Transplantation is the golden standard for the treatment of end-stage renal disease. During this process, the transplanted organ is often damaged. In this thesis, we investigated whether activation... Show moreTransplantation is the golden standard for the treatment of end-stage renal disease. During this process, the transplanted organ is often damaged. In this thesis, we investigated whether activation of the complement system, part of our innate immune system, plays a local role. We reviewed that properdin, the only known positive regulator of the complement system, was detected in serum, plasma and urine from patients with various complement-mediated renal diseases. In protocol biopsies obtained 10 days after transplantation, properdin was found deposited in addition to complement activation markers. Next, we showed that dendritic cells secrete properdin and a decrease in properdin levels during dendritic cell- T-cell interaction resulted in reduced T-cell proliferation and activation. We also showed that properdin is able to bind to surfaces of both viable and dead cells, contributing to complement activation. Macrophages can also produce properdin and negative regulators factor H and its splice variant FHL-1. Increasing knowledge on complement factor production by other cells than hepatocytes, including immune cells, hints towards a local role of the complement system in various processes. These findings contribute to a better understanding of the local role of the complement system and are important for the applications of (new) complement-inhibiting drugs. Show less
Immunisation against Human Leucocyte Antigens (HLA) can be caused by pregnancy, blood transfusion, or organ transplants. The HLA antibody status of a given patient significantly influences their... Show moreImmunisation against Human Leucocyte Antigens (HLA) can be caused by pregnancy, blood transfusion, or organ transplants. The HLA antibody status of a given patient significantly influences their access and waiting time to transplant. For some highly sensitised patients (HSP) there is hardly any suitable donor available in the deceased donor pool of their allocation organisation and therefore they wait a very long time before being offered a kidney for transplant. Especially patients with rare HLA phenotypes in relation to the actual donor pool are waiting extremely long. As HLA phenotypes are different in the various European populations, we hypothesized that extension of the donor pool outside the respective allocation system will increase the chance of receiving a compatible transplant for this subgroup of highly sensitised patients. One of the objectives of the EUROSTAM project, (a Europe-wide Strategy to enhance Transplantation of highly sensitised patients on the basis of Acceptable HLA Mismatches) was to develop a tool to compare the chance of transplanting HSP in different European populations with donor organs from within and outside their own donor pool.Information on the HLA type and ABO blood group of the actual donor population, as well as the acceptable mismatches of long waiting HSP were obtained from the EUROSTAM partner organizations i.e. Eurotransplant (ET), UK National Health Service Blood and Transplant (NHSBT), Barcelona, Prague and Athens.Results from simulations using the newly developed tool shows that 195 (27%) of the 724 long waiting highly sensitised patients registered at each partner organisation have increased chances of transplant in a different European donor pool. This makes a strong case for sharing kidneys between European countries for selected difficult to transplant patients. Show less
Koning, M.; Berg, C.W. van den; Rabelink, T.J. 2019
Kidney organoids can be generated from human pluripotent stem cells (PSCs) using protocols that resemble the embryonic development of the kidney. The renal structures thus generated offer great... Show moreKidney organoids can be generated from human pluripotent stem cells (PSCs) using protocols that resemble the embryonic development of the kidney. The renal structures thus generated offer great potential for disease modeling, drug screening, and possibly future therapeutic application. At the same time, use of these PSC-derived organoids is hampered by lack of maturation and off-target differentiation. Here, we review the main protocols for the generation of kidney organoids from human-induced PSCs, discussing their advantages and limitations. In particular, we will focus on the vascularization of the kidney organoids, which appears to be one of the critical factors to achieve maturation and functionality of the organoids. 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
Westerveld, K.J.H. van; Verweij, J.P.; Toxopeus, E.E.; Fiocco, M.; Mensink, G.; Merkesteyn, J.P.R. van 2019
This thesis emphasizes the presence of minor H antigen specific immune responses directly after birth, which will be present throughout life. The presence of minor H antigen mismatched... Show moreThis thesis emphasizes the presence of minor H antigen specific immune responses directly after birth, which will be present throughout life. The presence of minor H antigen mismatched microchimeric cells obtained through pregnancy from a mother or a child play a crucial role in this. Subsequent immunization against minor H antigens can lead to both cytotoxic and tolerogenic responses. Furthermore HA-1 specific T cells can share the same TCR Vbeta, yet being functionally different. The here performed studies enhances our understanding of immune reactions after HSCT and if applicable after renal transplantation, especially regarding the birth order effect and the assumed less favourable role of women as transplant donors. Show less
Rood, J.J. van; Claas, F.H.J.; Brand, A.; Tilanus, M.G.J.; Kooten, C. van 2014
