| 1. |
- Broecker, Verena, et al.
(författare)
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Uterus transplantation: Histological findings in explants at elective hysterectomy
- 2021
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Ingår i: American Journal of Transplantation. - : Elsevier BV. - 1600-6135. ; 21:2, s. 798-808
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Tidskriftsartikel (refereegranskat)abstract
- Uterus transplantation has enabled women with absolute uterine factor infertility to carry a pregnancy. The first human uterus transplantation trial was initiated in 2013 in Gothenburg, Sweden. It was completed with 7 transplantations with long-term allograft survival and 9 children born from 6 women. In the present study we describe the histopathology of these 7 allografts, which were removed at 22-83 months after transplantation, and compare findings to control cases. Morphological findings in a subset of explants included linear subepithelial inflammation and perivascular stromal inflammation in the cervix, small inflammatory foci in the myometrium, and intimal inflammation in larger arteries. The average number of T cells, B cells, and macrophages was higher in transplants compared to normal controls, but variability was high among transplants. Chronic-active vascular rejection was seen in 2 of 7 transplants, both showed also inflammation in the cervix. Further, the inflammation seen in the cervix reflected the inflammation in the myometrium, suggesting that cervical biopsies are suitable to monitor rejection. However, the degree of inflammation and signs of rejection in explants did not reflect on the possibility to become pregnant in this limited series.
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| 2. |
- Brännström, Mats, 1958, et al.
(författare)
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Live birth after robotic-assisted live donor uterus transplantation.
- 2020
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Ingår i: Acta obstetricia et gynecologica Scandinavica. - : Wiley. - 1600-0412 .- 0001-6349. ; 99:9, s. 1222-1229
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Tidskriftsartikel (refereegranskat)abstract
- The proof-of-concept of uterus transplantation, as a treatment for absolute uterine factor infertility, came with the first live birth after uterus transplantation, which took place in Sweden in 2014. This was after a live donor procedure, with laparotomy in both donor and recipient. In our second, ongoing trial we introduced a robotic-assisted laparoscopic surgery of the donor to develop minimal invasive surgery for this procedure. Here, we report the surgery and pregnancy behind the first live birth from that trial.In the present study, within a prospective observational study, a 62-year-old mother was the uterus donor and her 33-year-old daughter with uterine absence as part of the Mayer-Rokitansky-Küster-Hauser syndrome, was the recipient. Donor surgery was mainly done by robotic-assisted laparoscopy, involving dissections of the utero-vaginal fossa, arteries and ureters. The last part of surgery was by laparotomy. Recipient laparotomy included vascular anastomoses to the external iliac vessels. Data relating to in vitro fertilization, surgery, follow up, obstetrics and postnatal growth are presented.Three in vitro fertilization cycles prior to transplantation gave 12 cryopreserved embryos. The surgical time of the donor in the robot was 360minutes, according to protocol. The durations for robotic surgery for dissections of the utero-vaginal fossa, arteries and ureters were 30, 160 and 84minutes, respectively. The remainder of donor surgery was by laparotomy. Recipient surgery included preparations of the vaginal vault, three end-to-side anastomoses (one arterial, two venous) on each side to the external iliacs and fixation of the uterus. Ten months after transplantation, one blastocyst was transferred and resulted in pregnancy, which proceeded uneventfully until elective cesarean section in week 36+1 . A healthy boy (Apgar 9-10-10) was delivered. Follow up of child has been uneventful for 12months.This is the first report of a live birth after use of robotic-assisted laparoscopy in uterus transplantation and is thereby a proof-of-concept of use of minimal invasive surgery in this new type of transplantation.
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| 3. |
- Brännström, Mats, 1958, et al.
(författare)
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Livebirth after uterus transplantation.
- 2015
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Ingår i: Lancet. - 1474-547X. ; 385:9968, s. 607-616
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Tidskriftsartikel (refereegranskat)abstract
- Uterus transplantation is the first available treatment for absolute uterine infertility, which is caused by absence of the uterus or the presence of a non-functional uterus. Eleven human uterus transplantation attempts have been done worldwide but no livebirth has yet been reported.
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| 4. |
- Brännström, Mats, 1958, et al.
(författare)
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One uterus bridging three generations: first live birth after mother-to-daughter uterus transplantation
- 2016
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Ingår i: Fertility and Sterility. - : Elsevier BV. - 0015-0282 .- 1556-5653. ; 106:2, s. 261-266
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To determine whether a uterus from the mother of a woman with absolute uterine factor infertility can be transplanted to daughter and carry a pregnancy with delivery of a healthy child. Patient(s): Twenty eight-year-old woman with uterine agenesis, her male partner, and her 50-year-old mother. Intervention(s): In vitro fertilization with embryo cryopreservation before live donor uterus transplantation (UTx). Induction immunosuppression. Embryo transfer 12 months after UTx, pregnancy controls, delivery, and hysterectomy. Main Outcome Measure(s): Results of IVF-ET, parameters of pregnancy/birth, and surgical data of transplantation/cesarean section/hysterectomy. Result(s): Two IVF cycles before UTx resulted in 10 cryopreserved embryos. Donor surgery included hysterectomy with vascular pedicles of uterine vessels and proximal vessels up to and including parts of internal iliacs. Recipient surgery was by bilateral vascular connections to external iliacs, vaginal-vaginal anastomosis, and uterine fixation. Pregnancy occurred at the first single ET, and the pregnancy proceeded uneventfully until gestational week 34, when the patient developed cholestasis with intense pruritus. Cesarean section was performed at 34+6, with delivery of a healthy boy (weight 2,335 g). Hysterectomy was performed 3.5 months after delivery. The weight of the healthy child at 12 months was 9.3 kg. Grandmother (uterus donor) and mother are in good health 3 years after UTx. Conclusion(s): This is the first report of a live birth after mother-to-daughter UTx, and it also represents the second birth ever after human UTx. (C) 2016 by American Society for Reproductive Medicine.
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| 5. |
- Brännström, Mats, 1958, et al.
(författare)
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Outcome of Recipient Surgery and 6-Month Follow-Up of the Swedish Live Donor Robotic Uterus Transplantation Trial.
- 2020
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Ingår i: Journal of clinical medicine. - : MDPI AG. - 2077-0383. ; 9:8
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Tidskriftsartikel (refereegranskat)abstract
- Uterus transplantation has proved to be a feasible treatment for uterine factor infertility. Herein, we report on recipient outcome in the robotic uterus transplantation trial of 2017-2019. The eight recipients had congenital uterine aplasia. The donors were six mothers, one sister, and one family friend. Donor surgery was by robotic-assisted laparoscopy. Recipient surgery was by laparotomy and vascular anastomoses to the external iliacs. The duration (median (ranges)) of recipient surgery, blood loss, measured (left/right) uterine artery blood flow after reperfusion, and length of hospital stay were 5.15 h (4.5-6.6), 300 mL (150-600), 43.5 mL/min (20-125)/37.5 mL/min (10-98), and 6 days (5-9), respectively. Postoperative uterine perfusion evaluated by color Doppler showed open anastomoses but restricted blood distribution in two cases. Repeated cervical biopsies in these two cases initially showed ischemia and, later, necrosis. Endometrial growth was not seen, and hysterectomy was later performed, with pathology showing partly viable myometrium and fibrosis but necrosis towards the cavity. The other six patients acquired regular menstrual cyclicity. Surgery was performed in two patients to correct vaginal stenosis. Reversible rejection episodes were seen in two patients. In conclusion, the rate of viable uterine grafts during the initial 6-months of the present study (75%) leaves room for improvement in the inclusion/exclusion criteria of donors and in surgical techniques. Initial low blood flow may indicate subsequent graft failure.
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| 6. |
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| 7. |
- Mölne, Johan, 1958, et al.
(författare)
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Monitoring of human uterus transplantation with cervical biopsies - a provisional scoring system for rejection.
- 2017
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Ingår i: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. - : Elsevier BV. - 1600-6143. ; 17:6, s. 1628-1636
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Tidskriftsartikel (refereegranskat)abstract
- Until now, absolute uterine factor infertility has been the major untreatable form of female infertility. Recently, uterus transplantation has proven to be the first successful treatment for absolute uterine factor infertility, with demonstration of live births. Here, live donation uterus transplantation was performed in nine women. 163 cervical biopsies (149 protocol, 14 follow-up) were taken to detect histopathological signs of rejection. Based on experience from animal experiments, we used a three-grade scoring system to evaluate biopsies systematically. Nine episodes of rejection were diagnosed in five patients: grade-1 in six episodes, grade-2 in two episodes and grade-3 in one episode. Treatment decisions were based on histopathology, and all rejection episodes were reversed after treatment. The biopsies were reviewed retrospectively and immunohistochemistry was performed to characterize the inflammatory infiltrates. A borderline category was introduced to avoid overtreatment of patients. Based on our review of all biopsies, we put forward a simple grading system for monitoring of rejection and to guide immunosuppressive treatment in uterus transplantation. This article is protected by copyright. All rights reserved.
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| 8. |
- Davidson, Thomas, et al.
(författare)
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The costs of human uterus transplantation: a study based on the nine cases of the initial Swedish live donor trial
- 2021
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Ingår i: Human Reproduction. - : Oxford University Press (OUP). - 0268-1161 .- 1460-2350. ; 36:2, s. 358-366
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Tidskriftsartikel (refereegranskat)abstract
- STUDY QUESTION: What are the costs of live donor uterus transplantation in a European setting? SUMMARY ANSWER: The total costs for preoperative investigations, including IVF, and live donor uterus transplantation including postoperative costs for 2 months, were calculated to be (sic) 74 564 (mean), with the costs of recipient being somewhat higher than for donor and the cost components of total costs distributed between sick leave (25.7%), postoperative hospitalization (17.8%), surgery (17.1%), preoperative investigations (15.7%), anaesthesia (9.7%), drugs (7.8%), tests after surgery (4.0%) and for re-hospitalization (2.2%). WHAT IS KNOWN ALREADY: Uterus transplantation has proved to be successful by demonstrations of live births, both after live donor and deceased donor procedures. The transplantation is considered as a complex and expensive infertility treatment. There exist no analyses of costs involved in uterus transplantation. STUDY DESIGN, SIZE, DURATION: This prospective cohort study included nine uterus transplantations procedures, performed in Sweden in 2013. Study duration of this health economic study included 6-12 months of pre-transplantation investigations and the time interval from transplantation to 2 months after. PARTICIPANTS/MATERIALS, SETTING, METHODS: Nine triads of uterus recipient, partner of recipient and uterus donor participated. All prospective recipients were in stable relationships and performed IVF with their partners before transplantation. The nine donors were relatives or family friends. The recipients and donors underwent pre-transplantation investigations with imaging, laboratory tests and psychological/medical screening prior to transplantation. Transplantation was by laparotomy in both donor and recipient. Standard immunosuppression and postoperative medication were used. After discharge from the hospital, the recipients were followed frequently with laboratory tests and examinations. MAIN RESULTS AND THE ROLE OF CHANCE: The mean costs for preoperative investigations, including IVF, and live donor uterus transplantation with postoperative costs for 2 months, were calculated to be (sic)74 564 (range (sic) 50 960-(sic)99 658), from a societal perspective. The four largest components were cost of sick leave (sic) 19 164), cost of postoperative hospitalization (sic)13 246), surgery cost (sic)12 779) and costs for preoperative investigations, including IVF (sic) 11 739). Smaller components were costs for anaesthesia (sic) 7207), costs for drugs (sic) 5821), costs for post-surgical tests (sic) 2985) and costs for re-hospitalization (sic)1623). The costs of the recipient (sic) 42 984) were somewhat higher than the costs of the donor (sic) 31 580), but in terms of costs, they should be viewed as one entity. By using a health care perspective, excluding cost for productivity loss, the total costs would be reduced by 26%. LIMITATIONS, REASONS FOR CAUTION: A limitation is the restricted sample size and that this is in the experimental, clinical stage of development. WIDER IMPLICATIONS OF THE FINDINGS: The results provide the first information concerning the costs for pre-transplantation investigations and uterus transplantation procedures with postoperative follow-up. We consider the total estimate to be in the higher interval, because of the extensive research protocol. It is likely that the cost of live donor uterus transplantation will vary between countries and that the costs will be lower in a future clinical setting.
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| 9. |
- Ekberg, Jana, 1964, et al.
(författare)
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A Randomized Controlled Trial on Safety of Steroid Avoidance in Immunologically Low-Risk Kidney Transplant Recipients
- 2022
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Ingår i: Kidney International Reports. - : Elsevier BV. - 2468-0249. ; 7:2, s. 259-269
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Steroid-based immunosuppression after transplantation increases the risk of post-transplant diabetes mellitus (PTDM), with adverse effects on patient and graft survival. In the SAILOR study, we investigated the safety and efficacy of complete steroid avoidance in immunologically low-risk kidney recipients without diabetes on the current standard-of-care maintenance regimen with tacrolimus/mycophenolate mofetil (MMF). Methods: In this 2-year, multicenter, open-label trial, a total of 222 patients were randomized to receive either steroid avoidance protocol (tacrolimus/MMF/antithymocyte globulin [ATG] induction [n = 113]) or steroid maintenance protocol (tacrolimus/MMF/prednisolone/basiliximab-induction [n = 109]). Results: At 1 year, no significant differences were found between steroid avoidance and steroid maintenance arms in the incidence of PTDM, the primary end point (12.4% vs. 18.3%, respectively, P = 0.30, CI: 16.3–4.4), or in overall biopsy-proven rejections (15% vs. 13.8%, respectively, P = 0.85). At 2 years, the composite end point of freedom from acute rejection, graft loss, and death (81% vs. 85%, respectively, P = 0.4), kidney function, or adverse events was comparable between the 2 arms. Moreover, 63.9% of the patients in the steroid avoidance arm remained free from steroids at 2 years. Conclusion: The SAILOR study provides further evidence for the feasibility, safety, and efficacy of early steroid-free treatment at 2 years in immunologically low-risk kidney recipients with tacrolimus/MMF maintenance regimen. © 2021 International Society of Nephrology
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| 10. |
- Ekberg, Jana, 1964, et al.
(författare)
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Long-term Course of Kidney Function in Uterus Transplant Recipients Under Treatment With Tacrolimus and After Transplantectomy: Results of the First Clinical Cohort
- 2023
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Ingår i: TRANSPLANTATION DIRECT. - 2373-8731. ; 9:10
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Tidskriftsartikel (refereegranskat)abstract
- Background.Chronic kidney disease is common after non-renal solid organ transplantation, mainly secondary to calcineurin inhibitors toxicity. Uterus transplantation (UTx) is an innovative treatment for women with absolute uterine factor infertility. UTx is exclusive because it is transient with the absence of lifelong immunosuppression and is performed in young healthy participants. Therefore, UTx provides a unique setting for evaluating the effect of time-limited calcineurin inhibitors treatment on recipients' kidney function.Methods.In the first UTx cohort worldwide, we studied kidney function using estimated glomerular filtration rate (eGFR) in 7 women over a median follow-up of 121 (119-126) mo.Results.Median eGFR (mL/min/1.73 m2) of the cohort was 113 at UTx, which declined to 74 during month 3, 71 at months 10-12, 76 at hysterectomy (HE), and 83 at last follow-up. Median duration of tacrolimus exposure was 52 (22-83) mo, and median trough levels (mu g/L) were 10 during month 3 and 5.8 at HE. Between UTx and month 3, decline in kidney function was observed in all 7 participants with a median eGFR slope for the whole cohort of -24 mL/min/1.73 m2, which declined further by -4 mL/min/1.73 m2 until months 10-12. Thereafter, eGFR slope improved in 3 participants, remained stable in 3, and worsened in 1 until HE/tacrolimus discontinuation, after which it improved in 2. Eventually, between UTx and last follow-up, 4 of 7 participants had a decline in their eGFR, the median annual eGFR slope being negative at -1.9 mL/min/1.73 m2/y for the whole group.Conclusions.Kidney function declined in all recipients early after UTx followed by a persistent long-term decrease in majority, despite transplantectomy and discontinuation of immunosuppression. Thus, UTx may incur an increased risk of chronic kidney disease even in this young and healthy population, highlighting the importance of close surveillance of kidney function and minimization of tacrolimus exposure.
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| 11. |
- Larsson, P., et al.
(författare)
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Difficult-to-Treat Rejections in Kidney Transplant Recipients: Our Experience with Everolimus-Based Quadruple Maintenance Therapy
- 2023
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Ingår i: Journal of Clinical Medicine. - 2077-0383. ; 12:20
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Tidskriftsartikel (refereegranskat)abstract
- All chronic and treatment-resistant acute rejections are "difficult-to-treat" and lead to progressive loss of graft function in kidney transplant recipients (KTR), as no effective treatment exists for such rejections to date. We review our experience with a novel strategy to treat such rejections by adding everolimus as a "rescue" to conventional triple maintenance therapy with prednisolone, mycophenolate mofetil and calcineurin inhibitor. We retrospectively analysed data in 28 KTR who received everolimus-based quadruple therapy at our institution for biopsy-proven chronic active T cell-mediated or antibody-mediated rejection (n = 19) or treatment-resistant acute rejections (n = 9) between 2011-2017. The primary outcome was 5-year death-censored graft survival. Main secondary outcomes were response to treatment defined by stable or improved graft function, 5-year patient survival and discontinuation rate of treatment. The Kaplan-Meier estimate for 5-year death-censored graft survival was 79% in all patients, 90% for patients with chronic active T cell-mediated rejections, 78% for chronic active antibody-mediated rejection and 67% for acute rejections. Response to treatment was achieved in 43% and 5-year patient survival was 94%. Treatment was stopped in 12 (43%) patients due to adverse events. Everolimus-based maintenance quadruple therapy, despite high rate of everolimus discontinuation due to adverse events, may be a valid approach in a subset of kidney transplant recipients with such difficult-to-treat rejections, which otherwise would lead to a high rate of graft loss.
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| 12. |
- Streichart, Lillian, 1983, et al.
(författare)
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Tocilizumab in chronic active antibody-mediated rejection: rationale and protocol of an in-progress randomized controlled open-label multi-center trial (INTERCEPT study)
- 2024
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Ingår i: TRIALS. - : BioMed Central (BMC). - 1745-6215. ; 25:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundChronic active antibody-mediated rejection (caAMR) in kidney transplants is associated with irreversible tissue damage and a leading cause of graft loss in the long-term. However, the treatment for caAMR remains a challenge to date. Recently, tocilizumab, a recombinant humanized monoclonal antibody directed against the human interleukin-6 (IL-6) receptor, has shown promise in the treatment of caAMR. However, it has not been systematically investigated so far underscoring the need for randomized controlled studies in this area.MethodsThe INTERCEPT study is an investigator-driven randomized controlled open-label multi-center trial in kidney transplant recipients to assess the efficacy of tocilizumab in the treatment of biopsy-proven caAMR. A total of 50 recipients with biopsy-proven caAMR at least 12 months after transplantation will be randomized to receive either tocilizumab (n = 25) added to our standard of care (SOC) maintenance treatment or SOC alone (n = 25) for a period of 24 months. Patients will be followed for an additional 12 months after cessation of study medication. After the inclusion biopsies at baseline, protocol kidney graft biopsies will be performed at 12 and 24 months. The sample size calculation assumed a difference of 5 ml/year in slope of estimated glomerular filtration rate (eGFR) between the two groups for 80% power at an alpha of 0.05.The primary endpoint is the slope of eGFR at 24 months after start of treatment. The secondary endpoints include assessment of the following at 12, 24, and 36 months: composite risk score iBox, safety, evolution and characteristics of donor-specific antibodies (DSA), graft histology, proteinuria, kidney function assessed by measured GFR (mGFR), patient- and death-censored graft survival, and patient-reported outcomes that include transplant-specific well-being, adherence to immunosuppressive medications and perceived threat of the risk of graft rejection.MethodsThe INTERCEPT study is an investigator-driven randomized controlled open-label multi-center trial in kidney transplant recipients to assess the efficacy of tocilizumab in the treatment of biopsy-proven caAMR. A total of 50 recipients with biopsy-proven caAMR at least 12 months after transplantation will be randomized to receive either tocilizumab (n = 25) added to our standard of care (SOC) maintenance treatment or SOC alone (n = 25) for a period of 24 months. Patients will be followed for an additional 12 months after cessation of study medication. After the inclusion biopsies at baseline, protocol kidney graft biopsies will be performed at 12 and 24 months. The sample size calculation assumed a difference of 5 ml/year in slope of estimated glomerular filtration rate (eGFR) between the two groups for 80% power at an alpha of 0.05.The primary endpoint is the slope of eGFR at 24 months after start of treatment. The secondary endpoints include assessment of the following at 12, 24, and 36 months: composite risk score iBox, safety, evolution and characteristics of donor-specific antibodies (DSA), graft histology, proteinuria, kidney function assessed by measured GFR (mGFR), patient- and death-censored graft survival, and patient-reported outcomes that include transplant-specific well-being, adherence to immunosuppressive medications and perceived threat of the risk of graft rejection.DiscussionNo effective treatment exists for caAMR at present. Based on the hypothesis that inhibition of IL-6 receptor by tocilizumab will reduce antibody production and reduce antibody-mediated damage, our randomized trial has a potential to provide evidence for a novel treatment strategy for caAMR, therewith slowing the decline in graft function in the long-term.
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| 13. |
- Young, M. H. H., et al.
(författare)
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Immunosuppression and treatment of rejection in uterus transplantation: Current practice and future potential
- 2019
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Ingår i: Uterus Transplantation. Brännström, M. (red.). - Cham : Springer. - 9783319941622 ; , s. 151-166
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Uterus transplantation has recently been introduced as a novel infertility treatment in a small number of centers around the world. In this chapter, the immunosuppressive armamentarium at our current disposal will be discussed. We will also examine recent immunosuppression protocols employed as induction, maintenance, and rejection treatment for uterus transplantation and discuss specific aspects of immunosuppression during pregnancy. Moreover, future aspects of immunosuppression in uterus transplantation will be discussed. © Springer Nature Switzerland AG 2020.
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