
    Skejby Hospital, Aarhus, Denmark.
    Gronhagen-Riska, C.
    Grönhagen-Riska, C., Helsinki University Central Hospital, Helsinki, Finland.
    Neumayer, H.-H.
    Charité, Universitätsmedizin, Berlin, Germany.
    Maes, B.
    University Hospital, Leuven, Belgium.
    Ambuhl, P.
    Ambühl, P., University Hospital, Zürich, Switzerland.
    Hartmann, A.
    Rikshospitalet, Oslo, Norway.
    Staffler, B.
    Novartis Pharma AG, Basel, Switzerland.
    Jardine, A.G.
    University of Glasgow, Glasgow, United Kingdom.
    Long-term cardiac outcomes in renal transplant recipients receiving fluvastatin: The ALERT extension study2005In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 5, no 12, p. 2929-2936Article in journal (Refereed)
    Abstract [en]

    Renal transplant recipients (RTR) have an increased risk of premature cardiovascular disease. The ALERT study is the first trial to evaluate the effect of statin therapy on cardiac outcomes following renal transplantation. Patients initially randomized to fluvastatin or placebo in the 5-6 year ALERT study were offered open-label fluvastatin XL 80 mg/day in a 2-year extension to the original study. The primary endpoint was time to first major adverse cardiac event (MACE). Of 1787 patients who completed ALERT, 1652 (92%) were followed in the extension. Mean total follow-up was 6.7 years. Mean LDL-cholesterol was 98 mg/dL (2.5 mmol/L) at last follow-up compared to a pre-study level of 159 mg/dL (4.1 mmol/L). Patients randomized to fluvastatin had a reduced risk of MACE (hazards ratio [HR] 0.79, 95% CI 0.63-0.99, p = 0.036), and a 29% reduction in cardiac death or definite non-fatal MI (HR 0.71, 95% CI 0.55-0.93, p = 0.014). Total mortality and graft loss did not differ significantly between groups. Fluvastatin produces a safe and effective reduction in LDL-cholesterol associated with reduced risk of MACE in RTR. The lipid-lowering and cardiovascular benefits of fluvastatin are comparable to those of statins in other patient groups, and support use of fluvastatin in RTR. Copyright © Blackwell Munksgaard 2005.

  • 21. Holdaas, Hallvard
    et al.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jardine, Alan G.
    Clinical practice guidelines for managing dyslipidemias in kidney transplant patients: lessons to be learnt from the assessment of Lescol in renal transplantation (ALERT) trial2005In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 5, no 6, p. 1574-1575Article in journal (Refereed)
  • 22.
    Horneland, R.
    et al.
    Oslo Univ Hosp, Oslo, Norway..
    Guvag, S.
    Oslo Univ Hosp, Oslo, Norway..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Aandahl, E.
    Oslo Univ Hosp, Oslo, Norway..
    Pancreatectomy and Islet Autotransplantation After Combined Split Liver Transplantation and Pancreaticoduodenectomy: A Case Report2017In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 17, no S3, p. 693-694Article in journal (Other academic)
  • 23. Jardine, Alan G.
    et al.
    Holdaas, Hallvard
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Cole, Edward
    Nyberg, Gudrun
    Grönhagen-Riska, Carola
    Madsen, Sören
    Neumayer, Hans-Hellmut
    Maes, Bart
    Ambühl, Patrice
    Olsson, Anders G.
    Holme, Ingar
    Fauchald, Per
    Gimpelwicz, Claudio
    Pedersen, Terje R.
    Fluvastatin prevents cardiac death and myocardial infarction in renal transplant recipients: post-hoc subgroup analyses of the ALERT Study2004In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 4, no 6, p. 988-995Article in journal (Refereed)
    Abstract [en]

    Renal transplant recipients have a greatly increased risk of premature cardiovascular disease. The ALERT study was a multicenter, randomized, double-blind, placebo-controlled trial of fluvastatin (40-80 mg/day) in 2102 renal transplant recipients followed for 5-6 years. The main study used a composite cardiac end-point including myocardial infarction, cardiac death and cardiac interventions. Although reduced by fluvastatin, this primary end-point failed to achieve statistical significance thus precluding analysis of predefined subgroups. Therefore, in the present survival analysis, we used an alternative primary end-point of cardiac death or definite nonfatal myocardial infarction (as used in other cardiac outcome trials) which was significantly reduced by Fluvastatin therapy and permits subgroup analysis. Fluvastatin reduced LDL-cholesterol by 1 mmol/L compared with placebo, and the incidence of cardiac death or definite myocardial infarction was reduced from 104 to 70 events (RR 0.65; 95% CI 0.48, 0.88; p = 0.005). Fluvastatin use was associated with reduction in cardiac death or nonfatal myocardial infarction, which achieved statistical significance in many subgroups. The subgroups included patients at lower cardiovascular risk, who were younger, nondiabetic, nonsmokers and without pre-existing CVD. These data support the early introduction of statins following renal transplantation.

  • 24.
    Johansson, H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Goto, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Dufrane, D.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Elgue, Graciela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Gianello, P.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Low molecular weight dextran sulfate: a strong candidate drug to block IBMIR in clinical islet transplantation2006In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 6, no 2, p. 305-12Article in journal (Refereed)
    Abstract [en]

    The instant blood-mediated inflammatory reaction (IBMIR) is triggered in clinical islet transplantation when human pancreatic islets come in contact with blood and may explain the initial tissue loss associated with this procedure. Low molecular weight dextran sulfate (LMW-DS; MM 5000), today available for clinical use, inhibits both complement and coagulation activation. In a tubing loop model, LMW-DS at concentrations ranging from 0.01 to 1 g/L showed a dose-dependent inhibition of IBMIR with an inhibition of coagulation and complement activation and less consumption of platelets and other blood cells. In blood or plasma APTT was demonstrated to be an excellent method for monitoring the LMW-DS concentration both in vitro and in vivo in a nonhuman primate model. The toxicity was assessed using a glucose challenge test and the pharmacokinetics was tested in the nonhuman primate model. Here, we present a tentative protocol for using LMW-DS in clinical islet transplantation.

  • 25.
    Johansson, Ulrika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Elgue, Graciela
    Nilsson, Bo
    Korsgren, Olle
    Composite islet-endothelial cell grafts: a novel approach to counteract innate immunity in islet transplantation2005In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 5, no 11, p. 2632-2639Article in journal (Refereed)
    Abstract [en]

    An instant blood-mediated inflammatory reaction (IBMIR) is elicited when islets come in contact with blood after intraportal transplantation. In contrast, endothelial cells (EC) readily tolerate contact with blood. A conceivable strategy to overcome IBMIR would be to create composite islet-EC grafts. Human islets were co-cultured with primary human aortic endothelial cells (HAEC) for 2-7 days to obtain 50-90% coverage. HAEC-coated islets were exposed to ABO-identical blood and analyzed with regard to clotting time, signs of inflammation and cell infiltration. Composite islet-HAEC graft survival was assessed after transplantation to athymic (nu/nu) nude mice. Exposed to blood, HAEC-coated islets induced less activation of coagulation and complement compared to control islets. Also, platelet and leukocyte consumption in blood was decreased. Clots with entrapped HAEC-coated islets showed less infiltration of CD11b+ cells. The extent of protection correlated to the level of HAEC coverage. Transplanted composite grafts stained positive for insulin and PECAM-1 demonstrating presence of both islets and HAEC within the islet graft 7 weeks after transplantation. Composite islet-HAEC grafts reduce all components of IBMIR. Refinement of the technique will allow introduction of composite islet-EC grafts in clinical islet transplantation, using autologous EC expanded in vitro and kept frozen until allogeneic islets become available for that specific recipient.

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  • 26.
    Järnum, S.
    et al.
    Hansa Med AB, Lund, Sweden.
    Runström, A.
    Hansa Med AB, Lund, Sweden.
    Winstedt, L.
    Hansa Med AB, Lund, Sweden.
    Lorant, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Kjellman, C.
    Hansa Med AB, Lund, Sweden.
    Effects of IdeS on HLA-SAB, C1q-SAB and CDC-XM2018In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 18, no S4: Oral Abstracts, p. 370-371Article in journal (Other academic)
  • 27.
    Kinch, Amelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Cavelier, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Bengtsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Thunberg, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Pauksens, Karlis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Donor or Recipient Origin of Posttransplant Lymphoproliferative Disorders Following Solid Organ Transplantation2014In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 14, no 12, p. 2838-2845Article in journal (Refereed)
    Abstract [en]

    Previous studies of donor or recipient origin of posttransplant lymphoproliferative disorders (PTLDs) following solid organ transplantation (SOT) have either been small or with selected patient groups. We studied tumor origin in a population-based cohort of 93 patients with PTLD following SOT. Tumor origin of PTLD tissue was analyzed by fluorescence in situ hybridization of the sex chromosomes in cases of sex mismatch between donor and recipient (n=41), or HLA genotyping in cases of identical sex but different HLA type (n=52). Tumor origin of PTLD could be determined in 67 of the 93 cases. All 67 PTLDs were of recipient origin. They were found in recipients of kidney (n=38), liver (n=12), heart (n=10) and lung (n=7). The most common recipient-derived lymphomas were monomorphic B-cell PTLDs (n=45), monomorphic T cell PTLDs (n=9), indolent lymphomas (n=6), and polymorphic PTLD (n=4). Half of the recipient-derived PTLDs were Epstein–Barr virus-positive. Twelve of the recipient-derived PTLDs were located in the grafts: in four cases exclusively and in eight cases in combination with disseminated disease outside the graft. Tumor origin was indeterminable in 26 cases, probably due to low DNA quality. We conclude that the vast majority of PTLDs after SOT was of recipient origin.

  • 28. Koskinen, A. R.
    et al.
    Tukiainen, E.
    Arola, J.
    Nordin, A.
    Hockerstedt, H. K.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Isoniemi, H.
    Jokiranta, T. S.
    Complement Activation During Liver Transplantation: Special Emphasis on Patients With Atypical Hemolytic Uremic Syndrome2011In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 11, no 9, p. 1885-1895Article in journal (Refereed)
    Abstract [en]

    Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy often caused by mutations in complement factor H (CFH), the main regulator of alternative complement pathway. Because CFH is produced mainly by the liver, combined liver-kidney transplantation is a reasonable option in treatment of patients with severe aHUS. We studied complement activation by monitoring activation markers during liver transplantation in two aHUS patients treated extensively with plasma exchange and nine other liver transplantation patients. After the reperfusion, a clear increase in all the activation markers except C4d was observed indicating that the activation occurs mainly through the alternative pathway. Concentration of SC5b-9 was higher in the hepatic than the portal vein indicating complement activation in the graft. Preoperatively and early during the operation, the aHUS patients showed highest C3d concentrations but otherwise their activation markers were similar to the other patients. In the other patients, correlation was found between perioperative SC5b-9 concentration and postoperative alanine aminotransferase and histological changes. This study explains why supply of normal CFH by extensive plasma exchange is beneficial before combined liver-kidney transplantation of aHUS patients. Also the results suggest that perioperative inhibition of the terminal complement cascade might be beneficial if enhanced complement activation is expected.

  • 29. Kraemer, B. K.
    et al.
    Charpentier, B.
    Bäckman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Silva, H. Tedesco, Jr.
    Mondragon-Ramirez, G.
    Cassuto-Viguier, E.
    Mourad, G.
    Sola, R.
    Rigotti, P.
    Ortuno Mirete, J.
    Tacrolimus Once Daily (ADVAGRAF) Versus Twice Daily (PROGRAF) in De Novo Renal Transplantation: A Randomized Phase III Study2010In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 10, no 12, p. 2632-2643Article in journal (Refereed)
    Abstract [en]

    This multicenter, 1:1-randomized, parallel-group, noninferiority study compared the efficacy and safety of twice-daily tacrolimus (Tacrolimus BID; Prograf) and once-daily tacrolimus prolonged release (Tacrolimus QD; Advagraf), combined with steroids and low-dose mycophenolate mofetil without antibody induction, in 667 de novo kidney transplant recipients. A double-blind, double-dummy 24-week period was followed by an open extension of up to 12 months posttransplant. Biopsy-proven acute rejection rate at 24 weeks (primary endpoint, per-protocol analysis) was 15.8% for Tacrolimus BID versus 20.4% for Tacrolimus QD (p = 0.182; treatment difference 4.5%, 95% confidence interval-1.8%, 10.9%, just outside the prespecified 10% noninferiority margin). Kaplan-Meier 12-month patient and graft survival rates were 97.5% and 92.8% for Tacrolimus BID and 96.9% and 91.5% for QD. Both treatment groups showed equally well-maintained renal function at 12 months (mean creatinine clearance approximately 67 mL/min) and similar adverse event profiles. Overall results obtained with either Tacrolimus QD or BID, without antibody induction, were good, supporting use of the once-daily formulation as an effective alternative to the established twice-daily formulation.

  • 30.
    Lorant, Tomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Bengtsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eich, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eriksson, Britt-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Winstedt, Lena
    Hansa Medical AB, Lund, Sweden.
    Järnum, Sofia
    Hansa Medical AB, Lund, Sweden.
    Stenberg, Yvonne
    Hansa Medical AB, Lund, Sweden.
    Robertson, Anna-Karin
    Hansa Medical AB, Lund, Sweden.
    Mosén, Kristina
    Hansa Medical AB, Lund, Sweden.
    Björck, Lars
    Department of Clinical Sciences, Division of Infection Medicine, Lund University, Lund, Sweden.
    Bäckman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Wood, Kathryn
    Nuffield Department of Surgical Sciences, Oxford University, Oxford, UK.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Kjellman, Christian
    Hansa Medical AB, Lund, Sweden.
    Safety, immunogenicity, pharmacokinetics, and efficacy of degradation of anti-HLA antibodies by IdeS (imlifidase) in chronic kidney disease patients.2018In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 18, no 11, p. 2752-2762Article in journal (Refereed)
    Abstract [en]

    Safety, immunogenicity, pharmacokinetics, and efficacy of the IgG-degrading enzyme of Streptococcus pyogenes (IdeS [imlifidase]) were assessed in a single-center, open-label ascending-dose study in highly sensitized patients with chronic kidney disease. Eight patients with cytotoxic PRAs (median cytotoxic PRAs of 64%) at enrollment received 1 or 2 intravenous infusions of IdeS on consecutive days (0.12 mg/kg body weight ×2 [n = 3]; 0.25 mg/kg ×1 [n = 3], or 0.25 mg/kg ×2 [n = 2]). IgG degradation was observed in all subjects after IdeS treatment, with <1% plasma IgG remaining within 48 hours and remaining low up to 7 days. Mean fluorescence intensity values of HLA class I and II reactivity were substantially reduced in all patients, and C1q binding to anti-HLA was abolished. IdeS also cleaved the IgG-type B cell receptor on CD19+ memory B cells. Anti-IdeS antibodies developed 1 week after treatment, peaking at 2 weeks. A few hours after the second IdeS infusion, 1 patient received a deceased donor kidney offer. At enrollment, the patient had a positive serum crossmatch (HLA-B7), detected by complement-dependent cytotoxicity, flow cytometry, and multiplex bead assays. After IdeS infusion (0.12 mg/kg ×2) and when the HLA-incompatible donor (HLA-B7+ ) kidney was offered, the HLA antibody profile was negative. The kidney was transplanted successfully.

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  • 31. Lundberg, J.
    et al.
    Stone-Elander, S.
    Zhang, X. -M
    Korsgren, O.
    Jonsson, Stefan
    KTH, School of Industrial Engineering and Management (ITM), Materials Science and Engineering, Mechanical Metallurgy.
    Holmin, S.
    Endovascular Method for Transplantation of Insulin-Producing Cells to the Pancreas Parenchyma in Swine2014In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 14, no 3, p. 694-700Article in journal (Refereed)
    Abstract [en]

    Insulin-producing cells are transplanted by portal vein injection as an alternative to pancreas transplantation in both clinical and preclinical trials. Two of the main limitations of portal vein transplantation are the prompt activation of the innate immunity and concomitant loss of islets and a small but significant risk of portal vein thrombosis. Furthermore, to mimic physiological release, the insulin-producing cells should instead be located in the pancreas. The trans-vessel wall approach is an endovascular method for penetrating the vessel wall from the inside. In essence, a working channel is established to the parenchyma of organs that are difficult to access by percutaneous technique. In this experiment, we accessed the extra-vascular pancreatic parenchyma in swine by microendovascular technique and injected methylene blue, contrast fluids and insulin-producing cells without acute adverse events. Further, we evaluated the procedure itself by a 1-year angiographical follow-up, without adverse events. This study shows that the novel approach utilizing endovascular minimal invasiveness coupled to accurate trans-vessel wall placement of an injection in the pancreatic parenchyma with insulin-producing cells is possible. In clinical practice, the potential benefits compared to portal vein cell transplantation should significantly improve endocrine function of the graft and potentially reduce adverse events. This study presents one-year follow-up safety data on the microendovascular trans-vessel wall technique and shows that the technique can be used to transplant insulin-producing cells to the swine pancreas parenchyma.

  • 32. Lundberg, J.
    et al.
    Stone-Elander, S.
    Zhang, X. -M
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Jonsson, S.
    Holmin, S.
    Endovascular Method for Transplantation of Insulin-Producing Cells to the Pancreas Parenchyma in Swine2014In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 14, no 3, p. 694-700Article in journal (Refereed)
    Abstract [en]

    Insulin-producing cells are transplanted by portal vein injection as an alternative to pancreas transplantation in both clinical and preclinical trials. Two of the main limitations of portal vein transplantation are the prompt activation of the innate immunity and concomitant loss of islets and a small but significant risk of portal vein thrombosis. Furthermore, to mimic physiological release, the insulin-producing cells should instead be located in the pancreas. The trans-vessel wall approach is an endovascular method for penetrating the vessel wall from the inside. In essence, a working channel is established to the parenchyma of organs that are difficult to access by percutaneous technique. In this experiment, we accessed the extra-vascular pancreatic parenchyma in swine by microendovascular technique and injected methylene blue, contrast fluids and insulin-producing cells without acute adverse events. Further, we evaluated the procedure itself by a 1-year angiographical follow-up, without adverse events. This study shows that the novel approach utilizing endovascular minimal invasiveness coupled to accurate trans-vessel wall placement of an injection in the pancreatic parenchyma with insulin-producing cells is possible. In clinical practice, the potential benefits compared to portal vein cell transplantation should significantly improve endocrine function of the graft and potentially reduce adverse events. This study presents one-year follow-up safety data on the microendovascular trans-vessel wall technique and shows that the technique can be used to transplant insulin-producing cells to the swine pancreas parenchyma.

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  • 33. Mjörnstedt, L.
    et al.
    Sörensen, S. S.
    von zur Mühlen, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Jespersen, B.
    Hansen, J. M.
    Bistrup, C.
    Andersson, H.
    Gustafsson, B.
    Undset, L. H.
    Fagertun, H.
    Solbu, D.
    Holdaas, H.
    Improved Renal Function After Early Conversion From a Calcineurin Inhibitor to Everolimus: a Randomized Trial in Kidney Transplantation2012In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 12, no 10, p. 2744-2753Article in journal (Refereed)
    Abstract [en]

    In an open-label, multicenter trial, de novo kidney transplant recipients at low to medium immunological risk were randomized at week 7 posttransplant to remain on CsA (n = 100, controls) or convert to everolimus (n = 102), both with enteric-coated mycophenolate sodium and corticosteroids. The primary endpoint, change in measured GFR (mGFR) from week 7 to month 12, was significantly greater with everolimus than controls: 4.9 (11.8) mL/min versus 0.0 (12.9) mL/min (p = 0.012; analysis of covariance [ANCOVA]). Per protocol analysis demonstrated a more marked difference: an increase of 8.7 (11.2) mL/min with everolimus versus a decrease of 0.4 (12.0) mL/min in controls (p < 0.001; ANCOVA). There were no differences in graft or patient survival. The 12-month incidence of biopsy-proven acute rejection (BPAR) was 27.5% (n = 28) with everolimus and 11.0% (n = 11) in controls (p = 0.004). All but two episodes of BPAR in each group were mild. Adverse events occurred in 95.1% of everolimus patients and 90.0% controls (p = 0.19), with serious adverse events in 53.9% and 38.0%, respectively (p = 0.025). Discontinuation because of adverse events was more frequent with everolimus (25.5%) than controls (3.0%; p = 0.030). In conclusion, conversion from CsA to everolimus at week 7 after kidney transplantation was associated with a greater improvement in mGFR at month 12 versus CNI-treated controls but discontinuations and BPAR were more frequent.

  • 34.
    Olsson, Anders
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Jardine, A
    Holdaas, H
    Fellström, B
    Cole, E
    Nyberg, G
    Grönhagen-Riska, C
    Madsen, S
    Neumayer, H-H
    Maes, B
    Fluvastatin prevents cardiac death and myocardial infarction in renal transplant recipients: Post-hoc subgroup analyses of the ALERT study2004In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 4, no 6, p. 988-995Article in journal (Refereed)
    Abstract [en]

    Renal transplant recipients have a greatly increased risk of premature cardiovascular disease. The ALERT study was a multicenter, randomized, double-blind, placebo-controlled trial of fluvastatin (40-80 mg/day) in 2102 renal transplant recipients followed for 5-6 years. The main study used a composite cardiac end-point including myocardial infarction, cardiac death and cardiac interventions. Although reduced by fluvastatin, this primary end-point failed to achieve statistical significance thus precluding analysis of predefined subgroups. Therefore, in the present survival analysis, we used an alternative primary end-point of cardiac death or definite nonfatal myocardial infarction (as used in other cardiac outcome trials) which was significantly reduced by Fluvastatin therapy and permits subgroup analysis. Fluvastatin reduced LDL-cholesterol by 1 mmol/L compared with placebo, and the incidence of cardiac death or definite myocardial infarction was reduced from 104 to 70 events (RR 0.65, 95% CI 0.48, 0.88, p = 0.005). Fluvastatin use was associated with reduction in cardiac death or nonfatal myocardial infarction, which achieved statistical significance in many subgroups. The subgroups included patients at lower cardiovascular risk, who were younger, nondiabetic, nonsmokers and without pre-existing CVD. These data support the early introduction of statins following renal transplantation.

  • 35. Pihlstrom, H.
    et al.
    Dahle, D.
    Mjoen, G.
    Pilz, S.
    Maerz, W.
    Holme, I.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Jardine, A.
    Holdaas, H.
    Hyperparathyroidism in Stable Renal Transplant Recipients Is Associated With All-Cause Mortality and Renal Graft Loss2014In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 14, p. 126-126Article in journal (Other academic)
  • 36. Pihlstrom, H.
    et al.
    Mjoen, G.
    Dahle, D.
    Pilz, S.
    Midtvedt, K.
    Maerz, W.
    Abedini, S.
    Holme, I.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Holdaas, H.
    Symmetric Dimethylarginine as Predictor of Graft Loss and All-Cause Mortality in Renal Transplant Recipients2014In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 14, p. 102-102Article in journal (Other academic)
  • 37.
    Pihlstrøm, H. K.
    et al.
    Natl Hosp Norway, Oslo Univ Hosp, Nephrol Sect, Dept Transplantat Med,Div Surg Inflammatory Med &, Oslo, Norway..
    Mjøen, G.
    Natl Hosp Norway, Oslo Univ Hosp, Nephrol Sect, Dept Transplantat Med,Div Surg Inflammatory Med &, Oslo, Norway..
    Mucha, S.
    Christian Albrechts Univ Kiel, Univ Hosp Schleswig Holstein, Inst Clin Mol Biol, Kiel, Germany..
    Haraldsen, G.
    Univ Oslo, Inst Clin Med, KG Jebsen Inflammat Res Ctr, Oslo, Norway.;Oslo Univ Hosp, Dept Pathol, Oslo, Norway..
    Franke, A.
    Christian Albrechts Univ Kiel, Univ Hosp Schleswig Holstein, Inst Clin Mol Biol, Kiel, Germany..
    Jardine, A.
    Glasgow Cardiovasc Res Ctr, British Heart Fdn, Glasgow, Lanark, Scotland..
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Holdaas, H.
    Natl Hosp Norway, Oslo Univ Hosp, Nephrol Sect, Dept Transplantat Med,Div Surg Inflammatory Med &, Oslo, Norway..
    Melum, E.
    Univ Oslo, Inst Clin Med, KG Jebsen Inflammat Res Ctr, Oslo, Norway.;Natl Hosp Norway, Oslo Univ Hosp, Div Surg Inflammatory Med & Transplantat, Norwegian PSC Res Ctr, Oslo, Norway.;Natl Hosp Norway, Oslo Univ Hosp, Div Surg Inflammatory Med & Transplantat, Internal Med Res Inst, Oslo, Norway.;Natl Hosp Norway, Oslo Univ Hosp, Div Surg Inflammatory Med & Transplantat, Sect Gastroenterol,Dept Transplantat Med, Oslo, Norway..
    Single Nucleotide Polymorphisms and Long-Term Clinical Outcome in Renal Transplant Patients: A Validation Study2017In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 17, no 2, p. 528-533Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) are designed to investigate single nucleotide polymor-phisms (SNPs) and the association with a clinical phenotype. A previous GWAS performed in 300 renal transplant recipients identified two SNPs (rs3811321 and rs6565887) associated with serum creatinine and clinical outcome. We sought to validate these findings. Genotyping of the two SNPs was performed using Taqman assays in 1638 Caucasians participating in the Assessment of LEscol in Renal Transplant (ALERT) study. Primary endpoint was death-censored graft loss, and secondary endpoint was all-cause mortality. Applying Cox regression, no crude association to graft loss was found for rs3811321 on chromosome 14 (hazard ratio [HR] 0.87, 95% CI 0.59-1.29, p = 0.50) or rs6565887 on chromosome 18 (HR 0.88, CI 0.62-1.25, p = 0.48). Multivariable adjustments did not change results, nor did evaluation of the number of risk alleles formed by the two SNPs. No association with mortality was detected. In conclusion, an impact of two SNPs on chromosomes 14 and 18 on death-censored graft survival or all-cause mortality was not confirmed. Our results emphasize the importance of validating findings from high-throughput genetics studies and call for large collaborative research initiatives in the field of transplantation outcomes.

  • 38. Pihlstrøm, Hege K
    et al.
    Mjøen, Geir
    Mucha, Sören
    Franke, Andre
    Jardine, Alan
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Dahle, Dag Olav
    Holdaas, Hallvard
    Melum, Espen
    Genetic markers associated with long term cardiovascular outcome in kidney transplant recipients2019In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 19, no 5, p. 1444-1451Article in journal (Refereed)
    Abstract [en]

    There is a clear genetic contribution to the risk of cardiovascular diseases, and a composite genetic risk score (GRS) based on 27 single nucleotide polymorphisms (SNPs) was reported to predict risk of cardiovascular events in the general population. We aimed to evaluate this risk score in renal transplant recipients, a population with heightened cardiovascular risk, with a yet unknown genetic contribution. This article is protected by copyright. All rights reserved.

  • 39.
    Podesta, Manuel A.
    et al.
    Columbia Univ, Dept Med, Med Ctr, Columbia Ctr Translat Immunol, New York, NY 10032 USA;Univ Milan, Milan, Italy;Ist Ric Farmacol Mario Negri IRCCS, Bergamo, Italy.
    Binder, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. ITB Med AB, Stockholm, Sweden.
    Sellberg, Felix
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. ITB Med AB, Stockholm, Sweden.
    DeWolf, Susan
    Columbia Univ, Dept Med, Med Ctr, Columbia Ctr Translat Immunol, New York, NY 10032 USA.
    Shonts, Brittany
    Columbia Univ, Dept Med, Med Ctr, Columbia Ctr Translat Immunol, New York, NY 10032 USA.
    Ho, Siu-Hong
    Columbia Univ, Dept Med, Med Ctr, Columbia Ctr Translat Immunol, New York, NY 10032 USA.
    Obradovic, Aleksandar
    Columbia Univ, Dept Med, Med Ctr, Columbia Ctr Translat Immunol, New York, NY 10032 USA.
    Waffarn, Elizabeth
    Columbia Univ, Dept Med, Med Ctr, Columbia Ctr Translat Immunol, New York, NY 10032 USA.
    Danzl, Nichole
    Columbia Univ, Dept Med, Med Ctr, Columbia Ctr Translat Immunol, New York, NY 10032 USA.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. ITB Med AB, Stockholm, Sweden.
    Sykes, Megan
    Columbia Univ, Dept Med, Med Ctr, Columbia Ctr Translat Immunol, New York, NY 10032 USA;Columbia Univ, Dept Microbiol & Immunol, Med Ctr, New York, NY 10032 USA;Columbia Univ, Med Ctr, Dept Surg, New York, NY 10032 USA.
    Siplizumab selectively depletes effector memory T cells and promotes a relative expansion of alloreactive regulatory T cells in vitro2020In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 20, no 1, p. 88-100Article in journal (Refereed)
    Abstract [en]

    Siplizumab, a humanized anti-CD2 monoclonal antibody, has been used in conditioning regimens for hematopoietic cell transplantation and tolerance induction with combined kidney-bone marrow transplantation. Siplizumab-based tolerance induction regimens deplete T cells globally while enriching regulatory T cells (Tregs) early posttransplantation. Siplizumab inhibits allogeneic mixed-lymphocyte reactions (MLRs) in vitro. We compared the impact of siplizumab on Tregs versus other T cell subsets in HLA-mismatched allogeneic MLRs using PBMCs. Siplizumab predominantly reduced the percentage of CD4(+) and CD8(+) effector memory T cells, which express higher CD2 levels than naive T cells or resting Tregs. Conversely, siplizumab enriched proliferating CD45RA(-) FoxP3(HI) cells in MLRs. FoxP3 expression was stable over time in siplizumab-containing cultures, consistent with enrichment for bona fide Tregs. Consistently, high-throughput TCR beta CDR3 sequencing of sorted unstimulated and proliferating T cells in MLRs revealed selective expansion of donor-reactive Tregs along with depletion of donor-reactive CD4(+) effector/memory T cells in siplizumab-containing MLRs. These results indicate that siplizumab may have immunomodulatory functions that may contribute to its success in tolerance-inducing regimens. Our studies also confirm that naive in addition to effector/memory T cells contribute to the allogeneic MLR and mandate further investigation of the impact of siplizumab on alloreactive naive T cells.

  • 40.
    Poole, Jennifer
    et al.
    Ryerson University, Toronto.
    Shildrick, Margrit
    Queens University, Belfast.
    De Luca, Enza
    University Health Network, University of Toronto.
    Abbey, Susan E
    University Health Network, University of Toronto.
    Mauthner, Oliver E.
    University Health Network, University of Toronto.
    McKeever, Patricia
    Bloorview Research Institute, University of Toronto.
    Ross, Heather J.
    University Health Network, University of Toronto.
    On Heart Transplants and Distress: A Qualitative Response to Selves and Burroughs2010In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 11, no 9, p. 1996-1997Article, review/survey (Other academic)
  • 41.
    Poole, Jennifer
    et al.
    Ryerson University, Toronto.
    Shildrick, Margrit
    Queens University, Belfast.
    De Luca, Enza
    University Health Network, University of Toronto.
    Abbey, Susan E.
    University Health Network, University of Toronto.
    Mauthner, Oliver E.
    University Health Network, University of Toronto.
    McKeever, Patricia
    Bloorview Research Institute, University of Toronto.
    Ross, Heather J.
    University Health Network, University of Toronto.
    The obligation to say 'thank you': Heart transplant recipients experience of writing to the donor family2010In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 11, no 3, p. 619-622Article in journal (Refereed)
    Abstract [en]

    Transplant recipients are encouraged to write anonymous thank-you letters to the donor family. We prospectively explored heart transplant recipients' embodied responses to the 'obligation' to write a thank-you letter using audio/video-taped open-ended interviews (N = 27). Fifteen of the 19 participants, who wrote letters to the donor family, expressed or visually revealed significant distress about issues such as the obligation to write anonymously and the inadequacy of the 'thank-you'. Writing the thank-you letter is not a neutral experience for heart transplant recipients. Rethinking the obligatory practice regarding the thank-you letter and developing the necessary support for the recipient through this process is necessary.

  • 42. Rafael, Ehab
    et al.
    Tibell, A.
    Rydén, M.
    Lundgren, T.
    Sävendahl, L.
    Borgström, B.
    Arnelo, U.
    Isaksson, B.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Permert, Johan
    Intramuscular autotransplantation of pancreatic islets in a 7-year-old child: a 2-year follow-up2008In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 8, no 2, p. 458-62Article in journal (Refereed)
    Abstract [en]

    A 7-year-old girl with severe hereditary pancreatitis underwent total pancreatectomy. A total of 160,000 islet equivalents (6400 islet/kg) were transplanted to the brachioradialis muscle of the right forearm. Her plasma C-peptide level was undetectable after pancreatectomy but increased to 1.37 ng/mL after 17 days; at this time point, her insulin requirement was 0.75 units of insulin/kg/day. At 5- and 27-months, her hemoglobin A1c (HbA1c) and insulin requirements were 4.5 and 5.3% and 0.3 and 0.18 units/kg/day, respectively. Basal and stimulated C-peptide levels were 0.67 +/- 0.07 and 3.36 +/- 1.37 ng/mL, respectively. Stimulated insulin levels were 30% higher in the islet-bearing arm compared to the contralateral arm after glucagon stimulation. After surgery and islet transplantation, the quality of life improved dramatically and she gained 8 kg of weight. In summary, a normal HbA1c, a low insulin requirement and the absence of recurrent hypoglycemia and the gradient of insulin between the arms indicate that the intramuscularly transplanted islets contribute to a long-term clinically significant metabolic control.

  • 43. Russ, G R
    et al.
    Tedesco-Silva, H
    Kuypers, D R
    Cohney, S
    Langer, R M
    Witzke, O
    Eris, J
    Sommerer, C
    von Zur-Mühlen, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Woodle, E S
    Gill, J
    Ng, J
    Klupp, J
    Chodoff, L
    Budde, K
    Efficacy of Sotrastaurin Plus Tacrolimus After De Novo Kidney Transplantation: Randomized, Phase II Trial Results2013In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 13, no 7, p. 1746-1756Article in journal (Refereed)
    Abstract [en]

    Sotrastaurin, a novel immunosuppressant, blocks early T cell activation through protein kinase C inhibition. Efficacy and safety of sotrastaurin with tacrolimus were assessed in a dose-ranging non-inferiority study in renal transplant recipients. A total of 298 patients were randomized 1:1:1:1 to receive sotrastaurin 100 (n = 77; discontinued in December 2011) or 200 mg (n = 73) b.i.d. plus standard tacrolimus (sTAC; 5-12 ng/mL), sotrastaurin 300 mg (n = 75) b.i.d. plus reduced tacrolimus (rTAC; 2-5 ng/mL) or enteric-coated mycophenolic acid (MPA) plus sTAC (n = 73); all patients received basiliximab and corticosteroids. Composite efficacy failure (treated biopsy-proven acute rejection ≥ grade IA, graft loss, death or loss to follow up) rates at Month 12 were 18.8%, 12.4%, 10.9% and 14.0% for the sotrastaurin 100, 200 and 300 mg, and MPA groups, respectively. The median estimated glomerular filtration rates were 55.7, 53.3, 64.9 and 59.2 mL/min, respectively. Mean heart rates were faster with higher sotrastaurin doses and discontinuations due to adverse events and gastrointestinal adverse events were more common. Fewer patients in the sotrastaurin groups experienced leukopenia than in the MPA group (1.3-5.5% vs. 16.5%). Sotrastaurin 200 and 300 mg had comparable efficacy to MPA in prevention of rejection with no significant difference in renal function between the groups.

  • 44. Simard, J. F.
    et al.
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Kinch, Amelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Brattström, C.
    Ingvar, Å.
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Adami, J.
    Fernberg, P.
    Wilczek, H.
    Ekbom, A.
    Smedby, K. E.
    Pediatric Organ Transplantation and Risk of Premalignant and Malignant Tumors in Sweden2011In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 11, no 1, p. 146-151Article in journal (Refereed)
    Abstract [en]

    Increased cancer risks are well documented in adult organ transplant recipients. However, the spectrum of malignancies and risk in the pediatric organ transplant population are less well described. We identified all solid organ transplanted patients aged < 18 in Sweden between 1970-2007 (n = 536) in the National Patient Register and linked to the Cancer Register. Nationwide rates were used to calculate standardized incidence rate ratios and 95% CI estimating the association between transplant and cancer during maximum 36 years of follow-up. Nearly 7% of pediatric solid organ transplant recipients developed a premalignant or malignant tumor during follow-up. Transplantation was associated with an increased risk of any cancer (n = 24, SIR = 12.5, 95% CI: 8.0-18.6): non-Hodgkin lymphoma (NHL) (n = 13, SIR = 127, 95% CI: 68-217), renal cell (n = 3, SIR = 105, 95% CI: 22-307), vulva/vagina (n = 3, SIR = 665, 95% CI: 137-1934) and nonmelanoma skin cancers (n = 2, SIR = 64.7, 95% CI: 7.8-233.8). NHL typically appeared during childhood, while other tumors were diagnosed during adulthood. Apart from short-term attention toward the potential occurrence of NHL, our results suggest cancer surveillance into adulthood with special attention to skin, kidneys and the female genitalia.

  • 45. Thorsen, T.
    et al.
    Bennet, W.
    Olausson, M.
    Ericzon, B.
    Nowak, G.
    Duraj, Frans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Isoniemi, H.
    Rasmussen, A.
    Karlsen, T.
    Foss, A.
    The Use of Deceased Donors Over 75 Years in Liver Transplantation: a Nordic Collaborative Study2014In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 14, p. 733-733Article in journal (Other academic)
  • 46. Tydén, G.
    et al.
    Mjornstedt, L.
    Ekberg, H.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Is Rituximab Safe to Use in Kidney Transplant Patients?2010In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 10, no 8, p. 1949-1949Article in journal (Refereed)
  • 47. Wadstrom, J.
    et al.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Yamamoto, S.
    von zur-Muhlen, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Single Centre Long-Term Follow-Up of Live Kidney Donors Demonstrates Preserved Kidney Function But the Necessity of a Structured Life-Long Follow-Up2014In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 14, p. 494-494Article in journal (Other academic)
  • 48.
    Wadström, J.
    et al.
    Karolinska Univ Hosp, Dept Transplantat Surg, Huddinge, Sweden; Hamad Med Corp, Dept Surg Transplantat, Doha, Qatar.
    von Zur-Mühlen, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Yamamoto, Shinji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Few Gender Differences in Attitudes and Experiences after Live Kidney Donation, with Minor Changes over Time2018In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 18, no S4: Oral Abstracts, p. 451-451Article in journal (Other academic)
  • 49.
    Wallin, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Wilczek, Henryk
    Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet.
    Nydert, Per S.
    Division of Pediatrics, Childrens Hospital in Huddinge, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Staatz, Christine
    School of Pharmacy, University of Queensland, Brisbane, Australia.
    Population pharmacokinetics of tacrolimus in paediatric liver transplant recipients: a model to describe early post-transplantation apparent clearanceIn: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143Article in journal (Refereed)
    Abstract [en]

     

    In this study 1) the predictive capacity of two previously derived population pharmacokinetic models of tacrolimus in paediatric liver transplant recipients were tested during Bayesian forecasting 2) a new population pharmacokinetic model was developed focusing on the immediate post-transplant period and 3) this new model was applied in a simulation exercise to devise a new dosing scheme for initial oral dosing of tacrolimus.  Pharmacokinetic, demographic and covariate data were collected retrospectively from patient records.  The Abbottbase PKS program was used for Bayesian forecasting.  Actual tacrolimus concentrations were compared to those predicted by the program and bias and precision determined.  The NONMEM program was used for building of a new population pharmacokinetic model.  Factors screened for influence on the pharmacokinetic parameters were weight, age, sex, post-operative day, whole/cut-down donor liver, haematocrit, serum albumin, bilirubin, serum creatinine, creatinine clearance, liver function tests and country of origin.  Data were collected from 20 patients for Bayesian forecasting and from 73 patients for population pharmacokinetic modelling.  Predictive performance of the two previous population models was poor in the immediate post-transplant period (range of precision, bias).  Tacrolimus pharmacokinetics appeared to change rapidly over this period.  During the first and third month after transplantation use of only one previous sample during Bayesian forecasting providing the best predictive performance.  The final population model estimated a typical apparent clearance of tacrolimus of 0.148 L/h/kg0.75 immediately following the transplantation, increasing to a maximum of 1.37 L/h/ kg0.75 and typical apparent distribution volume of 27.2 L/kg.  An alternative initial dosing schedule was developed based on an initial loading dose followed by a maintenance dose that increased with time, with drug dosing based on allometric scaling.

     

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  • 50. Winstedt, L.
    et al.
    Malmqvist, U.
    Bjorck, L.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Bengtsson, M.
    Uppsala University.
    Kjellman, C.
    The IgG Specific Cysteine Protease IdeS: A Novel Candidate Drug for Pre-Transplantation Desensitization2014In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 14, p. 666-666Article in journal (Other academic)
12 1 - 50 of 54
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