Living uterus donors' perceptions of decision-making and informed consent: a qualitative study of the Dallas Uterus Transplant Study participants.

Uterus transplantation is a growing field, but little is known about living uterus donors' perceptions of informed consent or their decision-making processes. This study used semistructured interviews to collect information regarding uterus donors' experiences with uterus donation, perceptions of the informed consent process, and information on how they decided to pursue uterus donation. Interviews were coded for thematic analysis. Three major themes emerged in this study. First, the decision-making process was based on individuals' motivations, rationale, and considerations of alternative contributions to help other women with infertility. Second, participants described how they felt about the process of informed consent, their decision-making processes, and how their experiences compared with their expectations. Third, participants discussed how uterus donation was a valuable experience. This study found that living uterus donors are motivated to give another woman the opportunity to experience pregnancy and childbirth. They were satisfied with the informed consent process, their experiences were in line with their expectations, and the value of uterus donation was associated with the act of donation itself. Our findings suggest that living donor uterus programs should develop robust informed consent processes that provide detailed information about uterus donation and encourage shared decision-making with potential uterus donors.

Can remote endarterectomy expand access to kidney transplantation in patients with severe iliac calcification?

Severe iliac artery calcification in patients with end-stage renal disease is a common barrier to listing for kidney transplant. While few surgical solutions to iliac calcification have been reported, improving treatment may thus improve access to transplant care. Here we present two cases of a novel application of remote endarterectomy of the external iliac artery to facilitate listing for renal transplant. Both patients were listed following remote endarterectomy, followed by successful renal transplants using the treated vessels.

A novel microsurgical reconstruction technique in a living-related liver donor hepatic artery dissection using the native hepatic artery.

In living donor liver transplantation, hepatic artery intimal dissection is a rare but devastating complication often resulting in the inability to utilize the graft. We detail the salvage of a dissected donor right hepatic artery utilizing the recipient hepatic artery. After removal of the right lobe, the donor artery was found to have an intimal dissection extending to multiple branches. The liver transplant surgeons requested their plastic microsurgeon colleague to assist with reconstruction. Ultimately, the native recipient hepatic artery was used as a branch graft as the caliber and branching pattern was appropriate. Back table microvascular reconstruction was performed using the explanted recipient hepatic artery branches as a graft to the four donor artery branches. Every anastomosis was assessed with intraoperative doppler; all were patent with acceptable flow characteristics. The patient did well post-operatively with post-operative ultrasounds demonstrating patency of the graft. Four months post-transplantation the patient developed two polymicrobial abscesses that were drained and resolved with normalization of liver function tests. This case highlights how collaboration with a microvascular surgeon enabled the salvage of a living donor graft when faced with a complex arterial dissection.

Single-stage long-segment tracheal transplantation.

Tracheal transplantation has been envisioned as a viable option for reconstruction of long-segment tracheal defects. We report the first human single-stage long-segment tracheal transplantation. Narrow-band imaging and bronchoscopic biopsies demonstrate allograft vascularization and viable epithelial lining. The recipient was immunosuppressed with Tacrolimus, Mycophenolate mofetil, and corticosteroids. Six months after transplantation, the trachea is both functional and the patient is breathing without the need of a tracheostomy or stent.

Full facial retransplantation in a female patient-Technical, immunologic, and clinical considerations.

There is limited experience with facial retransplantation (fRT). We report on the management of facial retransplantation in a facial vascularized composite allotransplant recipient following irreversible allograft loss 88 months after the first transplant. Chronic antibody-mediated rejection and recurrent cellular rejection resulted in a deteriorated first allograft and the patient underwent retransplantation. We summarize the events between the two transplantations, focusing on the final rejection episode. We describe the surgical technique of facial retransplantation, the immunological and psychosocial management, and the 6-month postoperative outcomes. Removal of the old allograft and inset of the new transplant were done in one operation. The donor and recipient were a good immunological match. The procedure was technically complex, requiring more proximal arterial anastomoses and an interposition vein graft. During the first and second transplantation, the facial nerve was coapted at the level of the branches. There was no hyperacute rejection in the immediate postoperative phase. Outcomes 6 months postoperatively are promising. We provide proof-of-concept that facial retransplantation is a viable option for patients who suffer irreversible facial vascularized composite allograft loss.

Face transplantation: A longitudinal histological study focusing on chronic active and mucosal rejection in a series with long-term follow-up.

The 2007 Banff working classification of skin-containing Tissue Allograft Pathology addressed only acute T cell-mediated rejection in skin. We report the longitudinal long-term histological follow-up of six face transplant recipients, focusing on chronic and mucosal rejection. We identified three patterns suggestive of chronic rejection (lichen planus-like, vitiligo-like and scleroderma-like). Four patients presented lichen planus-like and vitiligo-like chronic rejection at 52 ± 17 months posttransplant with severe concomitant acute T cell-mediated rejection. After lichen planus-like rejection, two patients developed scleroderma-like alterations. Graft vasculopathy with C4d deposits and de novo DSA led to subsequent graft loss in one patient. Chronic active rejection was frequent and similar patterns were noted in mucosae. Concordance between 124 paired skin and mucosal biopsies acute rejection grades was low (κ = 0.2, p = .005) but most grade 0/I mucosal rejections were associated with grade 0/I skin rejections. We defined discordant (grade≥II mucosal rejection and grade 0/I skin rejection) (n = 55 [70%]) and concordant (grade≥II rejection in both biopsies) groups. Mucosal biopsies of the discordant group displayed lower intra-epithelial GranzymeB/FoxP3 ratios suggesting a less aggressive phenotype (p = .08). The grading system for acute rejection in mucosa may require phenotyping. Whether discordant infiltrates reflect a latent allo-immune reaction leading to chronic rejection remains an open question.

Donor genetic variants as risk factors for thrombosis after liver transplantation: A genome-wide association study.

Thrombosis after liver transplantation substantially impairs graft- and patient survival. Inevitably, heritable disorders of coagulation originating in the donor liver are transmitted by transplantation. We hypothesized that genetic variants in donor thrombophilia genes are associated with increased risk of posttransplant thrombosis. We genotyped 775 donors for adult recipients and 310 donors for pediatric recipients transplanted between 1993 and 2018. We determined the association between known donor thrombophilia gene variants and recipient posttransplant thrombosis. In addition, we performed a genome-wide association study (GWAS) and meta-analyzed 1085 liver transplantations. In our donor cohort, known thrombosis risk loci were not associated with posttransplant thrombosis, suggesting that it is unnecessary to exclude liver donors based on thrombosis-susceptible polymorphisms. By performing a meta-GWAS from children and adults, we identified 280 variants in 55 loci at suggestive genetic significance threshold. Downstream prioritization strategies identified biologically plausible candidate genes, among which were AK4 (rs11208611-T, p = 4.22 × 10-05 ) which encodes a protein that regulates cellular ATP levels and concurrent activation of AMPK and mTOR, and RGS5 (rs10917696-C, p = 2.62 × 10-05 ) which is involved in vascular development. We provide evidence that common genetic variants in the donor, but not previously known thrombophilia-related variants, are associated with increased risk of thrombosis after liver transplantation.

Life underneath the VCA umbrella: Perspectives from the US Uterus Transplant Consortium.

The parallel emergence of uterus transplantation (UTx) and other transplantation innovations including face and hand transplantation led to the categorization of the uterus as a vascular composite allograft (VCA). With >60 transplants and >20 births worldwide, UTx is transitioning rapidly from a research endeavor to an effective treatment option for women with uterine factor infertility. While it originally made sense to group the innovations under one umbrella, it is time to revisit the designation of UTx as a VCA. We describe how UTx needs unique policy, procedural codes, insurance contracts, and educational initiatives. We contend that separating UTx from VCAs may become necessary in the future to avoid hindering the growth and regulation of this field.

Maximizing donors' gifts: A comparison of actual and expected solid organ yield among VCA donors.

Vascularized Composite Allograft (VCA) transplantation provides life-changing transplants, but VCA adds complexity to the donation process and timing, possibly impeding solid organ donation. Expanding upon descriptive analyses, this study examines risk-adjusted predictions versus the observed number of organs donated by VCA donors. Our cohort included VCA donors in the United States during January 1, 2008-December 31, 2017 (n = 51), using OPTN Deceased Donor Registration Form data and the Scientific Registry of Transplant Recipients (SRTR) donor yield models to calculate observed-to-expected (O:E) yield ratios. Almost all VCA donors' livers (48/51; 94.1%) and kidneys (92/102; 90.2%) were transplanted, with fewer hearts (28/51; 54.9%), lungs (46/102; 45.1%), pancreata (15/51; 29.4%), and intestines (3/51; 5.9%) transplanted. O:E ratios for overall organ yield were slightly greater than expected for VCA donors (1.10; 95% CI: 1.02-1.17). Liver (1.17: 1.08-1.27) and lung yields (1.38: 1.07-1.68) were both greater than expected, while kidney, heart, and pancreas yields were similar to expected. Across VCA types, bilateral upper limb and abdominal wall donors had better-than-expected yields while uterus, face, and unilateral upper limb donors all had similar-to-expected yields. Solid organ yield among VCA donors was as good or better than predicted, suggesting that VCA donation does not compromise recovery and transplantation of lifesaving organs.

Uterus transplantation: Histological findings in explants at elective hysterectomy.

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.

Cutaneous leukocyte lineages in tolerant large animal and immunosuppressed clinical vascularized composite allograft recipients.

Vascularized composite allografts (VCAs) can restore fully functional anatomic units in patients with limb amputations or severe facial tissue loss. However, acute rejection of the skin is frequently observed and underscores the importance of developing tolerance induction protocols. In this study, we have characterized the skin immune system in VCAs. We demonstrate infiltration of recipient leukocytes, regardless of rejection status, and in tolerant mixed hematopoietic chimeras, the co-existence of these cells with donor leukocytes in the absence of rejection. Here we characterize the dermal T cell and epidermal Langerhans cell components of the skin immune system in our porcine model of VCA tolerance, and the kinetics of cutaneous chimerism in both of these populations in VCAs transplanted to tolerant and nontolerant recipients, as well as in host skin. Furthermore, in biopsies from the first patient to receive a hand transplant in our program, we demonstrate the presence of recipient T cells in the skin of the transplanted limb in the absence of clinical or histological evidence of rejection.

Guidelines for standardized nomenclature and reporting in uterus transplantation: An opinion from the United States Uterus Transplant Consortium.

Uterus transplantation is a nascent but growing field. To support this growth, the United States Uterus Transplant Consortium proposes guidelines for nomenclature related to operative technique, vascular anatomy, and donor, recipient, and offspring outcomes. In terms of anatomy, the group recommends reporting donor arterial inflow and recipient anastomotic site delivering inflow to the graft and offers standardization of the names for the 4 veins originating from the uterus because of current inconsistency in this particular nomenclature. Seven progressive stages with milestones of success are defined for reporting on uterus transplantation outcomes: (1) technical, (2) menstruation, (3) embryo implantation, (4) pregnancy, (5) delivery, (6) graft removal, and (7) long-term follow-up. The 3 primary metrics for success are recipient survival (as reported for other organ transplant recipients), graft survival, and uterus transplant live birth rate (defined as live birth per transplanted recipient). A number of secondary outcomes should also be reported, most of which capture stage-specific milestones, as well as data on graft failure. Outcome metrics for living donors include patient survival, survival free of operative intervention, and data on complications and hospitalizations. Finally, we make specific recommendations on follow-up for offspring born from uterine grafts, which includes specialty surveillance as well as collection and reporting of routine pediatric outcomes. The goal of standardization in reporting is to create consistency and improve the quality of evidence available on the efficacy and value of the procedure.

Introducing a novel experimental model of bladder transplantation in mice.

Bladder dysfunction is a common clinical problem attributed to various conditions such as posterior urethral valves, neurogenic bladder, ureteral ectopy, or bladder exstrophy. Currently, the main therapeutic option for these dysfunctions is neobladder reconstruction with gastrointestinal tract segments. However, the latter was associated with significant long-term complications. To provide a new candidate of possible surgical solution for bladder dysfunction, we propose a novel orthotropic mouse bladder transplantation model. The donor bladder with abdominal aorta and inferior vena cava was isolated and orthotopically sutured to the recipient, whose bladder above the ureteral opening level was removed. The recipient mice showed more than 80% 6-month survival rate and comparable body weight to control mice. At both 1 month and 6 months posttransplant, the urine voiding behavior of recipient mice and control mice was monitored by cystometry. We found that the recipient mice displayed similar bladder pressure and urine secretion ability compared to control mice especially at 6 months posttransplant. Similarity of bladder structure between recipient and control mice was confirmed by histology. As a proof of principle, we tested our model in an allogeneic setting. Early acute rejection was noted after day 5 that was histologically more profound by day 10 posttransplant. These results indicate that the mouse bladder transplant is able to provide normal bladder function.

Adipose-derived stromal cell therapy combined with a short course nonmyeloablative conditioning promotes long-term graft tolerance in vascularized composite allotransplantation.

The risks of chronic immunosuppression limit the utility of vascularized composite allotransplantation (VCA) as a reconstructive option in complex tissue defects. We evaluated a novel, clinically translatable, radiation-free conditioning protocol that combines anti-lymphocyte serum (ALS), tacrolimus, and cytotoxic T-lymphocyte-associated protein 4 immunoglobulin (CTLA4-Ig) with adipose-derived stromal cells (ASCs) to allow VCA survival without long-term systemic immunosuppression. Full-mismatched rat hind-limb-transplant recipients received tacrolimus (0.5 mg/kg) for 14 days and were assigned to 4 groups: controls (CTRL) received no conditioning; ASC-group received CTLA4-Ig (10 mg/kg body weight i.p. postoperative day [POD] 2, 4, 7) and donor ASCs (1 × 106 iv, POD 2, 4, 7, 15, 28); the ASC-cyclophosphamide (CYP)-group received CTLA4-Ig, ASC plus cyclophosphamide (50 mg/kg ip, POD 3); the ASC-ALS-group received CTLA4-Ig, ASCs plus ALS (500 µL ip, POD 1, 5). Banff grade III or 120 days were endpoints. ASCs suppressed alloresponse in vitro. Median rejection-free VCA survival was 28 days in CTRL (n = 7), 34 in ASC (n = 6), and 27.5 in ASC-CYP (n = 4). In contrast, ASC-ALS achieved significantly longer, rejection-free VCA survival in 6/7 animals (86%), with persistent mixed donor-cell chimerism, and elevated systemic and allograft skin Tregs , with no signs of acute cellular rejection. Taken together, a regimen comprised of short-course tacrolimus, repeated CTLA4-Ig and ASC administration, combined with ALS, promotes long-term VCA survival without chronic immunosuppression.

Hand transplantation in the United States: A review of the Organ Procurement and Transplantation Network/United Network for Organ Sharing Database.

Hand transplantation is the most common application of vascularized composite allotransplantation (VCA). Since July 3, 2014, VCAs were added to the definition of organs covered by federal regulation (the Organ Procurement and Transplantation Network (OPTN) Final Rule) and legislation (the National Organ Transplant Act). As such, VCA is subject to requirements including data submission. We performed an analysis of recipients reported to the OPTN to have received hand transplantation between 1999 and 2018. Forty-three patients were identified as having been listed for upper extremity transplantation in the United States. Of these, 22 received transplantation prior to July 3, 2014 and 10 from then to December 31, 2018. Of patients transplanted after 2014, posttransplant functional scores included a decrease in Disabilities of the Arm, Shoulder and Hand questionnaire in 3 of 10 patients, Carroll test scores ranging from 9 to 60 of 99, and monofilament testing with protective sensation achieved in 4 of 6 patients. Complications included rejection in nine recipients with Banff scores from II-IV. One patient experienced graft failure 5 days after transplantation. Of the remaining patients, two were reported as receiving monotherapy and seven receiving dual or triple immunosuppression therapy. The inclusion of VCA in the OPTN Final Rule standardized parameters for safe implementation and data collection.

Nonvascularized human skin chronic allograft rejection.

A 65-year-old man had extensive burns of the lower legs in 1991, at the age of 40 years. He was treated by nonvascularized and de-epithelialized, allogeneic split-thickness skin allograft and cyclosporine monotherapy for 2 months. Ulcers developed between 10 and 25 years after transplantation and a surgical debridement on the lower extremities was required. Analyses of the removed tissue allografts showed chronic antibody-mediated and cellular rejection with extensive and dense fibrosis, and diffuse capillary C4d deposits. An anti-DRB1*08:01, donor-specific antibody was present. A unique clinical condition with late immunopathological features of human skin chronic allograft rejection is reported.

Small bowel and abdominal wall transplantation: A novel technique for synchronous revascularization.

Abdominal wall transplantation (AWT) was introduced in 1999 in the context of reconstruction of complex abdominal wall defects in conjunction with visceral organ transplantation. As of recently, 38 cases of total AWT have been performed worldwide, about half of which were performed in the United States. While AWT is technically feasible, one of the major challenges presenting to the reconstructive surgeon is time to revascularization of the donor abdominal wall (AW), given the immediate proximity of the visceral organ and AWT. The authors report a novel AW revascularization technique during a synchronous small bowel and AWT in a 37-year-old man.

Chronic rejection of human face allografts.

Face vascularized composite allografts (FVCAs) have helped patients with severe facial disfigurement, with acute rejection now largely controlled through iatrogenic immunosuppression. However, little is known regarding the incidence and mechanism(s) of more long-term pathologic alterations in FVCAs that may affect function and graft durability. Protocol surveillance biopsy specimens for up to an 8-year interval in 7 patients who received FVCAs at our institution revealed histopathologic evidence of chronic rejection. Clinical manifestations included features of premature aging, mottled leukoderma accentuating suture lines, telangiectasia, and dryness of nasal mucosa. Pathologic changes consisted of epidermal thinning accompanied by discrete foci of lymphocyte-mediated cytotoxicity, hyperkeratosis, follicular plugging, vascular ectasia, and sclerosis beneath the epidermal layer associated with collagen type I deposition. Genomic interrogation and immunohistochemistry of sclerotic zones revealed upregulation of the AP-1 pathway components, JunB and c-Fos, previously implicated in overproduction of type I dermal collagen in the setting of systemic sclerosis. We conclude that some patients develop chronic rejection in FVCAs with striking similarities to alterations seen in certain autoimmune cutaneous disorders (lupus erythematosus and scleroderma/chronic sclerodermoid graft-versus-host disease). Identification of relevant pathways and genes, such as JunB and c-Fos, may provide new targets for preventative therapies for chronic immune-mediated changes in vascularized composite allografts.