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  • 101. Jordan, Stanley C
    et al.
    Lorant, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Choi, Jua
    Kjellman, Christian
    Winstedt, Lena
    Bengtsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Zhang, Xiaohai
    Eich, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Toyoda, Mieko
    Eriksson, Britt-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ge, Shili
    Peng, Alice
    Järnum, Sofia
    Wood, Kathryn J
    Lundgren, Torbjörn
    Wennberg, Lars
    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.
    Villicana, Rafael
    Kahwaji, Joe
    Louie, Sabrina
    Kang, Alexis
    Haas, Mark
    Nast, Cynthia
    Vo, Ashley
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    IgG Endopeptidase in Highly Sensitized Patients Undergoing Transplantation.2017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, no 5, p. 442-453Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Donor-specific antibodies create an immunologic barrier to transplantation. Current therapies to modify donor-specific antibodies are limited and ineffective in the most highly HLA-sensitized patients. The IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS), an endopeptidase, cleaves human IgG into F(ab')2 and Fc fragments inhibiting complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, which suggests that IdeS might be useful for desensitization. We report on the combined experience of two independently performed open-label, phase 1-2 trials (conducted in Sweden and the United States) that assessed the efficacy of IdeS with regard to desensitization and transplantation of a kidney from an HLA-incompatible donor.

    METHODS: We administered IdeS to 25 highly HLA-sensitized patients (11 patients in Uppsala or Stockholm, Sweden, and 14 in Los Angeles) before the transplantation of a kidney from an HLA-incompatible donor. Frequent monitoring for adverse events, outcomes, donor-specific antibodies, and renal function was performed, as were renal biopsies. Immunosuppression after transplantation consisted of tacrolimus, mycophenolate mofetil, and glucocorticoids. Patients in the U.S. study also received intravenous immune globulin and rituximab after transplantation to prevent antibody rebound.

    RESULTS: Recipients in the U.S. study had a significantly longer cold ischemia time (the time elapsed between procurement of the organ and transplantation), a significantly higher rate of delayed graft function, and significantly higher levels of class I donor-specific antibodies than those in the Swedish study. A total of 38 serious adverse events occurred in 15 patients (5 events were adjudicated as being possibly related to IdeS). At transplantation, total IgG and HLA antibodies were eliminated. A total of 24 of 25 patients had perfusion of allografts after transplantation. Antibody-mediated rejection occurred in 10 patients (7 patients in the U.S. study and 3 in the Swedish study) at 2 weeks to 5 months after transplantation; all these patients had a response to treatment. One graft loss, mediated by non-HLA IgM and IgA antibodies, occurred.

    CONCLUSIONS: IdeS reduced or eliminated donor-specific antibodies and permitted HLA-incompatible transplantation in 24 of 25 patients. (Funded by Hansa Medical; ClinicalTrials.gov numbers, NCT02224820 , NCT02426684 , and NCT02475551 .).

  • 102.
    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)
  • 103. Kansoul, H A
    et al.
    Axelsson, R
    Yamamoto, Shinji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Savicheva, I
    Aspelin, P
    Ericzon, B-G
    Gjertsen, H
    Parameters obtained by hepatobiliary scintigraphy have significant correlation with biochemical factors early after liver transplantation2007In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 48, no 6, p. 597-604Article in journal (Refereed)
    Abstract [en]

    Background: Early postoperative hepatobiliary scintigraphy after liver transplantation is performed worldwide, but data on its significance for graft function are currently limited.

    Purpose: To examine the correlation between the result of early postoperative hepatobiliary scintigraphy and pre- and postoperative biochemical parameters in liver transplantation (LTx) patients.

    Material and Methods: Six parameters of hepatobiliary scintigraphy using 99mTc mebrofenin were statistically analyzed in 108 LTx patients: 1) half-life of the activity of elimination of mebrofenin from the blood; 2) total clearance of mebrofenin from the blood due to all possible routes; 3) half-life of the activity due to liver uptake; 4) clearance of mebrofenin from the blood due to liver uptake; 5) time to maximal uptake in the liver; and 6) the hepatic extraction fraction (HEF) and biochemical data. Analysis between patients with preoperative normal liver function, familial amyloid polyneuropathy (FAP), and end-stage liver disease (non-FAP) was also performed.

    Results: Univariate and multivariate analysis revealed that total bilirubin postoperative day 3 correlated with all three scintigraphic parameters, and peak aspartate aminotransferase and alanine aminotransferase correlated with HEF. The analysis between patients with FAP and non-FAP revealed no significant difference of scintigraphic data between the two groups.

    Conclusion: A significant correlation between early postoperative scintigraphic results and biochemical parameters was demonstrated.

  • 104.
    Kinch, Amelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Ekman, Tor
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Fernberg, Pia
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pauksens, Karlis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    A population-based study of 135 lymphomas after solid organ transplantation: The role of Epstein-Barr virus, hepatitis C and diffuse large B-cell lymphoma subtype in clinical presentation and survival.2014In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, no 5, p. 669-679Article in journal (Refereed)
    Abstract [en]

    Background. Epstein-Barr virus (EBV) plays a major role in the development of post-transplant lymphoproliferative disorder (PTLD), but there is an increasing awareness of EBV-negative PTLD. The clinical presentation of EBV-negative PTLD has not been as well characterised as EBV-positive cases. Further, there is limited knowledge on the clinical importance of diffuse large B-cell lymphoma (DLBCL) cell of origin subtype post-transplant. Materials and methods. We studied the role of EBV, hepatitis C (HCV) and DLBCL subtype in clinical presentation and survival in 135 post-transplant lymphomas diagnosed 1980-2006 in a population-based cohort of 10 010 Swedish solid organ transplant recipients. The lymphomas were re-evaluated according to WHO 2008, examined for EBV, and clinical data were collected from medical records. Results. Lymphoma incidence rate was 159/100 000 person-years and is also reported by lymphoma subtype. EBV-negative lymphomas constituted 48% and were associated with HCV infection (p = 0.02), bone marrow involvement (p < 0.001), and T-cell phenotype (p = 0.002). Among DLBCL, 78% were of non-germinal centre subtype, which was associated with EBV-positivity (69%, p = 0.001), early occurrence (p = 0.03), heart/liver/lung/pancreas recipients (p = 0.02), anti-T-cell globulin (p = 0.001), and tacrolimus treatment (p = 0.02). DLBCL subtypes had similar overall survival. Five-year overall survival was 42% in all treated patients. Independent poor prognostic factors were older age, B symptoms, ECOG 2-4, kidney/pancreas/heart recipients, T-cell lymphoma, and HCV-infection. Conclusions. With long follow-up, a large part of PTLD is EBV-negative, due to a high proportion of T-cell lymphomas and low of polymorphic PTLD. EBV-negative PTLD have a different clinical presentation. HCV may play an aetiological role in late-onset PTLD and was revealed as a new prognostic factor for inferior survival that needs to be confirmed in larger studies. The heavier immunosuppression in non-kidney transplantations seems to play a role in the development of non-germinal centre DLBCL. DLBCL cell of origin subtype lacks prognostic importance in the transplant setting.

  • 105.
    Kinch, Amelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Association between HLA-A1 and -A2 types and Epstein-Barr virus status of post-transplant lymphoproliferative disorder2016In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 57, no 10, p. 2351-2358Article in journal (Refereed)
    Abstract [en]

    The susceptibility to Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disorder (PTLD) may be affected by the human leukocyte antigen (HLA) type. We investigated HLA-A and HLA-B allele frequencies, focusing on HLA-A1 and -A2, in a population-based case series of EBV + (n = 60) and EBV- (n = 44) PTLD after solid organ transplantation. The proportion of EBV + PTLD was highest in HLA-A1 homozygotes (100%), lower in carriers of HLA-A1/AX (79%), HLA-A1/A2 (55%), HLA-A2/AX (54%), and lowest in HLA-A2 homozygotes (37%). HLA-A1 type was overrepresented (22% versus 7%, p = 0.05) and HLA-A2 type underrepresented (57% versus 80%, p = 0.01) in patients with EBV + compared with EBV - PTLD. EBV + PTLD in HLA-A1 carriers developed almost exclusively in already EBV-seropositive individuals. EBV status of PTLD was not related to any other HLA-A or HLA-B type. Our findings suggest that HLA-A1 carriers may have an increased risk of EBV + PTLD due to a decreased ability to control the latent EBV infection.

  • 106. Kliem, V
    et al.
    Michel, U
    Burg, M
    Bock, A
    Chapman, J
    Dussol, B
    Fritsche, L
    Lebranchu, Y
    Oppenheimer, F
    Pohanka, E
    Salvadori, M
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Geographical prevalence, risk factors and impact of hepatitis B and C after renal transplantation2009In: Clinical Nephrology, ISSN 0301-0430, Vol. 71, no 4, p. 423-429Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Hepatitis B (HBV) and hepatitis C (HCV) virus infections are major risk factors affecting long-term morbidity and mortality after renal transplantation. Hepatitis prevalence is subject to geographical variations. OBJECTIVE: To compare and analyze the geographical prevalence, risk factors and impact of HBV and HCV infection in multinational cohorts of renal transplant recipients. METHODS: From 1989 - 2002, data on 12,856 kidney transplant recipients in 37 countries were collected within the prospective MOST (Multinational Observational Study in Transplantation). Subgroup analyses of hepatitis-related prevalence, risk factors and impact were conducted on patients whose HBV and HCV status was available at time of transplantation. Countries were substratified according to population prevalence of > or = 5% HBV or > or = 10% HCV. RESULTS: The prevalence of HBV was 2.9%, of HCV 8.7% and of HBV together with HCV 0.4%. Risk factors for hepatitis infection in renal transplant recipients were long dialysis time, retransplantation and blood transfusions. At each study endpoint up to 5 years after transplantation, no significant differences in graft function were observed, although the 1-year acute rejection rate tended to be lower in HCV+ patients. At 5 years post-transplant, there were no differences between the subgroups and regions regarding infections, post-transplant diabetes mellitus or malignancies including PTLD. CONCLUSIONS: Overall, HCV infections are more prevalent than HBV. Despite large geographical differences in prevalence, HBV and HCV status did not appear to have a significant impact on renal graft function, infections, malignancies and post-transplant diabetes mellitus up to 5 years after renal transplantation throughout the MOST countries.

  • 107.
    Korsgren, Olle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Lundgren, Torbjörn
    Felldin, Marie
    Foss, Aksel
    Isaksson, B.
    Permert, Johan
    Persson, N. H.
    Rafael, E.
    Rydén, M.
    Salmela, Kaija
    Tibell, Annika
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Optimising islet engraftment is critical for successful clinical islet transplantation2008In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 51, no 2, p. 227-32Article in journal (Refereed)
    Abstract [en]

    Clinical islet transplantation is currently being explored as a treatment for persons with type 1 diabetes and hypoglycaemia unawareness. Although 'proof-of-principle' has been established in recent clinical studies, the procedure suffers from low efficacy. At the time of transplantation, the isolated islets are allowed to embolise the liver after injection in the portal vein, a procedure that is unique in the area of transplantation. A novel view on the engraftment of intraportally transplanted islets is presented that could explain the low efficacy of the procedure.

  • 108.
    Kraemer, B. K.
    et al.
    Heidelberg Univ, Univ Med Ctr Mannheim, Dept Med 5, Theodor Kutzer Ufer 1-3, D-68167 Mannheim, Germany.
    Albano, L.
    Nice Univ Hosp, Dept Nephrol, Nice, France.
    Banas, B.
    Univ Med Ctr Regensburg, Dept Nephrol, Regensburg, Germany.
    Charpentier, B.
    Univ Paris Sud 11, INSERM, UMR 1197, Villejuif, France;Univ Hosp Bicetre, Le Kremlin Bicetre, France.
    Bäckman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery. Uppsala Univ Hosp, Dept Transplantat, Uppsala, Sweden.
    Tedesco-Silva, H., Jr.
    Univ Fed Sao Paulo, Hosp Rim, Div Nephrol, Sao Paulo, Brazil.
    Lehner, F.
    Hannover Med Sch, Gen Visceral & Transplantat Surg, Hannover, Germany.
    Mondragon-Ramirez, G. A.
    Mexican Inst Transplants, Transplant Surg Dept, Morelos, Mexico.
    Glyda, M.
    Dist Publ Hosp, Dept Transplantol & Gen Surg, Poznan, Poland.
    Cassuto-Viguier, E.
    Pasteur 2 Nice Univ Hosp, Renal Transplant Unit, Nice, France.
    Viklicky, O.
    Inst Clin & Expt Med, Dept Nephrol, Prague, Czech Republic.
    Mourad, G.
    Montpellier Univ Hosp, Lapeyronie Hosp, Dept Nephrol Dialysis & Transplantat, Montpellier, France.
    Rigotti, P.
    Padua Univ Hosp, Kidney & Pancreas Transplant Unit, Padua, Italy.
    Schleibner, S.
    Astellas Pharma GmbH, Formerly Med Affairs, Munich, Germany.
    Kamar, N.
    Paul Sabatier Univ, CHU Rangueil, Dept Nephrol & Organ Transplantat, Toulouse, France.
    Efficacy of Prolonged- and Immediate-release Tacrolimus in Kidney Transplantation: A Pooled Analysis of Two Large, Randomized, Controlled Trials2017In: Transplantation Proceedings, ISSN 0041-1345, E-ISSN 1873-2623, Vol. 49, no 9, p. 2040-2049Article in journal (Refereed)
    Abstract [en]

    Background. Two large, prospective studies (12-03; OSAKA) compared the efficacy and tolerability of prolonged-release versus immediate-release tacrolimus in kidney transplant patients also receiving mycophenolate mofetil and low-dose corticosteroids (without induction therapy). Methods. Data were combined into one database to compare results over 24 weeks using 3 alternative endpoints: biopsy-confirmed acute rejection (BCAR); the Food and Drug Administration composite endpoint (graft loss, SCAR, and loss to follow-up), and the European Medicines Agency composite endpoint (graft loss, BCAR, and graft dysfunction). The 95% confidence intervals were calculated (10% noninferiority margin). Results. Overall, 633 patients received prolonged-release tacrolimus (12-03, n = 331; OSAKA, n = 302) and 645 received immediate-release tacrolimus (n = 336; n = 309). Baseline characteristics were comparable. Proportionately more patients receiving prolonged-release tacrolimus had trough levels of 5-15 ng/mL on day 1 (60.8%) and 2 (56.6%) versus immediate-release tacrolimus (42.5% and 43.9%, respectively, both P < .001). Efficacy of prolonged-release and immediate-release tacrolimus were similar as assessed by BCAR (13.9% vs 14.1%, respectively), European Medicines Agency composite endpoint (40.3% vs 38.3%) and US Food and Drug Administration composite endpoint (21.5% vs 19.8%). Conclusions. Novel efficacy endpoints as required by the European Medicines Agency and US Food and Drug Administration demonstrate noninferiority of prolonged-release versus immediate-release tacrolimus. Significantly more patients treated with prolonged release tacrolimus versus immediate-release tacrolimus achieved trough levels of 5 to 15 ng/mL early after transplantation.

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  • 109. Kraemer, Bernhard K.
    et al.
    Klinger, Marian
    Vitko, Stefan
    Glyda, Maciej
    Midtvedt, Karsten
    Stefoni, Sergio
    Citterio, Franco
    Pietruck, Frank
    Squifflet, Jean-Paul
    Segoloni, Giuseppe
    Krueger, Bernd
    Sperschneider, Heide
    Banas, Bernhard
    Bäckman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Weber, Markus
    Carmellini, Mario
    Perner, Ferenc
    Claesson, Kerstin
    Marcinkowski, Wojciech
    Ostrowski, Marek
    Senatorski, Grzegorz
    Nordstrom, Johan
    Salmela, Kaija
    Tacrolimus-Based, Steroid-Free Regimens in Renal Transplantation: 3-Year Follow-Up of the ATLAS Trial2012In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 94, no 5, p. 492-498Article in journal (Refereed)
    Abstract [en]

    Background. Long-term use of corticosteroids is associated with considerable morbidity, including cardiovascular and metabolic adverse effects. Methods. This study evaluated the long-term efficacy and safety of two steroid-free regimens compared with a triple immunosuppressive therapy in renal transplant recipients. This was a 3-year follow-up to a 6-month, open-label, randomized, multicenter study. Results. Data from 3 years were available for 421 (93.3%) of 451 patients in the original intent-to-treat population (143 tacrolimus/basiliximab [Tac/Bas], 139 tacrolimus/mycophenolate mofetil [Tac/MMF], and 139 tacrolimus/MMF/steroids [triple therapy]). In the time interval from 6 months to 3 years after transplantation, the incidence of biopsy-proven acute rejection was low and similar (Tac/Bas, 2.1%; Tac/MMF, 2.2%; triple therapy, 2.2%); Most rejection episodes occurred during the first 6 months of the study. Graft survival was high (Kaplan-Meier estimates: 92.7%, 92.5%, and 92.5%), as was patient survival (93.1%, 96.4%, and 97.0%). There were 10 graft losses (n=2, 4, and 4) and 12 patient deaths (n=5, 2, and 5). Renal function was well preserved throughout the study and similar between groups. There was a trend toward improved cardiovascular risk factors in the Tac/Bas group, including reduced total and low-density lipoprotein cholesterol and lower new-onset insulin use. There were no between-group differences in the incidence or type of adverse events. Conclusion. Higher rates of acute rejection early in treatment were seen with the steroid-free regimens, but this did not translate into poorer long-term outcomes, such as graft and patient survival and renal function. A trend for a more favorable cardiovascular risk profile was observed for steroid-free immunosuppression with Tac/Bas.

  • 110. Krämer, Bernhard K.
    et al.
    Klinger, Marian
    Wlodarczyk, Zbigniew
    Ostrowski, Marek
    Midvedt, Karsten
    Stefoni, Sergio
    Citterio, Franco
    Pietruck, Frank
    Squifflet, Jean-Paul
    Segoloni, Giuseppe
    Krüger, Bernd
    Sperschneider, Heide
    Banas, Bernhard
    Bäckman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Weber, Markus
    Carmellini, Mario
    Perner, Ferenc
    Claesson, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Marcinkowski, Wojciech
    Vítko, Stefan
    Senatorski, Grzegorz
    Salmela, Kaija
    Nordström, Johan
    Tacrolimus combined with two different corticosteroid-free regimens compared with a standard triple regimen in renal transplantation: one year observational results2010In: Clinical Transplantation, ISSN 0902-0063, E-ISSN 1399-0012, Vol. 24, no 1, p. E1-E9Article in journal (Refereed)
    Abstract [en]

    Side effects of steroid use have led to efforts to minimize their use in transplantation. Two corticosteroid-free regimens were compared with a triple immunosuppressive therapy. Data from the original intent-to-treat (ITT) population (153 tacrolimus/basiliximab [Tac/Bas], 151 tacrolimus/MMF [Tac/MMF], and 147 tacrolimus/MMF/steroids [control]) were analyzed in a 12-month follow-up. Percentage of graft survival were 92.8%, 95.4%, and 95.9% (KM estimates 89.9%, 95.3%, 95.9%), percentage of surviving patients were 98.7%, 98.0%, and 100% (KM estimates 95.9%, 92.8%, and 100%). During months 7-12, graft loss occurred in 3 Tac/Bas, 2 Tac/MMF, and zero control patients, patient deaths in 1 Tac/Bas, 2 Tac/MMF, and zero control, and biopsy-proven acute rejection episodes in 4 Tac/Bas, 3 Tac/MMF, and zero control. Mean serum creatinine at month 12 was 141.9 +/- 69.6 muM, 144.0 +/- 82.1 muM, and 134.5 +/- 71.2 muM (ns). New-onset insulin use in previously non-diabetic patients at month 12 was 1/138, 6/127, and 4/126. Patient and graft survival as well as renal function at 12 months were not different between patient groups, despite considerably higher rates of acute rejection occurring within the first six months after transplantation in both steroid-free patient groups. Tac/Bas therapy might offer benefits in terms of a trend for a more favorable cardiovascular risk profile.

  • 111.
    Lorant, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Studies of Rejection in Experimental Xenotransplantation2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    One main hurdle to xenotransplantation, i.e. transplantation between different species, is the immunological barrier that the organ meets in the recipient. The aim of this thesis was to characterise xenogeneic rejection mechanisms by using the concordant mouse-to-rat heart transplantation model.

    Graft-infiltrating immune cells could be isolated from both rejecting and non-rejecting grafts using ex vivo propagation, a technique based on incubation of graft biopsies in culture medium for 48 hours. The numbers of recovered T lymphocytes were considerably higher in grafts undergoing cell-mediated rejection than in grafts undergoing acute vascular rejection (AVR) or in non-rejecting transplants. Thus, ex vivo propagation should be a valuable tool for further studies of cell-mediated rejection.

    Cytokine patterns in the grafts, as measured by a quantitative real-time RT-PCR method, showed that AVR and cell-mediated rejection are associated with an increase of both pro-inflammatory cytokines (IL-1β and TNF-α) and more specific cytokines (IL-2, IL-10, IL-12p40 and IFN-γ). These data differed considerably from the patterns seen in the spleens of the recipients. Cell-mediated xenograft rejection was also found to be associated with a local accumulation of hyaluronan.

    Oral administration of xenogeneic cells stimulated a production of antibodies that could induce hyperacute rejection of cardiac xenografts when passively transferred to graft recipients. This is in contrast to several models for autoimmune diseases and allogeneic transplantation where oral administration of antigens is an effective way to induce unresponsiveness. Hence, future attempts to induce oral tolerance in xenotransplantation should be done with caution.

    List of papers
    1. Isolation of mouse-to-rat cardiac xenograft-infiltrating cells by ex vivo propagation
    Open this publication in new window or tab >>Isolation of mouse-to-rat cardiac xenograft-infiltrating cells by ex vivo propagation
    2002 (English)In: Xenotransplantation, Vol. 9, no 3, p. 209-219Article in journal (Refereed) Published
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90061 (URN)
    Available from: 2002-11-21 Created: 2002-11-21 Last updated: 2015-06-15Bibliographically approved
    2. Intragraft cytokine mRNA expression in rejecting and non-rejecting Vascularised Xenografts
    Open this publication in new window or tab >>Intragraft cytokine mRNA expression in rejecting and non-rejecting Vascularised Xenografts
    Show others...
    2003 (English)In: Xenotransplantation, ISSN 0908-665X, E-ISSN 1399-3089, Vol. 10, no 4, p. 311-324Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND:

    The aim of the present study was to further investigate the characteristics of both graft-infiltrating cells and splenocytes during acute vascular rejection (AVR), cell-mediated rejection and non-rejection of vascularized concordant xenografts, by analysing both proinflammatory [interleukin-1beta (IL-1beta) and tumour necrosis factor (TNF-alpha)] and more specific [(IL-2, IL-4, IL-10, IL-12p40 and interferon-gamma (IFN-gamma)] cytokines. A parallel investigation was made of the antibody response of IgM and IgG to the xenografts.

    METHODS:

    Mouse hearts were heterotopically transplanted to the neck vessels of recipient rats. Grafts, spleens and sera were collected from untreated (AVR) and cyclosporin A (CyA) treated animals on day 2 after transplantation. Organs from rats treated with 15-deoxyspergualin (DSG) or CyA and DSG in combination were harvested on both day 2 and day 8. Grafts from DSG-treated rats undergo cell-mediated rejection and stop beating on day 9 and forth, while CyA + DSG treatment results in long-term graft survival. Real-time quantitative reverse transcriptase polymerase chain reaction (RT-PCR) was applied for analysis of intragraft and splenic cytokine messenger RNA (mRNA) expression. The phenotypes of the graft infiltrating cells were characterized by immunohistochemistry. The antibody response was investigated by means of immunofluorescence, haemagglutination and flow cytometry.

    RESULTS:

    All the studied cytokines (IL-1beta, IL-2, IL-4, IL-10, IL-12p40, IFN-gamma and TNF-alpha) were up-regulated in the grafts from rejecting untreated (day 2) and DSG-treated animals (day 8) in comparison with grafts from CyA + DSG treated animals (day 8). On day 2 under immunosuppression with CyA, DSG or CyA + DSG no or low cytokine mRNA levels were found. The mRNA levels of IL-2, IL-4 and IFN-gamma in the spleens were suppressed under both DSG- and CyA + DSG treatment on day 8. Immunofluorescence showed deposits of both IgM and IgG in grafts from untreated, CyA-treated (day 2) and DSG-treated (day 8) animals, while CyA + DSG treatment diminished these deposits on both day 2 and day 8. No circulating antibodies were identified in either group.

    CONCLUSION:

    We hereby conclude that both AVR on day 2 and cell-mediated rejection on day 8 (under DSG treatment) in a concordant cardiac mouse-to-rat xenotransplantation model are associated with an increase of proinflammatory cytokines, T helper 1 (Th1)-associated cytokines as well as IL-10, while immunosuppression with CyA + DSG diminishes the levels of all examined cytokines. Grafts undergoing AVR or cellular rejection are subjected to deposits of both IgM and IgG, although circulating donor specific antibodies are undetectable in serum.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90017 (URN)10.1034/j.1399-3089.2003.02032.x (DOI)12795680 (PubMedID)
    Note

    De två första författarna delar förstaförfattarskapet.

    Available from: 2002-10-11 Created: 2002-10-11 Last updated: 2017-12-14Bibliographically approved
    3. Oral administration of xenogeneic erythrocytes induces production of antibodies that are capable of inducing hyperacute rejection of concordant vascularised xenografts
    Open this publication in new window or tab >>Oral administration of xenogeneic erythrocytes induces production of antibodies that are capable of inducing hyperacute rejection of concordant vascularised xenografts
    Show others...
    (English)Article in journal (Refereed) Submitted
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90063 (URN)
    Available from: 2002-11-21 Created: 2002-11-21 Last updated: 2015-06-15Bibliographically approved
    4. The graft content of hyaluronan is increased during xenograft rejection
    Open this publication in new window or tab >>The graft content of hyaluronan is increased during xenograft rejection
    (English)Article in journal (Refereed) Submitted
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90064 (URN)
    Available from: 2002-11-21 Created: 2002-11-21 Last updated: 2015-06-15Bibliographically approved
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  • 112.
    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.
    Biglarnia, Alireza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    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 Med AB, 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.
    Kjellman, Christian
    Hansa Med AB, Lund, Sweden..
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Rapid Removal Of Anti-Hla Antibodies In Immunized Patients Awaiting Renal Transplantation - A Dose Finding Study Of The Igg Degrading Enzyme Ides2015In: Transplant International, ISSN 0934-0874, E-ISSN 1432-2277, Vol. 28, p. 73-73Article in journal (Other academic)
  • 113.
    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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  • 114.
    Lorant, Tomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Björkland, Anna
    V Antibody response to xenogeneic transfusions: a study in the mouse-to-rat systemManuscript (Other academic)
  • 115.
    Lorant, Tomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Emanuelsson, Cecilia
    Quach, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Graft morphology correlates with fibroblast activity in cardiac allograft rejection2011In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 119, no 9, p. 588-596Article in journal (Refereed)
    Abstract [en]

    Several extracellular matrix substances, such as hyaluronan and fibronectin, may affect graft viability by their involvement in cell adhesion and in migration. These substances are produced locally in the tissue by fibroblasts. The aim of this study was to investigate the activation state of intragraft fibroblasts under various immunosuppressive treatments and to correlate these with morphological parameters. Syngeneic (n = 5) and allogeneic rat (n = 5-6/group) heterotopic heart transplantations were performed. Allogeneically transplanted animals were immunosuppressed with cyclosporine, mycophenolate mofetil or prednisolone. After 10 days, the transplanted hearts were removed for subsequent isolation of intragraft fibroblasts and for evaluation of graft morphology. The hyaluronan synthesis of graft fibroblasts correlated with the cellular infiltration (p < 0.05) and the interstitial oedema (p < 0.05) of the cardiac grafts. In general, proliferation rate and hyaluronan production were of the same magnitude in fibroblasts from allogeneic hearts under immunosuppression with cyclosporine, mycophenolate mofetil or prednisolone as in fibroblasts from syngeneic grafts. A pool of fibroblasts isolated from cardiac grafts of non-immunosuppressed, allogeneically transplanted rats (n = 4) showed considerably higher levels. We concluded that fibroblast activity correlates to the viability of the tissue rather than to the specific drug used for immunosuppression.

  • 116.
    Lorant, Tomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Engstrand, Mats
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Johnsson, Cecilia
    Isolation of mouse-to-rat cardiac xenograft-infiltrating cells by ex vivo propagation2002In: Xenotransplantation, Vol. 9, no 3, p. 209-219Article in journal (Refereed)
  • 117.
    Lorant, Tomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Krook, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Wilton, Jacob
    Olausson, Michael
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Johnsson, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Intragraft cytokine mRNA expression in rejecting and non-rejecting Vascularised Xenografts2003In: Xenotransplantation, ISSN 0908-665X, E-ISSN 1399-3089, Vol. 10, no 4, p. 311-324Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    The aim of the present study was to further investigate the characteristics of both graft-infiltrating cells and splenocytes during acute vascular rejection (AVR), cell-mediated rejection and non-rejection of vascularized concordant xenografts, by analysing both proinflammatory [interleukin-1beta (IL-1beta) and tumour necrosis factor (TNF-alpha)] and more specific [(IL-2, IL-4, IL-10, IL-12p40 and interferon-gamma (IFN-gamma)] cytokines. A parallel investigation was made of the antibody response of IgM and IgG to the xenografts.

    METHODS:

    Mouse hearts were heterotopically transplanted to the neck vessels of recipient rats. Grafts, spleens and sera were collected from untreated (AVR) and cyclosporin A (CyA) treated animals on day 2 after transplantation. Organs from rats treated with 15-deoxyspergualin (DSG) or CyA and DSG in combination were harvested on both day 2 and day 8. Grafts from DSG-treated rats undergo cell-mediated rejection and stop beating on day 9 and forth, while CyA + DSG treatment results in long-term graft survival. Real-time quantitative reverse transcriptase polymerase chain reaction (RT-PCR) was applied for analysis of intragraft and splenic cytokine messenger RNA (mRNA) expression. The phenotypes of the graft infiltrating cells were characterized by immunohistochemistry. The antibody response was investigated by means of immunofluorescence, haemagglutination and flow cytometry.

    RESULTS:

    All the studied cytokines (IL-1beta, IL-2, IL-4, IL-10, IL-12p40, IFN-gamma and TNF-alpha) were up-regulated in the grafts from rejecting untreated (day 2) and DSG-treated animals (day 8) in comparison with grafts from CyA + DSG treated animals (day 8). On day 2 under immunosuppression with CyA, DSG or CyA + DSG no or low cytokine mRNA levels were found. The mRNA levels of IL-2, IL-4 and IFN-gamma in the spleens were suppressed under both DSG- and CyA + DSG treatment on day 8. Immunofluorescence showed deposits of both IgM and IgG in grafts from untreated, CyA-treated (day 2) and DSG-treated (day 8) animals, while CyA + DSG treatment diminished these deposits on both day 2 and day 8. No circulating antibodies were identified in either group.

    CONCLUSION:

    We hereby conclude that both AVR on day 2 and cell-mediated rejection on day 8 (under DSG treatment) in a concordant cardiac mouse-to-rat xenotransplantation model are associated with an increase of proinflammatory cytokines, T helper 1 (Th1)-associated cytokines as well as IL-10, while immunosuppression with CyA + DSG diminishes the levels of all examined cytokines. Grafts undergoing AVR or cellular rejection are subjected to deposits of both IgM and IgG, although circulating donor specific antibodies are undetectable in serum.

  • 118.
    Lorant, Tomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Ribbe, Ingar
    Mahteme, Haile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Gustafsson, Ulla-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Graf, Wilhelm
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Sinus Excision and Primary Closure Versus Laying Open in Pilonidal Disease: A Prospective Randomized Trial2011In: Diseases of the Colon & Rectum, ISSN 0012-3706, E-ISSN 1530-0358, Vol. 54, no 3, p. 300-305Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Surgical excision is the standard treatment for chronic pilonidal disease, but all excisional techniques are associated with tissue loss, risk of wound break down, and chronic healing problems. OBJECTIVE: The aim of the study was to compare sinus excision and primary closure vs a laying open technique in a prospective randomized trial. DESIGN, PATIENTS, AND INTERVENTIONS: Eighty patients were randomly assigned to sinus excision and primary closure (n = 39) or laying open (n = 41). Follow-up was performed 1, 3, and 12 months after surgery. MAIN OUTCOME MEASURE: The main outcome measure was the healing rate after 1 year. RESULTS: The healing rate was significantly higher after excision and closure than after laying open at 1 month (20 of 39 vs 8 of 41; P=.005) and 3 months (36 of 38 vs 28 of 39; P=.013) after surgery. At follow-up 12 months after surgery no difference was seen in healing rate between the treatment arms (33 of 37 vs 37 of 38; P=.198). CONCLUSIONS: This prospective randomized trial shows that sinus excision and primary closure results in faster healing than laying open does, but there is no difference in healing rate after 1 year. The laying open procedure is minimally invasive with small risks for the patient, and it might therefore be considered more frequently as the first choice of treatment (www.clinicaltrials.gov. Unique identifier: NCT00997048).

  • 119.
    Lorant, Tomas
    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.
    Johnsson, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    The graft content of hyaluronan is increased during xenograft rejectionArticle in journal (Refereed)
  • 120.
    Lorant, Tomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Johnsson, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    The graft content of hyaluronan is increased during xenograft rejection.2004In: Xenotransplantation, ISSN 0908-665X, Vol. 11, no 3, p. 269-75Article in journal (Refereed)
  • 121.
    Lorant, Tomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Wilton, Jacob
    Olausson, Michael
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Johnsson, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Oral administration of xenogeneic erythrocytes induces production of antibodies that are capable of inducing hyperacute rejection of concordant vascularised xenograftsArticle in journal (Refereed)
  • 122.
    Lundqvist, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Segelsjö, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Andersson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Magnusson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Biglarnia, Ali-Reza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Measurement of transplanted pancreatic volume using computed tomography: reliability by intra- and inter-observer variability2012In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 53, no 9, p. 966-972Article in journal (Refereed)
    Abstract [en]

    Background

    Unlike other solid organ transplants, pancreas allografts can undergo a substantial decrease in baseline volume after transplantation. This phenomenon has not been well characterized, as there are insufficient data on reliable and reproducible volume assessments. We hypothesized that characterization of pancreatic volume by means of computed tomography (CT) could be a useful method for clinical follow-up in pancreas transplant patients.

    Purpose

    To evaluate the feasibility and reliability of pancreatic volume assessment using CT scan in transplanted patients.

    Material and Methods

    CT examinations were performed on 21 consecutive patients undergoing pancreas transplantation. Volume measurements were carried out by two observers tracing the pancreatic contours in all slices. The observers performed the measurements twice for each patient. Differences in volume measurement were used to evaluate intra- and inter-observer variability.

    Results

    The intra-observer variability for the pancreatic volume measurements of Observers 1 and 2 was found to be in almost perfect agreement, with an intraclass correlation coefficient (ICC) of 0.90 (0.77-0.96) and 0.99 (0.98-1.0), respectively. Regarding inter-observer validity, the ICCs for the first and second measurements were 0.90 (range, 0.77-0.96) and 0.95 (range, 0.85-0.98), respectively.

    Conclusion

    CT volumetry is a reliable and reproducible method for measurement of transplanted pancreatic volume.

  • 123.
    Lundqvist, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Duraj, Frans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Wadström, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Biglarnia, Ali-Reza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Ureteroperitoneostomy: a rare complication after kidney transplantation2011In: Transplant International, ISSN 0934-0874, E-ISSN 1432-2277, Vol. 24, no 9, p. e75-e76Article in journal (Refereed)
  • 124.
    Maffi, Paola
    et al.
    IRCCS Osped San Raffaele, San Raffaele Diabet Res Inst, Milan, Italy.
    Lundgren, Torbjorn
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Karolinska, Sweden.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Rafael, Ehab
    Skane Univ Hosp, Malmo, Sweden.
    Shaw, James A. M.
    Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England;Newcastle Upon Tyne Hosp NHS Fdn Trust, Freeman Hosp, Newcastle Upon Tyne, Tyne & Wear, England.
    Liew, Aaron
    Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England;Newcastle Upon Tyne Hosp NHS Fdn Trust, Freeman Hosp, Newcastle Upon Tyne, Tyne & Wear, England.
    Saudek, Frantisek
    Inst Clin & Expt Med, Prague, Czech Republic.
    Witkowski, Piotr
    Univ Chicago Med, Transplantat Inst, Chicago, IL USA.
    Golab, Karolina
    Univ Chicago Med, Transplantat Inst, Chicago, IL USA.
    Bertuzzi, Federico
    Osped Niguarda Ca Granda, Milan, Italy.
    Gustafsson, Bengt
    Univ Gothenburg, Gothenburg, Sweden.
    Daffonchio, Luisa
    Dompe Farmaceut SpA, Dept Res & Dev, Milan, Italy.
    Ruffini, Pier Adelchi
    Dompe Farmaceut SpA, Dept Res & Dev, Milan, Italy.
    Piemonti, Lorenzo
    IRCCS Osped San Raffaele, San Raffaele Diabet Res Inst, Milan, Italy.
    Nano, Rita
    IRCCS Osped San Raffaele, Milan, Italy.
    Mercalli, Alessia
    IRCCS Osped San Raffaele, Milan, Italy.
    Lampasona, Vito
    IRCCS Osped San Raffaele, Milan, Italy.
    Magistretti, Paola
    IRCCS Osped San Raffaele, Milan, Italy.
    Sordi, Valeria
    IRCCS Osped San Raffaele, Milan, Italy.
    Antonio, Secchi
    IRCCS Osped San Raffaele, Milan, Italy.
    Antonioli, Barbara
    Osped Niguarda Ca Granda, Milan, Italy.
    Galuzzi, Marta
    Osped Niguarda Ca Granda, Milan, Italy.
    Tosca, Marta Cecilia
    Osped Niguarda Ca Granda, Milan, Italy.
    De Carlis, Luciano
    Osped Niguarda Ca Granda, Milan, Italy.
    Colussi, Giacomo
    Osped Niguarda Ca Granda, Milan, Italy.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Pollard, Helena
    Skane Univ Hosp, Malmo, Sweden.
    Targeting CXCR1/2 Does Not Improve Insulin Secretion After Pancreatic Islet Transplantation: A Phase 3, Double-Blind, Randomized, Placebo-Controlled Trial in Type 1 Diabetes2020In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 43, no 4, p. 710-718Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Reparixin is an inhibitor of CXCR1/2 chemokine receptor shown to be an effective anti-inflammatory adjuvant in a pilot clinical trial in allotransplant recipients.

    RESEARCH DESIGN AND METHODS: A phase 3, multicenter, randomized, double-blind, parallel-assignment study () was conducted in recipients of islet allotransplants randomized (2:1) to reparixin or placebo in addition to immunosuppression. Primary outcome was the area under the curve (AUC) for C-peptide during the mixed-meal tolerance test at day 75 +/- 5 after the first and day 365 +/- 14 after the last transplant. Secondary end points included insulin independence and standard measures of glycemic control.

    RESULTS: The intention-to-treat analysis did not show a significant difference in C-peptide AUC at both day 75 (27 on reparixin vs. 18 on placebo, P = 0.99) and day 365 (24 on reparixin vs. 15 on placebo, P = 0.71). There was no statistically significant difference between treatment groups at any time point for any secondary variable. Analysis of patient subsets showed a trend for a higher percentage of subjects retaining insulin independence for 1 year after a single islet infusion in patients receiving reparixin as compared with patients receiving placebo (26.7% vs. 0%, P = 0.09) when antithymocyte globulin was used as induction immunosuppression.

    CONCLUSIONS: In this first double-blind randomized trial, islet transplantation data obtained with reparixin do not support a role of CXCR1/2 inhibition in preventing islet inflammation-mediated damage.

  • 125.
    Malenicka, S.
    et al.
    Karolinska Inst, Karolinska Univ Hosp Huddinge, Astrid Lindgren Childrens Hosp, Dept Pediat Gastroenterol Hepatol & Nutr,CLINTEC, Stockholm, Sweden..
    Ericzon, B. -G
    Jorgensen, M. H.
    Rigshosp, Dept Pediat & Adolescent Med, Copenhagen, Denmark..
    Isoniemi, H.
    Univ Helsinki, Dept Transplantat Surg, Cent Hosp, Helsinki, Finland..
    Karlsen, T. H.
    Oslo Univ Hosp, Dept Gastroenterol, Rikshosp, Oslo, Norway..
    Krantz, M.
    Queen Silvia Childrens Hosp, Dept Pediat Gastroenterol Hepatol & Nutr, Gothenburg, Sweden..
    Naeser, V.
    Rigshosp, Fac Med, Copenhagen, Denmark..
    Olausson, M.
    Sahlgrens Univ Hosp, Dept Transplantat Surg, Gothenburg, Sweden..
    Rasmussen, A.
    Rigshosp, Dept Transplantat Surg, Copenhagen, Denmark..
    Rönnholm, K.
    Univ Helsinki, Cent Hosp, Dept Pediat Nephrol, Helsinki, Finland..
    Sanengen, T.
    Oslo Univ Hosp, Dept Pediat Gastroenterol, Rikshosp, Oslo, Norway..
    Scholz, Tim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery. Univ Uppsala Hosp, Dept Transplantat Surg, Uppsala, Sweden..
    Fischler, B.
    Karolinska Inst, Karolinska Univ Hosp Huddinge, Astrid Lindgren Childrens Hosp, Dept Pediat Gastroenterol Hepatol & Nutr,CLINTEC, Stockholm, Sweden..
    Nemeth, A.
    Karolinska Inst, Karolinska Univ Hosp Huddinge, Astrid Lindgren Childrens Hosp, Dept Pediat Gastroenterol Hepatol & Nutr,CLINTEC, Stockholm, Sweden..
    Impaired intention-to-treat survival after listing for liver transplantation in children with biliary atresia compared to other chronic liver diseases: 20 years' experience from the Nordic countries2017In: Pediatric Transplantation, ISSN 1397-3142, E-ISSN 1399-3046, Vol. 21, no 2, article id e12851Article in journal (Refereed)
    Abstract [en]

    Biliary atresia (BA) is the most common indication for LT in children. We investigated whether this diagnosis per se, compared to other chronic liver diseases (OCLD), had an influence on patient survival. Data from 421 Scandinavian children, 194 with BA and 227 with OCLD, listed for LT between 1990 and 2010 were analyzed. The intention-to-treat survival and influencing risk factors were studied. Patients with BA had higher risk of death after listing than patients with OCLD. The youngest (< 1 year) and smallest (< 10 kg) children with the highest bilirubin (> 510 mu mol/L), highest INR (> 1.6), and highest PELD score (> 20) listed during 1990s had the worst outcome. Given the same PELD score, patients with BA had higher risk of death than patients with OCLD. For adolescents, low weight/BMI was the only prognostic marker. Impaired intention-to-treat survival in patients with BA was mainly explained by more advanced liver disease in younger ages and higher proportion of young children in the BA group rather than diagnosis per se. PELD score predicted death, but seemed to underestimate the severity of liver disease in patients with BA. Poor nutritional status and severe cholestasis had negative impact on survival, supporting the "sickest children first" allocation policy and correction of malnutrition before surgery.

  • 126.
    Malm, Helene
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Bäckman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Biglarnia, Alireza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Hellström, Vivan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Larsson, Erik
    Lorant, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    von Zuhr-Muhlen, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Nilsson, Thomas
    Sedigh, Amir
    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.
    The Uppsala Experience of Switching from Cni:s to Belatacept after Kidney Transplantation2013In: Transplant International, ISSN 0934-0874, E-ISSN 1432-2277, Vol. 26, p. 92-93Article in journal (Other academic)
  • 127. Mastellos, Dimitrios C.
    et al.
    Yancopoulou, Despina
    Kokkinos, Petros
    Huber-Lang, Markus
    Hajishengallis, George
    Biglarnia, Alireza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Lupu, Florea
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Risitano, Antonio M.
    Ricklin, Daniel
    Lambris, John D.
    Compstatin: a C3-targeted complement inhibitor reaching its prime for bedside intervention2015In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 45, no 4, p. 423-440Article, review/survey (Refereed)
    Abstract [en]

    There is a growing awareness that complement plays an integral role in human physiology and disease, transcending its traditional perception as an accessory system for pathogen clearance and opsonic cell killing. As the list of pathologies linked to dysregulated complement activation grows longer, it has become clear that targeted modulation of this innate immune system opens new windows of therapeutic opportunity for anti-inflammatory drug design. Indeed, the introduction of the first complement-targeting drugs has reignited a vibrant interest in the clinical translation of complement-based inhibitors. Compstatin was discovered as a cyclic peptide that inhibits complement activation by binding C3 and interfering with convertase formation and C3 cleavage. As the convergence point of all activation pathways and a molecular hub for crosstalk with multiple pathogenic pathways, C3 represents an attractive target for therapeutic modulation of the complement cascade. A multidisciplinary drug optimization effort encompassing rational wet' and in silico synthetic approaches and an array of biophysical, structural and analytical tools has culminated in an impressive structure-function refinement of compstatin, yielding a series of analogues that show promise for a wide spectrum of clinical applications. These new derivatives have improved inhibitory potency and pharmacokinetic profiles and show efficacy in clinically relevant primate models of disease. This review provides an up-to-date survey of the drug design effort placed on the compstatin family of C3 inhibitors, highlighting the most promising drug candidates. It also discusses translational challenges in complement drug discovery and peptide drug development and reviews concerns related to systemic C3 interception.

  • 128. Melum, Espen
    et al.
    Friman, Styrbjörn
    Björo, Kristian
    Rasmussen, Allan
    Isoniemi, Helena
    Gjertsen, Henrik
    Bäckman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Oksanen, Antti
    Olausson, Michael
    Duraj, Frans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Ericzon, Bo-Göran
    Hepatitis C impairs survival following liver transplantation irrespective of concomitant hepatocellular carcinoma2007In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 47, no 6, p. 777-783Article in journal (Refereed)
    Abstract [en]

    Background/Aims: Liver transplantation (LTX) is the only curative treatment for end-stage liver disease caused by hepatitis C (HCV). Hepatocellular carcinoma (HCC) is common in patients with HCV cirrhosis. Methods:Two hundred and eighty-two HCV patients listed for LTX in the Nordic countries in a 17-year period were included. For comparison a group of patients with non-viral chronic liver disease (n = 1552) was used. Results:Two hundred and fifty-three (90%) patients received a first liver allograft. HCC was found in 38%, of the explanted livers. Survival at 1, 3 and 5 years was 82%, 69% and 61% vs. 85%, 80%) and 76% for the comparison group (p < 0.0001), this survival difference was also evident when excluding patients with HCC (p = 0.007). HCV patients with HCC had 1, 3 and 5 year survival of 73%, 52% and 46%) compared with 88%, 80% and 71 % for the HCV patients without HCC (p = 0.0005). In an intention-to-treat analysis (from time of acceptance to the waiting list) HCV was also associated with an impaired survival. Conclusions:HCV cirrhosis, which is now also an important indication for LTX in the Nordic countries, and significantly impairs survival following LTX. Concomitant HCC and donor age are the two most important factors contributing to an impaired survival.

  • 129. Mjornstedt, Lars
    et al.
    Sorensen, Soren Schwartz
    von zur Mühlen, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Jespersen, Bente
    Hansen, Jesper M.
    Bistrup, Claus
    Andersson, Helene
    Gustafsson, Bengt
    Solbu, Dag
    Holdaas, Hallvard
    Renal function three years after early conversion from a calcineurin inhibitor to everolimus: results from a randomized trial in kidney transplantation2015In: Transplant International, ISSN 0934-0874, E-ISSN 1432-2277, Vol. 28, no 1, p. 42-51Article in journal (Refereed)
    Abstract [en]

    In a 36-month, open-label, multicenter trial, 202 kidney transplant recipients were randomized at week 7 post-transplant to convert to everolimus or remain on cyclosporine: 182 were analyzed to month 36 (92 everolimus, 90 controls). Mean (SD) change in measured GFR (mGFR) from randomization to month 36 was 1.3 (14.0)ml/min with everolimus versus -1.7 (15.4)ml/min in controls (P=0.210). In patients who remained on treatment, mean mGFR improved from randomization to month 36 by 7.9 (11.5)ml/min with everolimus (n=37) but decreased by 1.4 (14.7)ml/min in controls (n=62) (P=0.001). During months 12-36, death-censored graft survival was 100%, patient survival was 98.9% and 96.7% in the everolimus and control groups, respectively, and 13.0% and 11.1% of everolimus and control patients, respectively, experienced mild biopsy-proven acute rejection (BPAR). Protocol biopsies in a limited number of on-treatment patients showed similar interstitial fibrosis progression. Donor-specific antibodies were present at month 36 in 6.3% (2/32) and 18.0% (9/50) of on-treatment everolimus and control patients with available data (P=0.281). During months 12-36, adverse events were comparable, but discontinuation was more frequent with everolimus (33.7% vs. 10.0%). Conversion from cyclosporine to everolimus at 7weeks post-transplant was associated with a significant benefit in renal function at 3years when everolimus was continued.

  • 130. 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.

  • 131. Moberg, Lisa
    et al.
    Johansson, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Lukinius, Agneta
    Berne, Christian
    Foss, Aksel
    Kallen, Ragnar
    Ostraat, O
    Salmela, Kaija
    Tibell, Annika
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation2002In: Lancet, ISSN 12504401, Vol. 360, no 9350, p. 2039-45Article in journal (Refereed)
  • 132.
    Moberg, Lisa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Johansson, Helena
    Lukinius, Agneta
    Berne, Christian
    Foss, Aksel
    Källén, Ragnar
    Østraat, Øyvind
    Salmela, Kaija
    Tibell, Annika
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation2002In: Lancet, Vol. 360, no December 21/28, p. 2039-2045Article in journal (Refereed)
  • 133.
    Moberg, Lisa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Olsson, Annika
    Berne, Christian
    Felldin, Marie
    Foss, Aksel
    Källen, Ragnar
    Samela, Kaija
    Tibell, Annika
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Nilsson, Bo
    Nicotinamide inhibits tissue factor expression in isolated human pancreatic islets: implications for clincal islet transplantation2003In: Transplantation, ISSN 0041-1337037609-12850, Vol. 76, no 9, p. 1285-1288Article in journal (Refereed)
  • 134.
    Molnár, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Wennberg, Lars
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Islet Engraftment and Revascularization in Clinical and Experimental Transplantation2013In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 22, no 2, p. 243-251Article in journal (Refereed)
    Abstract [en]

    Background:

    Proper revascularization after transplantation is assumed to be crucial forappropriate islet graft function.

    Methods:

    We developed a novel non-invasive imagingmethod, based on adenoviral transduction of islets with a hypoxia responsive reporter gene,for continuous in vivo monitoring of hypoxia in islet grafts in a mouse model. In addition,morphological data was obtained from a deceased patient previously subject to intraportaltransplantation.

    Results:

    We detected only transient hypoxia in a minority of the animalstransplanted. Importantly, a clear response to hypoxia was observed in vitro after removal ofthe islet-grafts on day twenty-eight after transplantation. Also, the morphological data fromthe deceased patient demonstrated an extensive revascularization of the transplanted islets. Infact, no differences could be seen between native, in pancreas biopsies taken prior to isletisolation, and transplanted islets regarding the number, distribution and shape of the bloodvessels. However, fewer small islets (diameter <39μm) were found in the liver compared to those found in native pancreases. Notably, an absolute majority of the transplanted islets were found remaining within the venous lumen, in direct contact with the vessel wall.

    Conclusions:

    In conclusion results presented show less pronounced islet graft hypoxia after subcapsulartransplantation than previously reported using more invasive methods. Also, formation of anextensive intra-islet capillary network, similar to that seen in native islets in the pancreas, wasseen after clinical islet transplantation.

  • 135. Nadalin, Silvio
    et al.
    Biglarnia, Ali Reza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Testa, Giuliano
    Koppara, Tobias R.
    Schaffer, Randolph
    Johnson, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Toetsch, Martin
    Broelsch, Christoph E.
    Malagó, Massimo
    Role and significance of plasma citrulline in the early phase after small bowel transplantation in pigs2007In: Transplant International, ISSN 0934-0874, E-ISSN 1432-2277, Vol. 20, no 5, p. 425-431Article in journal (Refereed)
    Abstract [en]

    A reliable serological marker of acute cellular rejection (ACR) after small bowel transplantation (SBTx) is still missing. Plasma citrulline level (PCL) reflects the functional integrity of intestinal mucosa which is partially lost during ACR. The aim of our study was to investigate the role of PCL as marker of ACR after SBTx. Eighteen German landrace pigs were used and divided into three groups. Group 1 (G1), autologous SBTx (n = 4) as control; group 2 (G2), allogeneic SBTx without immunosuppression (IS) (n = 7) and group 3 (G3), allogeneic SBTx with IS (n = 7). IS consisted of tacrolimus and steroids without induction treatment. Observation period was 14 days. Mucosal biopsies were obtained intraoperatively and daily using a Thiry-Vella loop. ACR was differentiated into indeterminate, mild, moderate and severe using a standardized grading schema. PCL was measured daily. An ACR onset occurred generally from postoperative day 4 both in G2 and G3 as mild form and developed differently in the two groups: moderate to severe in G2 and indeterminate to mild in G3. A significant decline of PCL occurred only in cases of moderate and severe ACR, but not in cases of indeterminate and mild ACR. The PCL failed as a marker in the early diagnosis of ACR and became reliable only when advanced mucosal damage was present.

  • 136. Nilsson, Madeleine
    et al.
    Forsberg, Anna
    Bäckman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Lennerling, Annette
    Persson, Lars-Olof
    The perceived threat of the risk for graft rejection and health-related quality of life among organ transplant recipients2011In: Journal of Clinical Nursing, ISSN 0962-1067, E-ISSN 1365-2702, Vol. 20, no 1-2, p. 274-282Article in journal (Refereed)
    Abstract [en]

    Aims. This study was primarily aimed for developing and testing a valid and reliable instrument that measures perceived threat of the risk for graft rejection after organ transplantation. A second aim was to report descriptive data regarding graft rejection and Health-Related Quality of Life. Background. The most serious risk connected with transplantations besides infection is graft rejection. Design. Non experimental, descriptive involving instrument development and psychometric assessment. Method. Questionnaires about perceived threat of the risk for graft rejection and Health-Related Quality of Life were mailed to 229 OTRs between 19-65 years old. The items were formed from a previous interview study. Patients were transplanted with a kidney, a liver or a heart and/or a lung. All patients with follow-up time of one year +/- three months and three years +/- three months were included. Results. With an 81% response rate, the study comprised of 185 OTRs, who had received either a kidney (n = 117), a liver (n = 39) or heart or lung (n = 29). Three homogenous factors of perceived threat for graft rejection were revealed, labelled 'intrusive anxiety', 'graft-related threat' and 'lack of control'. Tests of internal consistency showed good item-scale convergent and discriminatory validity. A majority of the OTRs scored low levels for 'intrusive anxiety'. The kidney transplant recipients experienced more 'graft-related threat' by acute graft rejection than those transplanted with a liver, heart or lung. Conclusion. In conclusion, this study suggests that it is possible to measure the perceived threat of the risk for graft rejection in three homogenous factors. Relevance to clinical practice. The instrument perceived threat of the risk for graft rejection, might be usable to measure the impact of fear of graft rejection, to predict needs of pedagogical intervention strategies to reduce fear and to improve Health-Related Quality of Life related to graft rejection.

  • 137.
    Nordling, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Brännström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Carlsson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lu, Bo
    St Vincents Hosp Melbourne, Immunol Res Ctr, Melbourne, Vic, Australia.
    Salvaris, Evelyn
    St Vincents Hosp Melbourne, Immunol Res Ctr, Melbourne, Vic, Australia.
    Wanders, Alkwin
    Umea Univ, Dept Med Biosci, Umea, Sweden.
    Buijs, Jos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Cowan, Peter J.
    Univ Melbourne, St Vincents Hosp Melbourne, Immunol Res Ctr, Melbourne, Vic, Australia;Univ Melbourne, Dept Med, Melbourne, Vic, Australia.
    Lorant, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Magnusson, Peetra U.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Enhanced protection of the renal vascular endothelium improves early outcome in kidney transplantation: Preclinical investigations in pig and mouse2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 5220Article in journal (Refereed)
    Abstract [en]

    Ischemia reperfusion injury is one of the major complications responsible for delayed graft function in kidney transplantation. Applications to reduce reperfusion injury are essential due to the widespread use of kidneys from deceased organ donors where the risk for delayed graft function is especially prominent. We have recently shown that coating of inflamed or damaged endothelial cells with a unique heparin conjugate reduces thrombosis and leukocyte recruitment. In this study we evaluated the binding capacity of the heparin conjugate to cultured human endothelial cells, to kidneys from brain-dead porcine donors, and to murine kidneys during static cold storage. The heparin conjugate was able to stably bind cultured endothelial cells with high avidity, and to the renal vasculature of explanted kidneys from pigs and mice. Treatment of murine kidneys prior to transplantation reduced platelet deposition and leukocyte infiltration 24 hours post-transplantation, and significantly improved graft function. The present study thus shows the benefits of enhanced protection of the renal vasculature during cold storage, whereby increasing the antithrombotic and anti-adhesive properties of the vascular endothelium yields improved renal function early after transplantation.

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  • 138. Omar, Faisal
    et al.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Welin, Stellan
    Compensated living kidney donation: a plea for pragmatism2010In: Health Care Analysis, ISSN 1065-3058, E-ISSN 1573-3394, Vol. 18, no 1, p. 85-101Article in journal (Refereed)
    Abstract [en]

    Kidney transplantation is the most efficacious and cost-effective treatment for end-stage renal disease. However, the treatment's accessibility is limited by a chronic shortage of transplantable kidneys, resulting in the death of numerous patients worldwide as they wait for a kidney to become available. Despite the implementation of various measures the disparity between supply and needs continues to grow. This paper begins with a look at the current treatment options, including various sources of transplantable kidneys, for end-stage renal disease. We propose, in accordance with others, the introduction of compensated kidney donation as a means of addressing the current shortage. We briefly outline some of the advantages of this proposal, and then turn to examine several of the ethical arguments usually marshaled against it in a bid to demonstrate that this proposal indeed passes the ethics test. Using available data of public opinions on compensated donation, we illustrate that public support for such a program would be adequate enough that we can realistically eliminate the transplant waiting list if compensation is introduced. We urge a pragmatic approach going forward; altruism in living kidney donation is important, but altruism only is an unsuccessful doctrine.

  • 139. Omar, Faisal
    et al.
    Welin, Stellan
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Reply: Ethical Perspectives on Living Donor Organ Transplantation in Asia2010In: Liver transplantation, ISSN 1527-6465, E-ISSN 1527-6473, Vol. 16, no 7, p. 917-917Article in journal (Refereed)
  • 140.
    Penno, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Johnsson, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Ultrasmall iron oxide particle contrast agent and MRI can be used to monitor the effect of anti-rejection treatment2007In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 84, no 3, p. 374-379Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The purpose of the study was to investigate the feasibility of monitoring anti-rejection treatment using a blood pool contrast agent and magnetic resonance (MR) imaging. METHODS: Allogeneic heterotopic heart transplantations in rats were performed. In one group (treated group), a mild acute rejection was developed and subsequently treated and MR imaging was performed before and after anti-rejection treatment. In the other group (nontreated group), a mild acute rejection was developed and allowed to progress without treatment and MR examinations were performed before and after the advance of the acute rejection. After injecting ultrasmall superparamagnetic contrast agent, the relative change of signal intensity (SI) over time was measured. The SI difference between both radiological investigations for every animal was calculated; hence, every animal served as its own control. RESULTS: In both treated and nontreated groups, a significant difference over time was found between the two MR examinations seen as a decrease in the treated group and an increase in the nontreatment group. CONCLUSION: It is concluded that the effect of anti-rejection treatment can be detected using a blood pool agent and MR imaging, as a change in SI corresponding to changes in the vascular permeability.

  • 141.
    Penno, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Johnsson, C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Macrophage uptake of ultra-small iron oxide particles for magnetic resonance imaging in experimental acute cardiac transplant rejection2006In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 47, no 3, p. 264-271Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    To discriminate between acutely rejecting and non-rejecting transplanted hearts using a blood pool contrast agent and T2* magnetic resonance imaging (MRI) in a clinical 1.5T scanner.

    MATERIAL AND METHODS:

    Allogeneic and syngeneic heterotopic heart transplantations were performed in rats. One allogeneic and one syngeneic group each received either the ultra-small iron oxide particle (USPIO), at two different doses, or no contrast agent at all. MRI was performed on postoperative day 6. Immediately after the MR scanning, contrast agent was injected and a further MRI was done 24 h later. Change in T2* was calculated.

    RESULTS:

    No significant difference in change in T2* could be seen between rejecting and non-rejecting grafts in either of the doses, or in the control groups. There was a difference between the allogeneic group that received the higher contrast agent dose and the allogeneic group that did not receive any contrast agent at all.

    CONCLUSION:

    In our rat model, measurements of T2* after myocardial macrophage uptake of AMI-227 in a clinical 1.5T scanner were not useful for the diagnosis of acute rejection.

  • 142.
    Purins, Karlis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Sedigh, Amir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Molnar, Christian
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lorant, Tomas
    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.
    Wennberg, Lars
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Lewén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Standardized experimental brain death model for studies of intracranial dynamics, organ preservation, and organ transplantation in the pig2011In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 39, no 3, p. 512-517Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:: Brain death impairs organ function and outcome after transplantation. There is a need for a brain death model to allow studies of organ viability and preservation. For neurointensive care research, it is also of interest to have a relevant brain death model for studies of intracranial dynamics and evaluation of cerebral monitoring devices. Therefore, the objective was to develop a standardized clinically relevant brain death model. METHODS:: Six pigs of both sexes (10-12 wks old; mean weight, 24.5 ± 1.4 kg) were included. Mean arterial blood pressure, heart rate, intracranial pressure, intracranial compliance, cerebral perfusion pressure, and brain tissue oxygenation (BtiPo2) were recorded during stepwise elevation of intracranial pressure by inflation of an epidural balloon catheter with saline (1 mL/20 mins). Brain death criteria were decided to be reached when cerebral perfusion pressure was <0 mm Hg for 60 mins and at least 10 mL saline was inflated epidurally. BtiPo2 and arterial injections of microspheres were used for confirmation of brain death. RESULTS:: A gradual volume-dependent elevation of intracranial pressure was observed. After 10 mL of balloon infusion, mean intracranial pressure was 89.8 ± 9.7 (sd) mm Hg. Intracranial compliance decreased from 0.137 ± 0.069 mL/mm Hg to 0.007 ± 0.001 mL/mm Hg. The mean arterial pressure decreased and the heart rate increased when the intracranial volume was increased to between 5 and 6 mL. All animals showed cerebral perfusion pressure ≤0 after 7 to 10 mL of infusion. In all animals, the criteria for brain death with negative cerebral perfusion pressure and BtiPo2 ∼0 mm Hg were achieved. Only a negligible amount of microspheres were found in the cerebrum, confirming brain death. The kidneys showed small foci of acute tubular necrosis. CONCLUSIONS:: The standardized brain death model designed in pigs simulates the clinical development of brain death in humans with a classic pressure-volume response and systemic cardiovascular reactions. Brain death was convincingly confirmed.

  • 143. 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.

  • 144. Rydgard, KJ
    et al.
    Song, Z
    Foss, A
    Östraat, Ö
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Wennberg, L
    Lundgren, T
    Tibell, A
    Groth, C
    Korsgren, O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Procurement of human pancreases for islet isolation - the initiation of a Scandinavian collaborative network2001Other (Other academic)
  • 145.
    Rügheimer, Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Johnsson, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Renal Hyaluronan Content During Experimental Uncontrolled Diabetes in Rats2008In: Journal of Physiology and Pharmacology, ISSN 0867-5910, E-ISSN 1899-1505, Vol. 59, no 1, p. 115-128Article in journal (Refereed)
    Abstract [en]

    With diabetes mellitus, the ability of the kidneys to maintain fluid balance is affected. Hyperglycaemia increases production of hyaluronan in cultured kidney cells implying that diabetes promotes induction of hyaluronan in the kidney. The aim of the present study was to determine if the interstitial matrix component hyaluronan is differently distributed within the kidney in diabetic rats compared to non-diabetic rats. Furthermore, to test if diabetic rats are able to respond with diuresis upon a hypotonic fluid load. The normal heterogeneous intrarenal distribution of hyaluronan was confirmed in non-diabetic control rats, with 60-fold more in the papilla than in the cortex. In diabetic animals, the cortical hyaluronan was unaffected but the papillary hyaluronan content was 3-fold higher than in non-diabetic rats. This increase correlated with a more than three-fold induction of the papillary hyaluronansynthase 2 mRNA expression. In non-diabetic animals, 2 h water loading increased papillary hyaluronan (+93%) and diuresis (17-fold). In diabetic animals, baseline diuresis was 8-fold higher than in non-diabetic animals, which correlated with hyperglycaemia, glucosuria and proteinuria. Water loading in diabetic animals did not further increase papillary hyaluronan or diuresis: the urine flow rate decreased. To conclude, papillary hyaluronan is elevated in diabetic rats, which coincides with induction of hyaluronan-synthase 2 mRNA, hyperglycaemia, glucosuria, proteinuria and overt diuresis. The inability to respond to a water load with further diuresis may be related to the already elevated papillary hyaluronan and the inability to change hyaluronan during water loading.

  • 146.
    Rügheimer, Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Johnsson, C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Maric, C.
    Department of Medicine, Georgetown University Medical Centre, Washington, DC, USA.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hormonal regulation of renomedullary hyaluronan2008In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 193, no 2, p. 191-198Article in journal (Refereed)
    Abstract [en]

    AIM

    Hyaluronan (HA) is involved in renomedullary water handling through its water-binding capacity. This study addressed the effect of hormones involved in regulating fluid-electrolyte homeostasis on renomedullary HA content in vivo and in vitro.

    METHODS

    The kidneys from rats treated with L-NAME, indomethacin, vasopressin (AVP) or methylprednisolone (MP) during euvolaemia or water loading were analysed for HA by RIA, ELISA and histochemical staining. HA was measured in renomedullary interstitial cells treated with AVP, angiotensin II (Ang II) or a combination of AVP and Ang II.

    RESULTS

     Baseline renal cortical and medullary HA content was unaffected by 2 h of intravenous treatment with L-NAME (NOS inhibitor) or indomethacin (cyclo-oxygenase inhibitor), whereas AVP reduced medullary HA by 33%. During 2 h of acute water loading, diuresis was accompanied by an increase in renomedullary HA (+45%), but cortical HA was unaffected. In both L-NAME- and indomethacin-treated animals, the water loading-induced increase in renomedullary HA was absent, indicating involvement of NO and prostaglandins. After 7 days of MP treatment, medullary HA was reduced by 40%, but the water loading-induced elevation in HA remained. In cultured renomedullary interstitial cells, AVP reduced the HA content in the supernatant by 63%, and simultaneous treatment with Ang II reduced the HA content even further (95%).

    CONCLUSION

     AVP reduces HA content, and NO and prostaglandins are needed for the increase in HA during water loading.

  • 147.
    Rügheimer, Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Olerud, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Johnsson, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Takahashi, Tomoko
    School of Pharmaceutical Sciences, Ohu University, Koriyama, Japan.
    Shimizu, Kei
    School of Pharmaceutical Sciences, Ohu University, Koriyama, Japan.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Hyaluronan synthases and hyaluronidases in the kidney during changes in hydration status2009In: Matrix Biology, ISSN 0945-053X, E-ISSN 1569-1802, Vol. 28, no 7, p. 390-395Article in journal (Refereed)
    Abstract [en]

    Hyaluronan is a large glycosaminoglycan that is abundant in the   interstitium of the renal medulla/papilla. Papillary hyaluronan   increases during hydration and decreases during dehydration. Due to its   gel properties and ability to retain large volumes of water, hyaluronan   plays a role in renal water handling by affecting the permeability   characteristics of the papillary interstitium. The focus of the present   investigation was the regulation of hyaluronan metabolism in the   kidney, especially during variations in hydration status.   In control papillas, HAS 2 mRNA was heavily expressed and HAS 1 and 3   mRNA were weakly distributed. HYALs 1-3 mRNA were found at high   expression and HYAL 4 was only weakly expressed. in hydrated animals,   the diuretic response (12-fold) was followed by a 58% elevation in   papillary hyaluronan and a 45% reduction in the excreted urinary   hyaluronidase activity. No difference was determined in HAS 1-3 mRNA or   HYAL 1, 3-4 mRNA expression, suggesting a change in activity rather   than amount of protein. In dehydrated animals, antidiuresis was   followed by a 22% reduction in papillary hyaluronan and a 62% elevation   in excreted urinary hyaluronidase activity. Plasma vasopressin was   2.8-fold higher in dehydrated vs. hydrated rats.   In conclusion, HAS 2 appears a major contributor to the baseline levels   of hyaluronan. Reduced HAS 2 gene expression and increased excreted   urinary hyaluronidase activity during dehydration contribute to the   reduced amount of hyaluronan and to antidiuretic response.

  • 148. Salavadori et al.,
    et al.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    One-year posttransplant renal function is a strong predictor of long-term kidney function: results from the Neoral-MOST Observational Study2003Other (Other academic)
  • 149.
    Schive, Simen W.
    et al.
    Oslo Univ Hosp, Dept Transplant Med, Inst Canc, Oslo, Norway.;Oslo Univ Hosp, Inst Surg Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Foss, Aksel
    Oslo Univ Hosp, Dept Transplant Med, Inst Canc, Oslo, Norway.;Oslo Univ Hosp, Inst Surg Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Sahraoui, Afaf
    Oslo Univ Hosp, Dept Transplant Med, Inst Canc, Oslo, Norway.;Oslo Univ Hosp, Inst Surg Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Kloster-Jensen, Kristine
    Oslo Univ Hosp, Dept Transplant Med, Inst Canc, Oslo, Norway.;Oslo Univ Hosp, Inst Surg Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Hafsahl, Geir
    Oslo Univ Hosp, Dept Radiol, Inst Canc, Oslo, Norway..
    Kvalheim, Gunnar
    Oslo Univ Hosp, Dept Cell Therapy, Inst Canc, Oslo, Norway..
    Lundgren, Torbjorn
    Karolinska Inst, Div Transplantat Surg, CLINTEC, Stockholm, Sweden..
    von Zur-Mühlen, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Felldin, Marie
    Sahlgrens Univ Hosp, Dept Transplantat, Gothenburg, Sweden..
    Rafael, Ehab
    Univ Hosp, Dept Nephrol & Transplantat, Malmo, Sweden..
    Lempinen, Marko
    Helsinki Univ Hosp, Dept Surg, Helsinki, Finland..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jenssen, Trond G.
    Oslo Univ Hosp, Dept Transplant Med, Inst Canc, Oslo, Norway.;UiT, Metab & Renal Res Grp, Tromso, Norway..
    Mishra, Vinod
    Oslo Univ Hosp, Dept Finance, Oslo, Norway.;Oslo Univ Hosp, Resource Management Unit, Oslo, Norway..
    Scholz, Hanne
    Oslo Univ Hosp, Dept Transplant Med, Inst Canc, Oslo, Norway.;Oslo Univ Hosp, Inst Surg Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Cost and clinical outcome of islet transplantation in Norway 2010-20152017In: Clinical Transplantation, ISSN 0902-0063, E-ISSN 1399-0012, Vol. 31, no 1Article in journal (Refereed)
    Abstract [en]

    Islet transplantation is a minimally invasive -cell replacement strategy. Islet transplantation is a reimbursed treatment in Norway. Here, we summarize the cost and clinical outcome of 31 islet transplantations performed at Oslo University Hospital (OUS) from January 2010 to June 2015. Patients were retrospectively divided into three groups. Thirteen patients received either one or two islet transplantation alone (ITA), while five patients received islet transplantation after previous solid organ transplantation. For the group receiving 2 ITA, Kaplan-Meier estimates show an insulin independence of 20% more than 4years after their last transplantation. An estimated 70% maintain at least partial graft function, defined as fasting C-peptide >0.1nmolL(-1), and 47% maintain a HbA1c below 6.5% or 2 percent points lower than before ITA. For all groups combined, we estimate that 44% of the patients have a 50% reduction in insulin requirement 4years after the initial islet transplantation. The average cost for an islet transplantation procedure was 347297 +/- 60588NOK, or 35424 +/- 6182EUR, of which isolation expenses represent 34%. We hereby add to the common pool of growing experience with islet transplantation and also describe the cost of the treatment at our center.

  • 150.
    Sedigh, Amir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Management of Ischemia and Brain Death-Associated Injuries in Porcine Kidney Grafts2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Organs from deceased donors after brain death (BD) remain the major source of organs for transplantation. The catastrophic event of BD and the inevitable consequences of ischemia reperfusion injury (IRI) are linked to impaired graft quality and transplantation outcome. The aim of this thesis was to create a BD model in pigs to assess early effects on IRI in kidneys preserved with an oxygenated solution and to evaluate the protective effects of coating the renal vessel walls with a heparin conjugate during hypothermic machine perfusion (HMP).

    Brain death was achieved by raising the intracranial pressure (ICP) through stepwise increasing the volume of an epidurally placed balloon to the point of exceeding the mean arterial pressure (MAP) creating a negative cerebral perfusion pressure (CPP). This reproducible, clinically relevant experimental model makes evaluation of potential targeted methods to protect the organs possible. Kidneys retrieved from brain-dead pigs were preserved either in an oxygenated emulsion composed of 75% histidine-tryptophan-ketoglutarate (HTK) and 25% perfluorohexyloctane F6H8 or HTK alone. After 18h of cold storage the kidneys were transplanted into allogeneic pigs. F6H8 was associated with replenishment of adenosine triphosphate and lower gene expression of hypoxia inducible factor (HIF)-1a, vascular endothelial growth factor (VEGF), interleukin (IL)-1α and tumour necrosis factor (TNF)-α. F6H8 reduced early IRI at both the cellular and molecular level.

    Kidneys from BD pigs were evaluated for the feasibility of coating the vessel walls with the heparin conjugate CHC (Corline Systems AB, Uppsala, Sweden) to restore glycocalyx. Porcine kidneys were preserved by HMP for 20h with 50 mg biotinylated CHC added to the perfusion solution. CHC was detected on the inner surface of the kidney vessels by immunofluorescence, and its uptake in kidneys was confirmed by reduced content in the perfusate. An ex vivo normothermic perfusion circuit was developed to assess kidney function. Perfusion with CHC during HMP was associated with lower creatinine levels, increased urine volume and reduced tubular injury. Modifying renal vessels walls using CHC during HMP improved early graft function. Preservation with the oxygenated F6H8 solution or CHC could be used to improve graft quality and ameliorate IRI in kidneys retrieved from deceased donors.

    List of papers
    1. Standardized experimental brain death model for studies of intracranial dynamics, organ preservation, and organ transplantation in the pig
    Open this publication in new window or tab >>Standardized experimental brain death model for studies of intracranial dynamics, organ preservation, and organ transplantation in the pig
    Show others...
    2011 (English)In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 39, no 3, p. 512-517Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVES:: Brain death impairs organ function and outcome after transplantation. There is a need for a brain death model to allow studies of organ viability and preservation. For neurointensive care research, it is also of interest to have a relevant brain death model for studies of intracranial dynamics and evaluation of cerebral monitoring devices. Therefore, the objective was to develop a standardized clinically relevant brain death model. METHODS:: Six pigs of both sexes (10-12 wks old; mean weight, 24.5 ± 1.4 kg) were included. Mean arterial blood pressure, heart rate, intracranial pressure, intracranial compliance, cerebral perfusion pressure, and brain tissue oxygenation (BtiPo2) were recorded during stepwise elevation of intracranial pressure by inflation of an epidural balloon catheter with saline (1 mL/20 mins). Brain death criteria were decided to be reached when cerebral perfusion pressure was <0 mm Hg for 60 mins and at least 10 mL saline was inflated epidurally. BtiPo2 and arterial injections of microspheres were used for confirmation of brain death. RESULTS:: A gradual volume-dependent elevation of intracranial pressure was observed. After 10 mL of balloon infusion, mean intracranial pressure was 89.8 ± 9.7 (sd) mm Hg. Intracranial compliance decreased from 0.137 ± 0.069 mL/mm Hg to 0.007 ± 0.001 mL/mm Hg. The mean arterial pressure decreased and the heart rate increased when the intracranial volume was increased to between 5 and 6 mL. All animals showed cerebral perfusion pressure ≤0 after 7 to 10 mL of infusion. In all animals, the criteria for brain death with negative cerebral perfusion pressure and BtiPo2 ∼0 mm Hg were achieved. Only a negligible amount of microspheres were found in the cerebrum, confirming brain death. The kidneys showed small foci of acute tubular necrosis. CONCLUSIONS:: The standardized brain death model designed in pigs simulates the clinical development of brain death in humans with a classic pressure-volume response and systemic cardiovascular reactions. Brain death was convincingly confirmed.

    Keywords
    brain death, experimental animal model, intracranial pressure, cerebral perfusion pressure, brain tissue oxygenation, organ preservation
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-143532 (URN)10.1097/CCM.0b013e318206b824 (DOI)000287480000013 ()21187748 (PubMedID)
    Available from: 2011-01-21 Created: 2011-01-21 Last updated: 2017-12-11Bibliographically approved
    2. Oxygen-charged HTK-F6H8 emulsion reduces ischemia: reperfusion injury in kidneys from brain-dead pigs
    Open this publication in new window or tab >>Oxygen-charged HTK-F6H8 emulsion reduces ischemia: reperfusion injury in kidneys from brain-dead pigs
    Show others...
    2012 (English)In: Journal of Surgical Research, ISSN 0022-4804, E-ISSN 1095-8673, Vol. 178, no 2, p. 959-967Article in journal (Refereed) Published
    Abstract [en]

    Background:

    Prolonged cold ischemia is frequently associated with a greater risk of delayed graft function and enhanced graft failure. We hypothesized that media, combining a high oxygen-dissolving capacity with specific qualities of organ preservation solutions, would be more efficient in reducing immediate ischemia-reperfusion injury from organs stored long term compared with standard preservation media.

    Methods:

    Kidneys retrieved from brain-dead pigs were flushed using either cold histidine-tryptophan-ketoglutarate (HTK) or oxygen-precharged emulsion composed of 75% HTK and 25% perfluorohexyloctane. After 18 h of cold ischemia the kidneys were transplanted into allogeneic recipients and assessed for adenosine triphosphate content, morphology, and expression of genes related to hypoxia, environmental stress, inflammation, and apoptosis.

    Results:

    Compared with HTK-flushed kidneys, organs preserved using oxygen-precharged HTK-perfluorohexyloctane emulsion had increased elevated adenosine triphosphate content and a significantly lower gene expression of hypoxia inducible factor-1 alpha, vascular endothelial growth factor, interleukin-1 alpha, tumor necrosis factor-alpha, interferon-alpha, JNK-1, p38, cytochrome-c, Bax, caspase-8, and caspase-3 at all time points assessed. In contrast, the mRNA expression of Bcl-2 was significantly increased.

    Conclusions:

    The present study has demonstrated that in brain-dead pigs the perfusion of kidneys with oxygen-precharged HTK-perfluorohexyloctane emulsion results in significantly reduced inflammation, hypoxic injury, and apoptosis and cellular integrity and energy content are well maintained. Histologic examination revealed less tubular, vascular, and glomerular changes in the emulsion-perfused tissue compared with the HTK-perfused counterparts. The concept of perfusing organs with oxygen-precharged emulsion based on organ preservation media represents an efficient alternative for improved organ preservation.

    Keywords
    Brain death, Emulsion, Kidney transplantation, Organ preservation, Oxygen carrier, Pig
    National Category
    Surgery
    Identifiers
    urn:nbn:se:uu:diva-188407 (URN)10.1016/j.jss.2012.06.031 (DOI)000311090700064 ()
    Note

    De två första författarna delar förstaförfattarskapet.

    Available from: 2012-12-18 Created: 2012-12-17 Last updated: 2019-01-21Bibliographically approved
    3. Modifying the vessel walls in porcine kidneys during machine perfusion
    Open this publication in new window or tab >>Modifying the vessel walls in porcine kidneys during machine perfusion
    Show others...
    2014 (English)In: Journal of Surgical Research, ISSN 0022-4804, E-ISSN 1095-8673, Vol. 191, no 2, p. 455-462Article in journal (Refereed) Published
    Abstract [en]

    Background: Endothelial glycocalyx regulates the endothelial function and plays an active role in maintaining vascular homeostasis. During ischemia/reperfusion, the glycocalyx is rapidly shed into the blood stream. A heparin conjugate (CHC; Corline systems AB, Uppsala, Sweden) consists of 70 heparin molecules that have the capacity to adhere strongly to biological tissues expressing heparin affinity. We hypothesized that CHC could be used to restore disrupted glycocalyx in vivo in kidneys from brain-dead pigs.

    Materials and Methods: Brain death was induced in male landrace pigs (n=6) by inflating a balloon catheter in the epidural space until obtaining negative cerebral perfusion. The recovered kidneys (n=5+5) were perfused by hypothermic machine perfusion (HMP) using two Lifeport kidney transporters (Organ Recovery Systems, Chicago, IL, USA). 50 mg CHC (including 25 mg biotinylated CHC) or 50 mg unfractionated heparin (control) was added to the perfusion fluid in the respective machines. In one case, the kidneys were used only for dose escalation of CHC with the same procedure.

    Results: CHC was detected by immunofluorescence and confocal microscopy in the inner surface of vessel walls. The binding of CHC in the kidney was confirmed indirectly by consumption of CHC from the perfusion fluid.

    Conclusions: In this first attempt, we show that CHC may be used to coat the vessel walls of perfused kidneys during HMP, an approach that could become useful in restoring endothelial glycocalyx of kidneys recovered from deceased donors to protect vascular endothelium and possibly ameliorate ischemia/reperfusion injuries.

    National Category
    Surgery
    Identifiers
    urn:nbn:se:uu:diva-221875 (URN)10.1016/j.jss.2014.04.006 (DOI)000341358100027 ()24819743 (PubMedID)
    Available from: 2014-04-07 Created: 2014-04-06 Last updated: 2018-05-31Bibliographically approved
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