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Introduction: The first live birth after uterus transplantation occurred in Sweden in 2014. Uterus transplantation has repeatedly, and at many centers worldwide, proven to be a feasible treatment for absolute uterine factor infertility. Hysterectomy in live donors and transplantation are well described in numerous reports. However, there are no reports of hysterectomy in the recipient after uterus transplantation, which will occur at either graft failure, after childbirth, or after numerous failed pregnancy attempts. We present the first report of hysterectomy in recipients after uterus transplantation with detailed analyses of findings in conjunction with graft failures. Material and Methods: An analysis of recipient hysterectomies (n = 10), performed in 2012–2020, was conducted. Data from the international uterus transplantation registry (ISUTx registry) were extracted, and medical records were systematically reviewed, to collect and compile characteristics of recipients and donors, as well as pre‐, per‐, and postoperative data, including clinical course of graft failures. Results: Hysterectomy in recipients was performed in conjunction with cesarean section (n = 3), 3–6 months after cesarean section (n = 3), or after failed pregnancy attempts (n = 1) or graft failure (n = 3). The durations of anesthesia (2 h 36 min to 7 h 35 min) and hysterectomy surgery (1 h 42 min to 5 h 52 min) ranged widely, with long perioperative interruptions for insertion of ureteral catheters in two cases. Adhesions to the uterus were abundant, the majority being mild. Three uteri that subsequently showed graft failure (hysterectomy at 1, 3, and 8 months post transplantation) showed histological signs of ischemia in biopsies taken 1‐week post‐transplant and early signs of central hypoperfusion by Doppler ultrasound. In these graft failure explants, there were no epithelial linings in the uterine cavity or in the cervix. The inner uterine wall was severely ischemic and/or necrotic, whereas outer parts were partly viable. There were signs of moderate atherosclerosis of uterine arteries but no rejection. Mild postoperative complications were frequent (6/10), with one supravaginal hematoma requiring surgical drainage. Conclusions: Hysterectomy after uterus transplantation is a complex and time‐consuming procedure, and perioperative ureteral catheters may be helpful. Histopathology of early cervical biopsies showing ischemic signs may indicate subsequent irreversible damage, leading to graft failure. [ABSTRACT FROM AUTHOR]

Background Identification and quantification of the relevant factors for death can improve patients' individual risk assessment and decision-making. We used a well-documented patient cohort (n  = 892) in a renal transplant programme with protocol biopsies to establish multivariable Cox models for risk assessment at 3 and 12 months post-transplantation. Methods Patients transplanted between 2000 and 2007 were observed up to 11 years (total observation 5227 patient-years; median 5.9 years). Loss to follow-up was negligible (n  = 15). A total of 2251 protocol biopsies and 1214 biopsies for cause were performed. All rejections and clinical borderline rejections in protocol biopsies were treated. Results Overall 10-year patient survival was 78%, with inferior survival of patients with graft loss and superior survival of patients with living-donor transplantation. Eight factors were common in the models at 3 and 12 months, including age, pre-transplant heart failure and a score of cardiovascular disease and type 2 diabetes, post-transplant urinary tract infection, treatment of rejection, new-onset heart failure, coronary events and malignancies. Additional variables of the model at 3 months included deceased donor transplantation, transplant lymphocele, BK virus nephropathy and severe infections. Graft function and graft loss were significant factors of the model at 12 months. Internal validation and validation with a separate cohort of patients (n  = 349) demonstrated good discrimination of the models. Conclusions The identified factors indicate the important areas that need special attention in the pre- and post-transplant care of renal transplant patients. On the basis of these models, we provide nomograms as a tool to weigh individual risks that may contribute to decreased survival. [ABSTRACT FROM AUTHOR]

Acute tubular injury (ATI) is common in renal allografts and is related to inferior long-term allograft function. However, it is unknown which of the morphological features of ATI can predict outcome and how they should be graded. Here, we examine features of ATI systematically in protocol biopsies and biopsies for cause to define the most predictive features. Analyses included 521 protocol biopsies taken at 6 wk, 3 mo, and 6 mo after transplantation and 141 biopsies for cause from 204 patients. Features of ATI included brush border loss, tubular epithelial lucency, flattening, pyknosis, nuclei loss, and luminal debris, each graded semiquantitatively. Additional immunohistochemical stainings were performed for markers of cell injury (neutrophil gelatinase-associated lipocalin), cell death [cleaved caspase-3, fatty acid-coenzyme A ligase 4 (FACL4)], and proliferation (Ki-67). Interobserver reliability was good for pyknosis, flattening, and brush border loss and poor for lucency, nuclei loss, and luminal debris. In protocol biopsies between 6 wk and 6 mo, the degree of ATI remained virtually unchanged. Biopsies for cause had generally higher injury scores. Deceased donor source, delayed graft function, ganciclovir/valganciclovir treatment, and urinary tract infection correlated with ATI. The degree of pyknosis, flattening, and brush border loss correlated best with impaired allograft function. FACL4 expression was observed in areas of ATI. Only patients with Ki-67 expression showed stable or improved allograft function in the longitudinal assessment. Reliable assessment of ATI is possible by semiquantitative grading of tubular epithelial cell brush border loss, flattening, and pyknosis. Examination of Ki-67 expression can help determine the potential for recovery from this damage. [ABSTRACT FROM AUTHOR]

Background: Chronic allograft injury induced by immunological as well as non-immunological mechanisms is still a major cause of long-term graft loss after renal transplantation. Major histocompatibility complex (MHC) incompatibilities as well as donor-specific alloantibodies are known risk factors, but the interaction of cellular and humoral mechanisms leading to allograft damage remains to be defined. The aim of this study was to analyze the impact of donor-specific post-transplant antibodies against a non-classical MHC lb antigen apart from T-cell-dependent immune response. Therefore, we utilized a transplant rat model injecting a moAb directed against a donor MHC lb molecule into athymic nude recipients lacking an immunocompetent T-cell system. Methods: F344 kidneys were transplanted into LEW.RNU rats. Donor and recipient differ in the RT1.C locus (MHC lb) but are phenotypically identical for the RT1.A (MHC I) and RT1.BID (MHC II) loci. A moAb directed against the donors RT1.Clv1 was injected into recipients with stable graft function. A control group remained untreated after transplantation. The rats were monitored for renal function and grafts were analyzed for morphological changes, infiltrating cells and C4d deposition. Results: Antibody-infused rats developed renal impairment with massive urine albumin excretion. Histological changes consistent with antibody-mediated injury were interstitial fibrosis, tubular atrophy and severe glomerulopathy accompanied by an infiltrate of numerous macrophages. At time of death. grafts were negative for C4d at the peritubular capillaries and arterial endothelium. Conclusion: Antibodies directed against a MHC lb antigen are able to induce allograft injury in T-cell-deficient rats. This model underlines the role of non-classical MHC disparities for long-term allograft survival and demonstrates the long-term results of antibody-induced allograft damage. [ABSTRACT FROM AUTHOR]

Background: Uterus transplantation (UTx) is an emerging therapy for women with uterine infertility. However, critical questions remain with this procedure including the mechanisms involved in graft rejection., Methods: In this study, we analyzed the immune profile of ectocervical biopsies from 5 patients after UTx before and during their first episode of rejection using RNA sequencing, quantitative polymerase chain reaction, and imaging mass cytometry., Results: We identified 530 upregulated and 207 downregulated genes associated with graft rejection. Enrichment databases revealed abnormalities of skin-associated genes and the immune system, in particular activation of T and B lymphocytes, and macrophages. Imaging mass cytometry confirmed these observations; in cervical biopsies of 3 women, rejection was associated with the presence of B-cell structures linked to tertiary lymphoid structures, and 2 biopsies from 1 woman with severe rejection episodes and poor prognosis of graft function (repeated miscarriage and implantation failures) were associated with an accumulation of HLA-DR- macrophages, producing granzyme B at the surface of the epithelium., Conclusions: We showed that rejection of a UTx graft was associated with major alterations of immune markers including the involvement of tertiary lymphoid structures, the most organized of which may be a sign of chronic rejection, and with an increase in HLA-DR- macrophages expressing granzyme B in the case of grade 3 rejection episodes according Mölne's classification. We identified potential emerging biomarkers to predict or diagnose graft rejection (Keratin 1 granzyme B, IL1β). These findings could lead to development of improved strategies for the identification, prevention, and/or treatment of uterus graft rejection., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Noninvasive diagnosis of acute renal allograft rejection may be advantageous compared with the allograft biopsy., Experimental Design: In this study, a multi-marker classification model for rejection was defined on a training set of 39 allograft patients by statistical comparison of capillary electrophoresis mass spectrometry (CE-MS) peptide spectra in urine samples from 16 cases with subclinical acute T-cell-mediated tubulointerstitial rejection and 23 nonrejection controls., Results: Application of the rejection model to a blinded validation set (n=64) resulted in an AUC value of 0.91 (95% CI: 0.82-0.97, p=0.0001). In total, 16 out of 18 subclinical and 10 out of 10 clinical rejections (BANFF grades Ia/Ib), and 28 out of 36 controls without rejection were correctly classified. Acute tubular injury in the biopsies or concomitant urinary tract infection did not interfere with CE-MS-based diagnosis. Sequence information of identified altered collagen α(I) and α (III) chain fragments in rejection samples suggested an involvement of matrix metalloproteinase-8 (MMP-8). Biopsy stainings revealed matrix metalloproteinase-8 exclusively in neutrophils located within peritubular capillaries and sparsely, in the tubulointerstitium during rejection., Conclusions and Clinical Relevance: The established marker set contains peptides related to tubulointerstitial infiltration seen in acute rejection. The set of urinary peptide markers will be used for early diagnosis of acute kidney allograft rejection marker in a multicenter phase III prospective study., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)