This thesis demonstrates that kidneys from DCD donors can be fully embraced, and that the perception of DCD kidney transplantation being inferior to DBD kidney transplantation – mainly motivated by... Show moreThis thesis demonstrates that kidneys from DCD donors can be fully embraced, and that the perception of DCD kidney transplantation being inferior to DBD kidney transplantation – mainly motivated by concerns regarding high incidences of DGF and EGL – is no longer justified. One explanation for this phenomenon is that outcomes of transplanted DCD kidneys have improved over time, with a similar incidence of EGL following DBD and DCD kidney transplantation in the current era. Another explanation is that both donor types have different biological responses to DGF: whilst DGF severely impacts on DBD graft survival, DGF has no impact on DCD graft survival. This difference relates to donor type-specific regulation of resilience and pro-inflammatory pathways benefitting the DCD graft and its outcomes. As such, the persistent high incidence of DGF in DCD grafts should not be regarded an impediment toward the use of these donor kidneys.This thesis additionally explores a series of physiological and methodological contrasts between preclinical and clinical I/R injury, that all may contribute to the impaired translatability of preclinical studies in clinical practice. Awareness of these pitfalls may help to improve study designs in future research, bringing us one step closer towards bridging the translational gap. Show less
Vasiliauskaite, I.; Quilendrino, R.; Baydoun, L.; Dijk, K. van; Melles, G.R.J.; Oellerich, S. 2021
Purpose: To analyze if 6-month endothelial cell density (ECD) affects long-term ECD outcome and graft survival 5 years after Descemet membrane endothelial keratoplasty (DMEK) in eyes with Fuchs... Show morePurpose: To analyze if 6-month endothelial cell density (ECD) affects long-term ECD outcome and graft survival 5 years after Descemet membrane endothelial keratoplasty (DMEK) in eyes with Fuchs endothelial corneal dystrophy (FECD).Design: Retrospective cohort study.Participants: A total of 585 DMEK eyes were included. The study group was divided into 4 groups based on 6-month ECD quartiles: group 1 (n = 146) with 313 to 1245 cells/mm(2), group 2 (n = 148) with 1246 to 1610 cells/mm(2), group 3 (n = 145) with 1611 to 1938 cells/mm(2), and group 4 (n = 146) with 1939 to 2760 cells/mm(2). Group 1 was further split into subgroups 1a (n = 36) with 6-month ECD of <828 cells/mm(2), 1b (n = 37) with 829 to 1023 cells/mm(2), 1c (n = 37) with 1024 to 1140 cells/mm(2), and 1d (n = 36) 1141 to 1245 cells/mm(2).Methods: Descemet membrane endothelial keratoplasty.Main Outcome Measures: Long-term ECD, graft survival, and postoperative complication rates.Results: For group 1, 6-month ECD decreased from 951 (+/- 233) cells/mm(2) (n = 146) to 735 (+/- 216) cells/mm(2) (n = 99) at 5 years postoperatively. Group 1 graft survival probability was 0.95 (95% confidence interval [CI], 0.91-0.99] at 5 years postoperatively, which was lower than for groups 2 to 4 (P = 0.001). Five-year graft survival in subgroup 1a was 0.79 (95% CI, 0.67-0.94), which was lower than in subgroups 1b to 1d (P = 0.001). Preoperative ECD did not influence graft survival (P = 0.400), and higher 6-month ECD values were associated with lower graft failure rates (hazard ratio, 0.994; 95% CI, 0.99-1.00; P = 0.001).Conclusions: Six-month ECD is associated with DMEK graft survival. High early cell loss after DMEK negatively affects long-term ECD outcome and graft survival. Grafts in the lowest 6-month ECD subgroup (<828 cells/mm(2)) are at higher risk of failure within 5 years after DMEK. To ensure sufficiently high 6-month ECD, preoperative graft quality assessment should be optimized, and cellular stress induced to the graft should be minimized. Additionally, developing therapeutic options for the treatment of low postoperative ECD could further improve DMEK graft longevity. (C) 2021 by the American Academy of Ophthalmology Show less
Within the past two decades, full thickness penetrating keratoplasty (PK) has been largely supplanted by lamellar endothelial keratoplasty (EK) procedures that have revolutionized the treatment of... Show moreWithin the past two decades, full thickness penetrating keratoplasty (PK) has been largely supplanted by lamellar endothelial keratoplasty (EK) procedures that have revolutionized the treatment of corneal endothelial diseases such as Fuchs endothelial dystrophy. Since the introduction of EK in 1998, these techniques have undergone continuous transition, from Deep lamellar endothelial keratoplasty (DLEK) to Descemet stripping (automated) endothelial keratoplasty (DSEK/DSAEK) and eventually to Descemet membrane endothelial keratoplasty (DMEK). While the graft in DLEK and DSEK/DSAEK consists of endothelium, Descemet membrane and stroma, in DMEK only an isolated Descemet membrane with its endothelium, devoid of stroma, is transplanted. Notably, the thinner graft used in DMEK may have three main advantages over earlier techniques: Faster and better visual rehabilitation, predictable small refractive change, and a reduced risk of immunologic reactions. This thesis will investigate the clinical outcomes after DMEK, the latest refinement of lamellar endothelial keratoplasty techniques. The focus will be on DMEK graft survival and on allograft rejection (and its prediction), a complication that may potentially lead to graft failure and hereby reduce the overall survival probability. Show less
Aims: Chronic-active antibody mediated rejection (c-aABMR) is a major cause of kidney graft loss. Currently, little is known about the relation between histopathologic parameters and renal... Show moreAims: Chronic-active antibody mediated rejection (c-aABMR) is a major cause of kidney graft loss. Currently, little is known about the relation between histopathologic parameters and renal allograft survival.Methods and results: Between 2008 and 2014, 41 patients with a progressive decrease in renal function were diagnosed with c-aABMR according to Banff 2015 and followed up for at least 3 years. Clinical and renal biopsy characteristics were analyzed for association with graft survival.During follow-up 26 cases lost their graft because of c-aABMR at a median follow up of 40 months after diagnosis.Cases with v-lesions in their biopsy had a significant higher loss of eGFR prior to diagnosis. The total inflammation score (r = -0.45 p = .007) and the severity of interstitial fibrosis (r = -0.38 p = .023) were related to the eGFR at time of biopsy.Univariate regression analysis showed that eGFR at time of biopsy, total inflammation, interstitial fibrosis and the sum chronicity score were significantly related to the risk for graft failure during follow-up. In a multivariate analysis only the severity of interstitial fibrosis remained associated with decreased graft survival (HR 1.9 per score point, 95% CI 1.2-2.8, p = .004).Conclusion: Severity of renal interstitial fibrosis and not inflammation predicts graft survival in cases of c-aABMR. Show less
Acute kidney transplant rejection is an important risk factors for adverse graft outcome. Once diagnosed, it remains difficult to predict the risk of graft loss and the response to anti-rejection... Show moreAcute kidney transplant rejection is an important risk factors for adverse graft outcome. Once diagnosed, it remains difficult to predict the risk of graft loss and the response to anti-rejection treatment. The aim of this thesis was to identify biomarkers during acute rejection, which predict the response to corticosteroid therapy and renal allograft survival. We demonstrated that steroid resistance is a multifactorial condition, in which both immunological and non-immunological factors are involved. Response to steroid therapy correlates with the expression level and characteristics of allograft infiltrating T cells and macrophages, indicating that steroid resistance resides in specific cell populations and is not a feature of all lymphocytes. In addition, zinc regulation plays a role in the response to corticosteroids. Increased expression of zinc-regulating molecules may diminish the zinc-requiring anti-inflammatory effects of corticosteroids. Therefore, kidney transplant recipients may benefit from additional zinc intake to optimize steroid signaling. Furthermore, we demonstrated that a multivariate prediction model, containing biomarkers related to different aspects of corticosteroid signaling, offers the best prognostic value for assessing steroid response. Finally, we demonstrated that determination of S100A8 and S100A9 expression levels in renal allograft tissue can be used for assessing the risk of renal allograft loss over time. Show less
Laging, M.; Kal-van Gestel, J.A.; Haasnoot, G.W.; Claas, F.H.J.; Wetering, J. van de; IJzermans, J.N.M.; ... ; Roodnat, J.I. 2014
