| 1. |
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| 2. |
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| 3. |
- Tyden, Gunnar, et al.
(författare)
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A Randomized, Doubleblind, Placebo-Controlled, Study of Single-Dose Rituximab as Induction in Renal Transplantation
- 2009
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Ingår i: Transplantation. - 1534-6080 .- 0041-1337. ; 87:9, s. 1325-1329
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Tidskriftsartikel (refereegranskat)abstract
- We performed a prospective, double blind, randomized, placebo-controlled multicenter study on the efficacy and safety of rituximab as induction therapy, together with tacrolimus, mycophenolate mofetil, and steroids. The primary endpoint was defined as acute rejection, graft loss, or death during the first 6 months. Secondary endpoints were creatinine clearance, incidence of infections, and incidence of rituximab-related adverse event. Results. We enrolled 140 patients (44 living donor and 96 deceased donor), and of those, 68 rituximab and 68 placebo patients fulfilled the study. In all the patients receiving rituximab, there was a complete depiction of CD 19/CD20 cells, whereas there was no change in the number of CD19/CD20 cells in the placebo group. There were 10 treatment failures in the rituximab group versus 14 in the placebo group (P=0.348). There were eight rejection episodes in the rituximab group versus 12 in the placebo group (P=0.317) Creatinine clearance was 66 +/- 22 mL/min in the study group and 67 +/- 23 mL/min in the placebo group. There was no difference in the number of bacterial infections, cytomegalovirus infections, and BK virus infections or fungal infections. Conclusion. We performed a placebo-controlled study of rituximab induction in renal transplantation. There was a tendency toward fewer and milder rejections during the first 6 months in the rituximab group. Although induction with one dose of rituximab induced a complete depletion B cells, there was no increase in the incidence of infectious complications or leukopenia and it seems safe, therefore, to conduct further studies on the use of rituximab in transplantation.
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| 4. |
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| 5. |
- Tydén, Gunnar, et al.
(författare)
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Implementation of a Protocol for ABO-incompatible kidney transplantation--a three-center experience with 60 consecutive transplantations
- 2007
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Ingår i: Transplantation. - : Ovid Technologies (Wolters Kluwer Health). - 0041-1337 .- 1534-6080. ; 7, s. 157-158
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Tidskriftsartikel (refereegranskat)abstract
- Background. A new protocol for ABO-incompatible kidney transplantation has recently been introduced. We report here on the joint experience of the implementation in Stockholm and Uppsala, Sweden and Freiburg, Germany. Methods. The new protocol utilizes antigen-specific immunoadsorption to remove existing ABO-antibodies, rituximab, and intravenous immunoglobulin to prevent the rebound of antibodies, and conventional tacrolimus, mycophenolate-mofetil, and prednisolone immunosuppression. Sixty consecutive ABO-incompatible kidney transplantations were included in the study. The outcome is compared with the results of 274 ABO-compatible live donor transplantations performed during the same period. Results. Two of the ABO-incompatible grafts have been lost (non-compliance and death with functioning graft). All the remaining 58 grafts had good renal function at a follow-up of up to 61 months. We did not observe any late rebound of antibodies and there were no humoral rejections. Graft survival was 97% for the ABO-incompatible compared with 95% for the ABO-compatible. Patient survival was 98% in both groups. There was a significant variation in preoperative A/B-antibody titer between the centers, with a median 1:8 in Uppsala, median 1:32 in Stockholm and median 1:128 in Freiburg. More preoperative antibody adsorptions were therefore needed in Freiburg than in Stockholm and Uppsala. Conclusions. The new protocol was easily implemented and there were no graft losses that could be related to ABO-incompatibility. A significant inter-institutional variation in the measurement of anti-AB-antibodies was found, having a substantial impact on the number of immunoadsorptions and consequently on the total cost for the procedure. A standardized fluorescence-activated cell sorting technique for antibody quantification is much needed.
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| 6. |
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| 7. |
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| 8. |
- Berglund, David, et al.
(författare)
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Isolation, expansion and functional assessment of CD4+CD25+FoxP3+ regulatory T cells and Tr1 cells from uremic patients awaiting kidney transplantation
- 2012
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Ingår i: Transplant Immunology. - : Elsevier BV. - 0966-3274 .- 1878-5492. ; 26:1, s. 27-33
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Tidskriftsartikel (refereegranskat)abstract
- Background: The immunosuppressive properties of regulatory T cells have emerged as an attractive tool for the development of immunotherapies in various disease contexts, e.g. to treat transplantation induced immune reactions. This paper focuses on the process of obtaining and functionally characterizing CD4+CD25+FoxP3+ regulatory T cells and Tr1 cells from uremic patients awaiting kidney transplantation. Methods: From October 2010 to March 2011 uremic patients awaiting living donor kidney transplantation, and their corresponding kidney donors, were enrolled in the study. A total of seven pairs were included. Isolation of CD4+CD25+FoxP3+ regulatory T cells was performed by magnetic activated cell sorting of peripheral blood mononuclear cells obtained from the uremic patients. Donor specific Tr1 cells were differentiated by repetitive stimulation of immature CD4+ T cells with immature dendritic cells, with the T cells coming from the future kidney recipients and the dendritic cells from the corresponding kidney donors. Cells were then expanded and functionally characterized by the one-way mixed leukocyte reaction and assessment of IL-10 production. Phenotypic analysis was performed by flow cytometry. Results: The fraction of CD4+CD25+FoxP3+ regulatory T cells after expansion varied from 39.1 to 50.4% and the cells retained their ability to substantially suppress the mixed leukocyte reaction in all but one patient (3.8–19.2% of the baseline stimulated leukocyte activity, p<0.05). Tr1 cells were successfully differentiated from all but one patient and produced high levels of IL-10 when stimulated with immature dendritic cells (1,275–11,038% of the baseline IL-10 secretion, pb0.05). Conclusion: It is practically feasible to obtain and subsequently expand CD4+CD25+FoxP3+ regulatory T cells and Tr1 cells from uremic patients without loss of function as assessed by in vitro analyses. This forms a base for adoptive regulatory T cell therapy in the setting of living donor kidney transplantation.
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| 9. |
- Berglund, David, et al.
(författare)
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Obtaining regulatory T cells from uraemic patients awaiting kidney transplantation for use in clinical trials
- 2013
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Ingår i: Clinical and Experimental Immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 173:2, s. 310-322
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Tidskriftsartikel (refereegranskat)abstract
- Adoptive transfer of regulatory T cells (Tregs) has been proposed for use as a cellular therapy to induce transplantation tolerance. Preclinical data are encouraging, and clinical trials with Treg therapy are anticipated. In this study, we investigate different strategies for the isolation and expansion of CD4+CD25highCD127low Tregs from uraemic patients. We use allogeneic dendritic cells (DCs) as feeder cells for the expansion and compare Treg preparations isolated by either fluorescence activated cell sorting (FACS) or magnetic activated cell sorting (MACS) that have been expanded subsequently with either mature or tolerogenic DCs. Expanded Treg preparations have been characterized by their purity, cytokine production and in-vitro suppressive ability. The results show that Treg preparations can be isolated from uraemic patients by both FACS and MACS. Also, the type of feeder cells used in the expansion affects both the purity and the functional properties of the Treg preparations. In particular, FACS-sorted Treg preparations expanded with mature DCs secrete more interleukin (IL)-10 and granzyme B than FACS-sorted Treg preparations expanded with tolerogenic DCs. This is a direct comparison between different isolation techniques and expansion protocols with Tregs from uraemic patients that may guide future efforts to produce clinical-grade Tregs for use in kidney transplantation.
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| 10. |
- Berglund, David, 1984-
(författare)
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Preparatory Studies to Introduce Regulatory T Cells in Clinical Transplantation
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Solid organ transplantation has evolved from being an experimental procedure to a life-saving treatment for patients with end-stage organ failure. The risk of losing a transplant due to acute rejection is very low with the use of modern immunosuppressive protocols and the short-term results are impressive. However, long-term outcomes are suboptimal and transplant recipients are at increased risks for severe complications such as cancers, opportunistic infections and cardiovascular events. The previous struggle to achieve short-term survival has turned into a search for new strategies to improve patient and transplant longevity.Regulatory T cells (TRegs), a subset of T cells, occur naturally in the immune system and have the capacity to down regulate immune responses. Under normal conditions they maintain self-tolerance and prevent excessive immune activation. Functional TReg defects lead to a massive autoimmune response and are not compatible with life. Preclinical data support that TRegs can be used as a cell therapy to prevent transplant rejection, with the potential to minimize the need for traditional immunosuppression and improve the long-term outcome.This thesis aims to enhance the translation of TReg cell therapy to clinical organ transplantation. In particular, strategies for isolation and expansion of TRegs from uremic patients awaiting kidney transplantation have been assessed. A non-invasive imaging technique to study T cell products after intravenous administration was developed, for use in future clinical trials. The performance of a novel cell purification technique was investigated to potentially improve the clinical production of TRegs.The thesis demonstrates that TRegs can be isolated and expanded from uremic patients to display potent suppressive properties in vitro. The mode of isolation and expansion affect the functional characteristics, where cells purified with cytometry based techniques and expanded with mature dendritic cells were the most advantageous. T cells can be labeled using the radioactive tracer [111In]oxine with preserved viability and subsequently followed in vivo with SPECT/CT for more than 1 week after intravenous administration. The use of microfluidic switch technology offers a novel way of purifying TRegs at high speed, purity and viability, under conditions compatible with clinical use.
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| 11. |
- Berglund, David, et al.
(författare)
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Screening of mortality in transplant patients using an assay for immune function
- 2011
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Ingår i: Transplant Immunology. - : Elsevier BV. - 0966-3274 .- 1878-5492. ; 24:4, s. 246-250
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: So far, the ImmuKnow Immune Cell Function Assay (Cylex, Inc., Columbia, MD, USA) has been used to assess risks of infection and rejection in transplant patients. We hypothesized that the ImmuKnow assay might be used for mortality screening in transplant patients overall. METHODS: In the period of February 2007 to December 2009, at the Uppsala University Hospital, 362 patients who received either kidney, kidney+pancreas, kidney+islet cells, liver or liver+kidney allografts were randomly screened using the ImmuKnow assay. All causes of mortality were compared between two groups: patients with at least one ImmuKnow assay below 175ng/mL and patients with all ImmuKnow assays from 175ng/mL and above. Subsequently, the frequency of rejection within thirty days of the ImmuKnow assay was compared between these two groups. RESULTS: The study included 1031 ImmuKnow assays obtained from the 362 patients. A total of 111 patients had at least one ImmuKnow below 175ng/mL and 251 patients had all their ImmuKnow assays from 175ng/mL and above. By January 31st 2010, 16 of 111 patients (14.4%) with at least one ImmuKnow assay below 175ng/mL were deceased, compared to 13 of 251 patients (5.2%) with all ImmuKnow assays from 175ng/mL and above (p=0.0053, Fisher's exact test). There was no difference in the frequency of rejection between the two groups (19.8% versus 17.5%, p=0.66). CONCLUSIONS: In addition to assessing relative risks of infection and rejection in transplant patients, the ImmuKnow assay may be used to identify patients with increased risk of short-term mortality. Transplant patients being highly overimmunosuppressed as assessed by the ImmuKnow assay do not seem to have a lower risk of short-term rejection.
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| 12. |
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| 13. |
- Bersztel, Adam, et al.
(författare)
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Antibody responses to xenogenic antigens : a study in the mouse-to-rat system
- 2006
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Ingår i: Tissue Antigens. - : Wiley. - 0001-2815 .- 1399-0039. ; 68:6, s. 483-488
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Tidskriftsartikel (refereegranskat)abstract
- Antibodies play a crucial role in the rejection of an organ that has been transplanted between different animal species, i.e. xenotransplantation. In previous work, we have induced a state of humoral tolerance where mouse-to-rat heart grafts continued to beat under ciclosporine A monotherapy. Initially, a combined treatment with ciclosporine A and 15-deoxyspergualin was given. This state of tolerance could not be reproduced when the vascularised heart graft was replaced with a free tissue graft or xenogeneic blood transfusions. To gain further insight into the humoral response against mouse antigens, we studied the antibody production in naive rats and rats challenged with heart transplants, heart cells, mononuclear cells (MNC) and erythrocytes from mice. Rats not challenged with any mouse cells or organs had a moderate amount of antibodies targeted against mouse MNC as well as rosette-forming cells in the spleen targeted against mouse erythrocytes. A challenge with either mouse MNC or erythrocytes lead to immunisation with antibodies of both IgM and IgG subtype directed against both MNC and erythrocytes. Antibody titres against mouse erythrocytes in animals challenged with MNC were not detectable until day 7, whereas antibody titres against mouse MNC in animals challenged with erythrocytes were detected on day 1. Immunisation with mouse erythrocytes raised the titre of rosette-forming cells in the spleen compared with naive rats (P < 0.05). Our data indicate that different xenogeneic antigens in the mouse-to-rat system are shared between heart cells, MNC and erythrocytes; however, the immunisation patterns differ regarding the time when antibodies are first detected.
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| 14. |
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| 15. |
- Bersztel, Adam
(författare)
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Modulation of the Immune Response in Concordant Xenotransplantation
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Xenotransplantation, i.e. transplantation between different species, could be a possible solution to the present shortage of organ donors. The immunological response to a xenograft is strong and difficult to suppress. It is driven both by the humoral and cellular part of the immune system. The aim of this thesis was to characterise and modulate this response in a concordant mouse-to-rat model, using both vascularised and non-vascularised grafts.Exposure of mouse cells or tissue to the circulation of a rat, either through transplantation or transfusions, easily evoked an immune response, consisting of IgM antibodies. A response that was aimed both at antigens present on mouse mononuclear cells and on erythrocytes. A non-immunosuppressed rat rejected a mouse heart graft within three days. The combined use of cyclosporine A (CyA) and deoxyspergualin (DSG) as immunosuppression prevented the rejection of vascularised heart transplants as well as of non-vascularised pancreatic islet grafts. This acceptance was sustained for the heart transplant also after the termination of DSG treatment, but not for the pancreatic islet graft. Furthermore, a second heart graft was accepted when transplanted under monotherapy with CyA 56-154 days after the first transplantation. This finding was interpreted as a humoral unresponsiveness, which could not be reproduced when the primary heart was substituted with a cellular graft, consisting of pancreatic islets or heart cells, or by blood transfusions. However, the rejection of a mouse heart after blood transfusions occurred in the absence of antibodies directed against mouse erythrocytes, in contrast to the observations in non-transfused animals. This indicates that a partial humoral tolerance restricted to the response against erythrocytes can be induced. This mechanism may offer a possibility to induce total humoral tolerance against a xenograft if the appropriate antigens are administered in conjunction with CyA and DSG.
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| 16. |
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| 17. |
- Biglarnia, Ali-Reza, et al.
(författare)
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Desensitization With Antigen-Specific Immunoadsorption Interferes With Complement in ABO-Incompatible Kidney Transplantation
- 2012
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 93:1, s. 87-92
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Complement activation was characterized during and after desensitization treatment in 19 consecutive patients receiving ABO-incompatible (ABOi) living donor kidney transplants to assess the effect of desensitization protocol including antigen-specific immunoadsorption (IA) on complement activation.METHODS:All patients received rituximab- and tacrolimus-based triple treatment. Anti-A/B antibodies were removed by IA. Serial determinations of C3, C3a, the C3a/C3 ratio, and sC5b-9 were carried out between day -30 and postoperative day 30. C1q was measured on day -30 and the day before the transplantation. In two recipients, eluates from immunoadsorbent columns were analyzed for C3a, C1q, and immunoglobulins by western blotting. Same complement analysis was performed in eluate from a control column after in vitro perfusion of AB-plasma.RESULTS:Patient and graft survival were 100% for a median follow-up of 40 months (range, 12-60 months). There were no humoral rejections based on ABO-antigen-antibody interactions. C3a and the C3a/C3 ratio declined with the start of IA treatment, and this decline was maintained postoperatively. C1q declined from day -30 to a lower value on the day before transplantation (P<0.05). In eluates from both patient and control, immunoadsorbent column immunoglobulins together with C3a and C1q were detected.CONCLUSIONS:The current protocol including antigen-specific IA interferes with the complement system; this effect may be partially responsible for the absence of humoral rejection resulting from ABO-antigen-antibody interactions and the excellent outcomes obtained after ABO-incompatible kidney transplantation.
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| 18. |
- Biglarnia, Ali-Reza, 1973-, et al.
(författare)
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Efficacy and safety of continuous local infusion of ropivacaine after retroperitoneoscopic live donor nephrectomy
- 2011
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Ingår i: American Journal of Transplantation. - : Elsevier BV. - 1600-6135 .- 1600-6143. ; 11:1, s. 93-100
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Tidskriftsartikel (refereegranskat)abstract
- Morphine-based analgesia is effective but can compromise donor safety. We investigated whether continuous infusion of local anesthetics (CILA) can provide sufficient pain control and reduce morbidity related to opiate analgesics after hand-assisted retroperitoneoscopic (HARS) live donor nephrectomy. Forty consecutive live kidney donors underwent HARS and were treated with the ON-Q system providing CILA with 0.5% ropivacaine through two SilvaGard® catheters placed in the retroperitoneal cavity and the rectus sheath, respectively. The case control group consisted of 40 donors matched with regard to sex, age, BMI and surgical technique. All donors were maintained on standardized multimodal analgesia combining nurse-controlled oxycodone treatment and acetaminophen. CILA donors had lower median cumulative consumption of morphine equivalents (CCME) (7 mg [0-56] vs. 42 mg [15-127]; p < 0.0000001), lower incidence of nausea (18 [45%] vs. 35 [87.5%] donors; p < 0.001), shorter time in postoperative care unit (160 vs. 242.5 min; p < 0.001) and shorter hospital stay (4 [4-7] vs. 6 [4-11] days; p < 0.001). In 32.5% of CILA donors the CCME was 0 mg (0% in matched control group, p < 0.001). CILA with 0.5% ropivacaine provides effective postoperative pain relief, reduces the need for opioid treatment and promotes postoperative recovery. Continuous local infusion of ropivacaine provides sufficient analgesia and opioid-sparing effect as well as reduces the incidence of nausea and vomiting after hand-assisted retroperitoneoscopic live donor nephrectomy.
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| 19. |
- Biglarnia, Ali-Reza, et al.
(författare)
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Liver regeneration is impaired by FK778 in partially hepatectomized rats, while supplemental uridine restores both liver growth and hepatocyte proliferation
- 2009
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Ingår i: Hepatology Research. - 1386-6346 .- 1872-034X. ; 39:1, s. 86-92
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Tidskriftsartikel (refereegranskat)abstract
- Aim:The impact of mandatory immunosuppression on liver regeneration after segmental liver transplantation is of clinical importance. FK778, a novel immunosuppressant, inhibits pyrimidine biosynthesis and prevents rejection after organ transplantation in a dose-dependent manner. We investigated the effect of FK778 at a highly effective dose on liver regeneration in a small animal model.Methods: Inbred Lewis rats were subjected to 70% partial hepatectomy (PH) and treated with saline (n = 28), uridine (n = 16), FK778 alone (n = 28) or in combination with uridine (n = 16). FK778 was given intravenously daily at a dose of 25 mg/kg bodyweight (bw) and uridine was given daily intraperitoneally at a dose of 250 mg/kg bw. Liver bodyweight ratio (LBR), hepatocyte proliferation index (PI), blood chemistry and morphological analysis were incorporated. PI was determined by Ki-67 immunostaining. De Ritis ratio was calculated to assess the extent of liver damage.Results:In FK778-treated animals PI was decreased at 24 h and 72 h and LBR was lower at 48 h and 72 h (P < 0.05) after the PH. In addition, morphological analysis showed confluent central lobular necrosis at 72 h in four of seven animals. Uridine supplementation restored PI, LBR and the de Ritis ratio in FK778-treated animals and no confluent necroses were observed.Conclusion:FK778 is antihepatotrophic as well as antiproliferative during rat liver regeneration. Both liver growth and hepatocyte proliferation are completely restored by supplementation with uridine. In addition, supplemental uridine markedly reduces the severity of morphological abnormalities consistent with FK778 toxicity.
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| 20. |
- Biglarnia, Ali-Reza, 1973-
(författare)
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Minimizing Risks and Morbidity in Live Kidney Donors
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Live kidney donors are healthy volunteers who are exposed to major surgical procedure and physical harms with no direct therapeutic benefits. Efforts to minimize their risks and morbidity are therefore of utmost importance. The current thesis describes studies on donor evaluation, surgical procedure and postoperative management of live kidney donors. The overall purpose is to evaluate and possibly improve routines and treatments in order to reduce risks and the overall morbidity of live kidney donors. In Study I, we evaluated the assessment of kidney function during donor evaluation and found that the accuracy of iohexol glomerular filtration rate (GFR) is compromised by large variations in repeated measurements in presumably healthy donors. We proposed that there is a need for improvement of GFR measurements and that the assessment of predonation kidney function should be more comprehensive, involving GFR, laboratory investigations, functional and morphological examinations and sound clinical judgment. In Study II, we addressed the risk of perioperative venous thromboembolism (VTE) and concluded that expanding the standard screening protocol for VTE to include perioperative venous duplex can potentially decrease the VTE-related morbidity. In studies III and IV, we investigated the impact of hand-assisted retroperitoneoscopic (HARS) nephrectomy on donor safety and perioperative morbidity. The HARS nephrectomy uses the hand-assisted approach, which enables immediate manual compression for hemostasis in case of sudden and severe bleeding. Additionally, the pure retroperitoneal access further increases the safety margin of laparoscopic donor nephrectomy by 1) minimizing the risk of intestinal injury, and 2) exposure of the retroperitoneal nerves, making HARS suitable for continuous infusion of local anesthetics (CILA). CILA effectively reduces the need for opioid consumption and has the potential to totally obviate opiate analgesics postoperatively. Consequently, CILA in combination with HARS reduces morphine-related morbidity and promotes postoperative recovery. In accordance with these data, we recommend improvement and modification of the donor evaluation process as well as a broad introduction of HARS nephrectomy in combination with CILA to increase the safety margin for live kidney donors.
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| 21. |
- Biglarnia, Ali-Reza, et al.
(författare)
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Prompt reversal of a severe complement activation by eculizumab in a patient undergoing intentional ABO-incompatible pancreas and kidney transplantation
- 2011
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Ingår i: Transplant International. - : John Wiley & Sons. - 0934-0874 .- 1432-2277. ; 24:8, s. e61-e66
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Tidskriftsartikel (refereegranskat)abstract
- We describe the presumably first intentional ABO-incompatible deceased-donor kidney and pancreas transplantation with a severe antibody-mediated rejection during a rebound of isoagglutinins. Rejection was successfully treated with eculizumab, which inhibits the terminal pathway of complement. Complement analysis (C3, C3d,g, and a modified assay of classical complement-related hemolytic function) documented complement activation and confirmed that eculizumab completely blocked complement function. At 6 months, the patient had normal kidney and pancreas function, and histological evaluations revealed no evidence of sustained graft damage. This successful transplantation suggests that ABO barriers can safely be overcome without extensive preconditioning, when the complement inhibitor eculizumab is included.
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| 22. |
- Biglarnia, Ali-Reza, et al.
(författare)
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Prompt reversal of a severe complement activation by eculizumab in a patient undergoing intentional ABO-incompatible pancreas and kidney transplantation
- 2011
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Ingår i: Transplant International. - : Frontiers Media SA. - 0934-0874 .- 1432-2277. ; 24:8, s. e61-e66
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Tidskriftsartikel (refereegranskat)abstract
- We describe the presumably first intentional ABO-incompatible deceased-donor kidney and pancreas transplantation with a severe antibody-mediated rejection during a rebound of isoagglutinins. Rejection was successfully treated with eculizumab, which inhibits the terminal pathway of complement. Complement analysis (C3, C3d,g, and a modified assay of classical complement-related hemolytic function) documented complement activation and confirmed that eculizumab completely blocked complement function. At 6 months, the patient had normal kidney and pancreas function, and histological evaluations revealed no evidence of sustained graft damage. This successful transplantation suggests that ABO barriers can safely be overcome without extensive preconditioning, when the complement inhibitor eculizumab is included.
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| 23. |
- Biglarnia, Ali-Reza, et al.
(författare)
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Pulmonary Nocardiosis with Brain Abscess in a Sensitized Kidney Transplant Recipient with a History of Repeated Graft Loss and HLA-Antibody Depletion Treatment : A case report
- 2008
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Ingår i: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 113:1, s. 111-116
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Tidskriftsartikel (refereegranskat)abstract
- Nocardiosis is an opportunistic infection with unfavourable prognosis and is predominantly seen in immunocompromised patients. We here present a kidney transplant recipient with a history of two early graft losses who subsequently developed Human Leukocyte Antigen (HLA)-antibodies and underwent a desensitization treatment with plasmapheresis and monoclonal anti-CD20 antibody application. However, 3 months after a third HLA-identical kidney transplantation he developed Nocardiosis with pulmonary and asymptomatic brain manifestation. The present case report exemplifies this opportunistic infection and gives an overview of the literature.
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| 24. |
- Biglarnia, Ali-Reza, et al.
(författare)
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Transplantation av pankreas botande alternativ vid typ 1-diabetes : [Transplantation of pancreas, a curative option for type 1 diabetes]
- 2012
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Ingår i: Läkartidningen. - 0023-7205 .- 1652-7518. ; 109:39-40, s. 1754-1757
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Tidskriftsartikel (refereegranskat)abstract
- In the past decade, pancreas transplantation (PTx) has become increasingly attractive as a curative treatment in patients with labile diabetes and secondary complications. In the United Kingdom, the percentage of deceased-donors utilized for PTx increased 5-fold between 2003 and 2007. The trend towards a higher number of annual pancreas transplantations is also observed in Sweden. The increasing activity and the excellent outcome are consequences of meticulous surgery, effective immunsuppression and adequate follow-up. The present report descibes the current status of PTx and shows the short- and long-term results during the last decade in Sweden.
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| 25. |
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| 26. |
- Biglarnia, Alireza, et al.
(författare)
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The free radical scavenger S-PBN significantly prolongs DSG-mediated graft survival in experimental xenotransplantation
- 2012
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Ingår i: Xenotransplantation. - : Wiley. - 0908-665X .- 1399-3089. ; 19:3, s. 166-176
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Tidskriftsartikel (refereegranskat)abstract
- Background: Nitrones such as 2-sulfo-phenyl-N-tert-butyl nitrone (S-PBN) are known to trap and stabilize free radicals and to reduce inflammation. Recently, S-PBN was shown to reduce infiltration of T lymphocytes and the expression of adhesion molecules on the endothelium in experimental traumatic brain injury. We hypothesized that S-PBN could reduce infiltration of T lymphocytes during cell-mediated xenograft rejection and thereby increase graft survival. The concordant mouse-to-rat heart transplantation model was used to test the hypothesis. In this model, grafts undergo acute humoral xenograft rejection (AHXR) almost invariably on day 3 and succumb to cell-mediated rejection on approximately day 8 if AHXR is inhibited by treatment with 15-deoxyspergualin (DSG). Material and methods: Hearts from Naval Medical Research Institute (NMRI) mice were transplanted to the neck vessels of Lewis rats. Recipients were treated with S-PBN (n = 9), DSG (n = 9), S-PBN and DSG in combination (n = 10) or left untreated (n = 9) for survival studies. S-PBN was given daily intraperitoneally at a dose of 150 mg/kg body weight (BW) on day -1 to 30, and DSG was given daily intraperitoneally at a dose of 10 mg/kg BW on day -1 to 4 and 5 mg/kg BW on day 5 to 21. Nine additional recipients were given S-PBN only on days -1 and 0 in combination with continuous DSG treatment. Grafts were monitored until they stopped beating. Additional recipients were treated with S-PBN (n = 5), DSG (n = 5), S-PBN and DSG in combination (n = 6) or left untreated (n = 5) for morphological, immunohistochemical and flow cytometry analyses on days 2 and 6 after transplantation. Results: S-PBN treatment in combination with DSG resulted in increased median graft survival compared to DSG treatment alone (14 vs. 7 days; P = 0.019). Lower number of T lymphocytes on day 6 (P = 0.019) was observed by ex vivo propagation and flow cytometry when combining S-PBN with DSG, whereas immunohistochemical analyses demonstrated a significant reduction in the number of infiltrated CD4+, but not TCR+, cells. S-PBN treatment alone had no impact on graft survival compared to untreated rats (3 vs. 3 days). No differences were seen in ICAM-1 and VCAM-1 expression or in morphology between the groups. Conclusion: The combination of S-PBN and DSG treatment increases xenograft survival. The main effect of S-PBN appears to be in direct connection with the transplantation. Because of its low toxicity, S-PBN could become useful in combination with other immunosuppressants to reduce cell-mediated xenograft rejection.
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| 27. |
- Brandhorst, Heide, 1962-, et al.
(författare)
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A new oxygen carrier for improved long-term storage of human pancreata before islet isolation
- 2010
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 89:2, s. 155-60
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Pancreas oxygenation during cold storage has been established in islet isolation and transplantation to prevent ischemic tissue damage using perfluorodecalin (PFD) as hyperoxygen carrier. However, studies in humans and pigs provided conflicting results about the efficiency of PFD for pancreas oxygenation. The aim of this study was to compare PFD with a newly developed oxygen carrier composed of perfluorohexyloctane and polydimethylsiloxane 5 (F6H8S5) for long-term storage of human pancreata.METHODS: After 24-hr storage in preoxygenated PFD or F6H8S5, pancreata were processed using Liberase HI for pancreas dissociation and a Ficoll gradient for islet purification. Islet quality assessment was performed measuring glucose-stimulated insulin release, viability, islet ATP content, and posttransplant function in diabetic nude mice.RESULTS: Compared with PFD, F6H8S5 significantly increased the intrapancreatic partial oxygen pressure and islet ATP content. This corresponded to an increase of islet yield, recovery after culture, glucose stimulation index, viability, and improved graft function in diabetic nude mice.CONCLUSIONS: The present findings indicate clearly that F6H8S5 improves isolation outcome after prolonged ischemia compared with PFD. This observation seems to be related to the significant lipophilicity and almost pancreas-specific density of F6H8S5. Moreover, these characteristics facilitate pancreas shipment without using custom-made transport vessels as required for PFD.
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| 28. |
- Brandhorst, Heide, et al.
(författare)
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Large-Scale Comparison of Liberase HI and Collagenase NB1 Utilized for Human Islet Isolation
- 2010
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Ingår i: Cell Transplantation. - 0963-6897 .- 1555-3892. ; 19:1, s. 3-8
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Tidskriftsartikel (refereegranskat)abstract
- For more than a decade Liberase HI was commonly used as the standard enzyme blend for clinical human islet isolation until enforced replacement by collagenase NB1 (NB1). This change resulted initially in a reduction in islet isolation outcome and transplant activities worldwide. This retrospective study was initiated to compare the efficiency of NB1 premium grade with Liberase in 197 human islet isolations. All pancreata were processed between January 2006 and June 2008 utilizing the same procedures for isolation and quality assessment except the administration of preselected lots of either Liberase (n = 101) or NB1 (n = 96). Utilizing Liberase significantly more digested tissue and purified islet yield was produced compared to NB1. In contrast, the use of NB1 was associated with significantly higher purity and glucose stimulation index during dynamic perifusion. The expression of proinflammatory markers was almost identical except tissue factor expression that was higher after utilization of Liberase. No difference was found in the percentage of pancreata fulfilling the criteria for clinical islet transplantation. The results suggest that Liberase is more efficient for pancreas dissociation than collagenase NB1 but seems to be more harmful to exocrine cells and islet tissue.
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| 29. |
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| 30. |
- Brandhorst, Heide, 1962-, et al.
(författare)
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The importance of tryptic-like activity in purified enzyme blends for efficient islet isolation
- 2009
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 87:3, s. 370-5
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The isolation of islets from the human pancreas critically depends on an efficient enzyme blend. Previous studies have solely focused on the presence of collagenase and neutral protease/thermolysin. Despite improved characterization of these components, the lot-related variability in efficacy still persists suggesting that additional so far disregarded enzymes are required for efficient islet cleavage. METHODS: Varying activities of a tryptic-like enzyme were identified within collagenase NB1 lots, which were selected according to a matched ratio between tryptic-like and collagenase activity (TLA-ratio). Rat and human pancreata were processed with current standard procedures. RESULTS: Increasing the TLA-ratio from 1.3% to 10% reduced pancreas dissociation time in rats by 50% without affecting islet yield, viability, or posttransplant function in diabetic nude mice. Enhancing the TLA-ratio from 1.3% to 12.6% for human pancreas processing resulted in a significant reduction of recirculation time and increased incrementally human islet yield without affecting purity, in vitro function or recovery after culture. Optimized pancreas digestion correlated with a higher percentage of islet preparations fulfilling quality criteria for clinical transplantation. CONCLUSIONS: We conclude that TLA is an effective component that should be included in moderate amounts in enzyme blends for human islet isolation to optimize the efficiency and minimize the lot-related variability.
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| 31. |
- Caballero-Corbalán, José, et al.
(författare)
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No beneficial effect of two-layer storage compared with UW-storage on human islet isolation and transplantation
- 2007
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Ingår i: Transplantation. - : Ovid Technologies (Wolters Kluwer Health). - 0041-1337 .- 1534-6080. ; 84:7, s. 864-869
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Tidskriftsartikel (refereegranskat)abstract
- Background. Shipment of pancreata between distant centers is frequently associated with prolonged cold ischemia time (CIT) that leads to poorer outcomes for islet transplantation. Clinical pilot trials have indicated that oxygenation of explanted human pancreata utilizing the two-layer method (TLM) allows the use of marginal donor pancreata for islet transplantation. The present study aimed to clarify whether TLM enhances the ischemic tolerance of human pancreata. Methods. We analyzed retrospectively the outcome of 200 human islet isolations performed after TLM preservation or storage in University of Wisconsin solution (UWS). Results. Donor characteristics and digestion parameters did not vary significantly between TLM-preserved and UWS-stored pancreata. No differences were observed between experimental groups with regard to islet yield, purity, or dynamic glucose stimulation index after either short or prolonged CIT. However, CIT and stimulation index were negatively correlated in each experimental group. The isolation outcome in donors aged ≥60 years was not increased after TLM preservation when compared to UWS storage. No effect was observed regarding islet posttransplant function in recipients with established kidney grafts. Conclusions. The present study suggests that the ischemic tolerance of human pancreata cannot be extended by TLM preservation. In addition, TLM does not seem to improve the isolation outcome for pancreata from elderly donors.
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| 32. |
- Caballero-Corbalán, José, et al.
(författare)
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Using HTK for Prolonged Pancreas Preservation Prior to Human Islet Isolation
- 2012
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Ingår i: Journal of Surgical Research. - : Elsevier BV. - 1095-8673 .- 0022-4804. ; 175:1, s. 163-168
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Tidskriftsartikel (refereegranskat)abstract
- Background. Histidine-tryptophan-ketoglutarate (HTK) has been established as an alternative to University-of-Wisconsin solution (UWS) for abdominal organ preservation, but data about HTK efficiency to preserve pancreata during prolonged cold ischemia time (CIT) are conflicting. In human islet transplantation, HTK provided similar isolation outcomes after short CIT. The present study aimed to investigate whether islets can be successfully isolated from HTK-preserved pancreata after prolonged CIT compared with UWS. Materials and Methods. Sixty-four human pancreata retrieved from donors meeting criteria for kidney donation were perfused utilizing either HTK or UWS and preserved for more or less than 10 h prior to islet isolation. Along with parameters related to isolation and islet quality assessment, the dry-to-wet weight ratio was evaluated. Results. Donor-and procurement-related factors did not vary between HTK- and UWS-perfused pancreata. The dry-to-wet weight ratio was lower in HTK-preserved pancreata indicated tissue edema (21.0% +/- 3.5% versus 24.8% +/- 2.0%, P = 0.007). Isolation-related variables differed between experimental groups after prolonged CIT with respect to purified packed tissue volume (9.1 +/- 5.0 versus 17.2 +/- 8.1 mu L/g, P = 0.004) and islet yield (1910 +/- 980 versus 3150 +/- 1420 IE/g, P = 0.012). Islet purity and survival after culture were similar after HTK or UWS perfusion. The preservation solution did not affect in vitro function and transplantability of isolated islets. Conclusions. Compared with UWS, HTK has similar efficiency to preserve human pancreata for subsequent islet isolation during <10 h CIT but seems to be limited for prolonged cold storage. (C) 2012 Elsevier Inc. All rights reserved.
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| 33. |
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| 34. |
- Cabric, Sanja, et al.
(författare)
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Islet Surface Heparinization Prevents the Instant-Blood Mediated Inflammatory Reaction in Islet Transplantation
- 2007
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 56:8, s. 2008-2015
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE—In clinical islet transplantation, the instant blood-mediated inflammatory reaction (IBMIR) is a major factor contributing to the poor initial engraftment of the islets. This reaction is triggered by tissue factor and monocyte chemoattractant protein (MCP)-1, expressed by the transplanted pancreatic islets when the islets come in contact with blood in the portal vein. All currently identified systemic inhibitors of the IBMIR are associated with a significantly increased risk of bleeding or other side effects. To avoid systemic treatment, the aim of the present study was to render the islet graft blood biocompatible by applying a continuous heparin coating to the islet surface.RESEARCH DESIGN AND METHODS—A biotin/avidin technique was used to conjugate preformed heparin complexes to the surface of pancreatic islets. This endothelial-like coating was achieved by conjugating barely 40 IU heparin per full-size clinical islet transplant.RESULTS—Both in an in vitro loop model and in an allogeneic porcine model of clinical islet transplantation, this heparin coating provided protection against the IBMIR. Culturing heparinized islets for 24 h did not affect insulin release after glucose challenge, and heparin-coated islets cured diabetic mice in a manner similar to untreated islets.CONCLUSIONS—This novel pretreatment procedure prevents intraportal thrombosis and efficiently inhibits the IBMIR without increasing the bleeding risk and, unlike other pretreatment procedures (e.g., gene therapy), without inducing acute or chronic toxicity in the islets.
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| 35. |
- Chapman, Jeremy, et al.
(författare)
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Follow-up after renal transplantation with organs from donors after cardiac death
- 2006
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Ingår i: Transplant International. - : Frontiers Media SA. - 0934-0874 .- 1432-2277. ; 19:9, s. 715-719
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Tidskriftsartikel (refereegranskat)abstract
- Kidneys obtained from donors after cardiac death (DCD) are known to have higher rates of primary nonfunction and delayed graft function (DGF) than heart beating cadaveric donor (CAD) kidneys, but little is known about long-term function of DCD grafts that survive to 1 year. To investigate the outcomes of renal transplant recipients whose DCD graft functioned for at least 1 year, this study analyzed data collected from 326 DCD graft recipients and 340 CAD-matched controls enrolled in a prospective, multinational, observational study - Neoral (R)-MOST (Multinational Observational Study in Transplantation) (Novartis, Basel, Switzerland). No differences were found in the demographics or immunosuppression between the two groups. All patients received a Neoral (R)-based immunosuppressive regimen. Donors after cardiac death graft recipients had a higher incidence of DGF (40% vs. 27% CAD; P < 0.001). One year glomerular filtration rate (GFR) and GFR-decline after 1 year were similar in DCD and CAD recipients (GFR 56 ml/min DCD vs. 59 ml/min CAD; GFR-decline -1.3 ml/min DCD vs. -1.4 ml/min CAD; P = not significant). Multifactorial analyses confirmed that GFR at 1 year was significantly influenced by donor age and gender, DGF, and acute rejection; however, DCD status was not an independent risk factor in cyclosporine-treated patients with grafts that had functioned for at least 1 year.
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| 36. |
- Dyachok, Oleg, et al.
(författare)
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Ca2+-induced Ca2+ release by activation of inositol 1,4,5-trisphosphate receptors in primary pancreatic β-cells
- 2004
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Ingår i: Cell Calcium. - : Elsevier BV. - 0143-4160 .- 1532-1991. ; 36:1, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- The effect of sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) inhibition on the cytoplasmic Ca2+ concentration ([Ca2+]i) was studied in primary insulin-releasing pancreatic β-cells isolated from mice, rats and human subjects as well as in clonal rat insulinoma INS-1 cells. In Ca2+-deficient medium the individual primary β-cells reacted to the SERCA inhibitor cyclopiazonic acid (CPA) with a slow rise of [Ca2+]i followed by an explosive transient elevation. The [Ca2+]i transients were preferentially observed at low intracellular concentrations of the Ca2+ indicator fura-2 and were unaffected by pre-treatment with 100 μM ryanodine. Whereas 20 mM caffeine had no effect on basal [Ca2+]i or the slow rise in response to CPA, it completely prevented the CPA-induced [Ca2+]i transients as well as inositol 1,4,5-trisphosphate-mediated [Ca2+]i transients in response to carbachol. In striking contrast to the primary β-cells, caffeine readily mobilized intracellular Ca2+ in INS-1 cells under identical conditions, and such mobilization was prevented by ryanodine pre-treatment. The results indicate that leakage of Ca2+ from the endoplasmic reticulum after SERCA inhibition is feedback-accelerated by Ca2+-induced Ca2+ release (CICR). In primary pancreatic β-cells this CICR is due to activation of inositol 1,4,5-trisphosphate receptors. CICR by ryanodine receptor activation may be restricted to clonal β-cells.
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| 37. |
- Eich, Torsten, 1972-, et al.
(författare)
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Calcium: A Crucial Potentiator for Efficient Enzyme Digestion of the Human Pancreas
- 2018
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Ingår i: Cell Transplantation. - : SAGE Publications. - 0963-6897 .- 1555-3892. ; 27:7, s. 1031-1038
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Tidskriftsartikel (refereegranskat)abstract
- Background: Effective digestive enzymes are crucial for successful islet isolation. Supplemental proteases are essential because they synergize with collagenase for effective pancreatic digestion. The activity of these enzymes is critically dependent on the presence of Ca2+ ions at a concentration of 5-10 mM. The present study aimed to determine the Ca2+ concentration during human islet isolation and to ascertain whether the addition of supplementary Ca2+ is required to maintain an optimal Ca2+ concentration during the various phases of the islet isolation process. Methods: Human islets were isolated according to standard methods and isolation parameters. Islet quality control and the number of isolations fulfilling standard transplantation criteria were evaluated. Ca2+ was determined by using standard clinical chemistry routines. Islet isolation was performed with or without addition of supplementary Ca2+ to reach a Ca2+ of 5 mM. Results: Ca2+ concentration was markedly reduced in bicarbonate-based buffers, especially if additional bicarbonate was used to adjust the pH as recommended by the Clinical Islet Transplantation Consortium. A major reduction in Ca2+ concentration was also observed during pancreatic enzyme perfusion, digestion, and harvest. Additional Ca2+ supplementation of media used for dissolving the enzymes and during digestion, perfusion, and harvest was necessary in order to obtain the concentration recommended for optimal enzyme activity and efficient liberation of a large number of islets from the human pancreas. Conclusions: Ca2+ is to a large extent consumed during clinical islet isolation, and in the absence of supplementation, the concentration fell below that recommended for optimal enzyme activity. Ca2+ supplementation of the media used during human pancreas digestion is necessary to maintain the concentration recommended for optimal enzyme activity. Addition of Ca2+ to the enzyme blend has been implemented in the standard isolation protocols in the Nordic Network for Clinical Islet Transplantation.
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| 38. |
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| 39. |
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| 40. |
- Engstrand, Mats
(författare)
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Cellular Immune Responses to Allografts and Cytomegalovirus
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Today the immunosuppressive treatment is kept to a level were the incidence of acute rejection is below 20% within the first year after transplantation. As a consequence, a group of transplanted patients is over-immunosuppressed and at risk for infections. There is therefore an urgent need for tools which are able to determine the cellular immune response after organ transplantation. This knowledge would facilitate the task of prospectively opimize the immunosuppressive treatment and identify patients at risk of developing rejection episodes or infections.To address this issue, a rat-kidney transplantation model for acute rejection was developed to study immune responses to allografts. Infiltrating lymphocytes were analysed using an in vitro culture system which allowed cells to propagate from the biopsies to culture medium. The numbers of outgrowing cells were correlated with morphological and immunohistochemical signs of rejection. When immunosuppressive treatment was administered for 2 and four days after acute rejection, histology did not reveal any improvement, however cellular propagation was reduced by 50 and 75%, respectively. Using the tissue culture technique in human transplanted kidney grafts, which was originally developed for the animal model, the number of propagated cells measured was profoundly higher in grafts with acute cellular rejection than from grafts in other groups. In some cases the number of propagated cells was better correlated with the clinical outcome than the diagnosis made by morphological evaluation. To determine immune responses to cytomegalovirus (CMV), we utilised Human Leukocyte Antigen (HLA) tetramer staining and stimulation of T cells with viral antigens. Both of these techniques independently detected CMV specific T cells in immunosuppressed and healthy individuals with latent or active infection. Although the frequency of CMV specific T cells did not differ between groups, there was a functional impairment in immunosuppressed patients as evidenced by reduced interferon-gamma production. In conclusion, these techniques can be used to determine the cellular immune response to allografts and cytomegalovirus and prove valuable for the optimization of immunosuppressive protocols and antiviral treatment.
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| 41. |
- Engstrand, Mats, et al.
(författare)
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Lymphocyte propagation from biopsies of kidney allografts
- 2006
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Ingår i: Transplant Immunology. - : Elsevier BV. - 0966-3274 .- 1878-5492. ; 16:3-4, s. 215-219
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Tidskriftsartikel (refereegranskat)abstract
- Morphological evaluation of transplant biopsies, usually using the Banff classification, is the most important tool to diagnose rejection after kidney transplantation. However, morphological analysis only scores the amount and localisation of infiltrating cells, and studies show that up to 30% of grafts with a stable function display infiltration of lymphocytes consistent with acute cellular rejection. Methods to study the functional properties of the infiltrating lymphocytes are therefore needed. We applied a tissue culture system on biopsies from transplanted human kidneys, allowing infiltrating cells to propagate out from the tissue. Cells were then counted and subtyped by flow cytometry. The results were correlated to morphology. In total, 92 biopsies from 69 patients were analysed. For 14 patients, serial biopsies were available. In grafts with cellular or combined cellular and vascular rejection, the number of ex vivo propagated mononuclear cells was higher than from non-rejecting grafts. A similar pattern was seen for CD3(+) T cells as well as for T cells expressing CD25 or MHC class II antigens. However, the proportion of CD25(+) or MHC class II(+) T lymphocytes was similar in all groups (no rejection, vascular rejection, borderline changes, cellular rejection, combined cellular and vascular rejection). In all groups the number of CD4(+) cells was higher than the number of CD8(+) cells. The results confirm previous experimental studies showing that graft-infiltrating cells are possible to culture in vitro and that lymphocyte propagation correlates to acute cellular rejection. Tissue culturing is easy to perform and evaluate and can be used to determine and analyse the cellular immune response to allografts and may thus be used as a complement to morphological analyses.
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| 42. |
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| 43. |
- Eriksson, Britt-Marie, et al.
(författare)
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A prospective study of rapid methods of detecting cytomegalovirus in the blood of renal transplant recipients in relation to patient and graft survival
- 1996
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Ingår i: Clinical Transplantation. - 0902-0063 .- 1399-0012. ; 10:6 Pt 1, s. 494-502
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Tidskriftsartikel (refereegranskat)abstract
- Eighty-five renal transplant recipients were prospectively monitored for CMV infection up to 4 months post-transplantation by virus isolation from leukocytes, CMV antigen detection (pp65) in peripheral blood leukocytes (PBL), polymerase chain reaction (PCR) of alkaline treated plasma (P-PCR), PCR of extracted DNA from PBL (L-PCR) and serology. Additionally univariate and multivariate analyses of risk factors for patient and graft survival up to 4 yr post-transplantation were performed. The incidence of CMV infection was 78% and of CMV disease 33%. Antigen detection in PBL was positive before or at onset of symptoms in 23/24 (96%) evaluable patients with CMV disease. The corresponding figures for virus isolation were 22/24 (92%), P-PCR 21/24 (88%) and for L-PCR 18/24 (75%). The percentage of negative samples in patients without CMV disease was 89% for the antigen test, 92% for L-PCR and 83% for virus isolation and P-PCR. One rapid test (antigen test, P-PCR or L-PCR) was positive at a median of 16 d before the onset of symptoms. The antigen test was generally the first rapid test to become positive. CMV disease did not affect graft survival in the multivariate analysis but was associated with decreased patient survival.
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| 44. |
- Eriksson, Olof, et al.
(författare)
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Positron emission tomography in clinical islet transplantation
- 2009
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Ingår i: American Journal of Transplantation. - : Elsevier BV. - 1600-6135 .- 1600-6143. ; 9:12, s. 2816-2824
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Tidskriftsartikel (refereegranskat)abstract
- The fate of islets in clinical transplantation is unclear. To elude on this positron emission tomography combined with computed tomography (PET/CT) was performed for 60 min during islet transplantation in five patients receiving six transplants. A fraction of the islets (23%) were labeled with 18F-fluorodeoxyglucose ([(18)F]FDG) and carefully mixed with unlabeled islets just prior to intraportal transplantation. The peak radioactivity concentration in the liver was found at 19 min after start of islet infusion and corresponded to only 75% of what was expected, indicating that islets are lost during the transplantation procedure. No accumulation of radioactivity was found in the lungs. A nonphysiological peak of C-peptide was found in plasma during and immediately after transplantation in all subjects. Distribution in the liver was heterogeneous with wide variations in location and concentration. Islets found in areas with concentrations of >400 IEQ/cc liver tissue varied between 1% and 32% of the graft in different subjects. No side effects attributed to the PET/CT procedure were found. Clinical outcome in all patients was comparable to that previously observed indicating that the [(18)F]FDG labeling procedure did not harm the islets. The technique has potential to be used to assess approaches to enhance islet survival and engraftment in clinical transplantation.
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| 45. |
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| 46. |
- Fernberg, P., et al.
(författare)
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Time Trends in Risk and Risk Determinants of Non-Hodgkin Lymphoma in Solid Organ Transplant Recipients
- 2011
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Ingår i: American Journal of Transplantation. - : Elsevier BV. - 1600-6135 .- 1600-6143. ; 11:11, s. 2472-2482
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Tidskriftsartikel (refereegranskat)abstract
- Organ transplantation increases risk of non-Hodgkin lymphoma (NHL), but long-term risk and time trends have seldom been evaluated. Immunosuppressive drug load is an important risk determinant, but the details are unclear. We studied NHL risk in a nationwide Swedish cohort of 11 081 graft recipients transplanted 1970-2008. Relative risks (RRs) were estimated within the cohort and versus the general population by age, sex, follow-up time and calendar period. NHL risk was also assessed by cumulative and average doses of immunosuppressive treatments in a nested case-control design throughout 1997 using conditional logistic regression. We observed 153 NHL cases during 97 853 years of follow-up. Compared with the general population, NHL risk was eightfold increased (RR 7.9; 95% confidence interval [CI] 6.6-9.4), and increased risks persisted after >= 15 years of follow-up among kidney (6.1; 95% CI 3.5-10) and nonkidney recipients (44; 14-103). Among nonkidney recipients, NHL risk was lower in the 2000s compared with the 1990s (0.5; 95% CI 0.3-1.0; p = 0.04). A high average dose of antithymocyte immunoglobulin (ATG) conferred an eightfold increased risk of NHL (OR 8.5; 95% CI 1.9-38). To conclude, posttransplant NHL risk decreased during the last decade among nonkidney recipients, possibly because of a more careful use of ATG, the introduction of new drugs, or both.
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| 47. |
- Friberg, Andrew S, et al.
(författare)
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Transplantable functional islet mass – predictive biomarkers of graft function in islet after kidney transplanted patients
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The ability to predict clinical function of a specific islet batch released for clinical transplantation using standardized variables remains an elusive goal. Analysis of donor, islet isolation, quality control and recipient variables was undertaken in 110 islet after kidney (IAK) transplants and correlated to the pre- to 28-day posttransplant change in C-peptide to glucose and creatinine ratio (ΔCP/GCr). Using backward multiple regression the variables positively associated to ΔCP/GCr were islet volume transplanted (p<0.001) and glucose stimulated insulin secretion (SI) (p=0.009). Factors negatively associated to ΔCP/GCr were cold ischemia time (CIT) (p=0.002) and total tissue volume (p=0.009). Donor age, donor body mass index, number of retrieved organs from the donor, preservation solution, islet insulin content, body weight of the recipient of the islets had no influence on transplant function. The transplantable functional islet mass (TFIM), accounting for islet volume transplanted, SI, CIT, and total tissue volume explained 39% of the variance of the clinical outcome in the IAK data set. Therefore, the TFIM provides a straightforward and potent tool to guide the decision to utilize a specific islet preparation for clinical transplantation.
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| 48. |
- Friberg, Andrew S., et al.
(författare)
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Transplanted functional islet mass : donor islet preparation, and recipitent factors influence early graft function in islet-after-kidney patients
- 2012
-
Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 93:6, s. 632-638
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Tidskriftsartikel (refereegranskat)abstract
- Background.The ability to predict clinical function of a specific islet batch released for clinical transplantation using standardized variables remains an elusive goal.Methods. Analysis of 10 donor, 7 islet isolation, 3 quality control, and 6 recipient variables was undertaken in 110 islet-after-kidney transplants and correlated to the pre- to 28-day posttransplant change in C-peptide to glucose and creatinine ratio ([DELTA]CP/GCr).Results.Univariate analysis yielded islet volume transplanted (Spearman r=0.360, P<0.001) and increment of insulin secretion (r=0.377, P<0.001) as variables positively associated to [DELTA]CP/GCr. A negative association to [DELTA]CP/GCr was cold ischemia time (r=-0.330, P<0.001). A linear, backward-selection multiple regression was used to obtain a model for the transplanted functional islet mass (TFIM). The TFIM model, composed of islet volume transplanted, increment of insulin secretion, cold ischemia time, and exocrine tissue volume transplanted, accounted for 43% of the variance of the clinical outcome in the islet-after-kidney data set.Conclusion.The TFIM provides a straightforward and potent tool to guide the decision to use a specific islet preparation for clinical transplantation.
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| 49. |
- Friend, Peter, et al.
(författare)
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Incidence of anemia in sirolimus-treated renal transplant recipients : the importance of preserving renal function
- 2007
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Ingår i: Transplant International. - : Frontiers Media SA. - 0934-0874 .- 1432-2277. ; 20:9, s. 754-760
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Tidskriftsartikel (refereegranskat)abstract
- Sirolimus (SRL) has a concentration-related effect on hematopoiesis. In this study, 430 renal transplant recipients were randomized (1:1) 3 months post-transplantation to continue SRL-cyclosporine (CsA)-steroids (ST) or to have CsA withdrawn (SRL-ST). Over 5 years, on therapy calculated glomerular filtration rate (GFR), hematological indices, erythropoietin (EPO) use, and rates of mild, moderate, and severe anemia were determined. Longitudinal analyses using linear mixed models examined covariates predicting hemoglobin (Hgb) levels. Mean Hgb was significantly lower with SRL-ST at 6 months; but subsequently became significantly higher (at 2 years, 129 vs. 135 g/l, SRL-CsA-ST vs. SRL-ST, P<0.001). Mean corpuscular volume was low with both therapies, and significantly lower with SRL-ST. EPO use was similar in the two groups, approximately 30% during the first year and 10% thereafter. The incidence of anemia was significantly higher with SRL-CsA-ST>or=2 years. At year 5, only 39.1% of SRL-CsA-ST patients had normal Hgb vs. 68.5% of SRL-ST patients. GFR and recipient age as well as the interaction term x treatment time were significant covariates predicting Hgb. CsA withdrawal followed by SRL immunotherapy resulted in significantly less anemia than SRL-CsA-ST, despite twofold higher SRL exposure. This suggests that the improvement in GFR accompanying CsA withdrawal may mitigate the effect of SRL on hematopoiesis. (ClinicalTrials.gov number: NCT00428064).
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| 50. |
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