50 results on '"Baas, M.C."'
Search Results
2. Can We Predict Graft Intolerance Syndrome After Kidney Transplant Failure? External Validation of a Previously Developed Model.
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Bunthof, K.L.W., Saboerali, K., Wetering, J.V., Nurmohamed, A., Bemelman, F., Zuilen, A.V., Brand, J.V.D., Baas, M.C., Hilbrands, L.B., Bunthof, K.L.W., Saboerali, K., Wetering, J.V., Nurmohamed, A., Bemelman, F., Zuilen, A.V., Brand, J.V.D., Baas, M.C., and Hilbrands, L.B.
- Abstract
Item does not contain fulltext, Previously we established a prediction model for graft intolerance syndrome requiring graft nephrectomy in patients with late kidney graft failure. The aim of this study is to determine generalizability of this model in an independent cohort. The validation cohort included patients with late kidney graft failure between 2008 and 2018. Primary outcome is the prognostic performance of our model, expressed as the area under the receiver operating characteristic curve (ROC-AUC), in the validation cohort. In 63 of 580 patients (10.9%) a graft nephrectomy was performed because of graft intolerance. The original model, which included donor age, graft survival and number of acute rejections, performed poorly in the validation cohort (ROC-AUC 0.61). After retraining of the model using recipient age at graft failure instead of donor age, the model had an average ROC-AUC of 0.70 in the original cohort and of 0.69 in the validation cohort. Our original model did not accurately predict the graft intolerance syndrome in a validation cohort. However, a retrained model including recipient age at graft failure instead of donor age performed moderately well in both the development and validation cohort enabling identification of patients with the highest and lowest risk of graft intolerance syndrome.
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- 2023
3. Prevention and management of kidney graft failure
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Hilbrands, L.B., Baas, M.C., Bunthof, K.L.W., Hilbrands, L.B., Baas, M.C., and Bunthof, K.L.W.
- Abstract
Radboud University, 25 oktober 2023, Promotor : Hilbrands, L.B. Co-promotor : Baas, M.C., Contains fulltext : 296446.pdf (Publisher’s version ) (Closed access)
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- 2023
4. Rituximab as Induction Therapy After Renal Transplantation: A Randomized, Double-Blind, Placebo-Controlled Study of Efficacy and Safety
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van den Hoogen, M.W.F., Kamburova, E.G., Baas, M.C., Steenbergen, E.J., Florquin, S., Koenen, H.J.P.M., Joosten, I., and Hilbrands, L.B.
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- 2015
- Full Text
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5. A randomized crossover study comparing different tacrolimus formulations to reduce intrapatient variability in tacrolimus exposure in kidney transplant recipients
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Bunthof, K.L.W., Al-Hassany, L., Nakshbandi, G., Hesselink, D.A., Schaik, R.H. van, Dam, Marc A. ten, Baas, M.C., Hilbrands, L.B., Gelder, T. van, Bunthof, K.L.W., Al-Hassany, L., Nakshbandi, G., Hesselink, D.A., Schaik, R.H. van, Dam, Marc A. ten, Baas, M.C., Hilbrands, L.B., and Gelder, T. van
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Contains fulltext : 252049.pdf (Publisher’s version ) (Open Access), A high intrapatient variability (IPV) in tacrolimus exposure is a risk factor for poor long-term outcomes after kidney transplantation. The main objective of this trial was to investigate whether tacrolimus IPV decreases after switching patients from immediate-release (IR)-tacrolimus to either extended-release (ER)-tacrolimus or LifeCyclePharma (LCP)-tacrolimus. In this randomized, prospective, open-label, cross-over trial, adult kidney transplant recipients on a stable immunosuppressive regimen, including IR-tacrolimus, were randomized for conversion to ER-tacrolimus or LCP-tacrolimus, and for the order in which IR-tacrolimus and the once-daily formulations were taken. Patients were followed 6 months for each formulation, with monthly tacrolimus predose concentration assessments to calculate the IPV. The IPV was defined as the coefficient of variation (%) of dose corrected predose concentrations. Ninety-two patients were included for analysis of the primary outcome. No significant differences between the IPV of IR-tacrolimus (16.6%) and the combined once-daily formulations (18.3%) were observed (% difference +1.7%, 95% confidence interval [CI] -1.1% to -4.5%, p = 0.24). The IPV of LCP-tacrolimus (20.1%) was not significantly different from the IPV of ER-tacrolimus (16.5%, % difference +3.6%, 95% CI -0.1% to 7.3%, p = 0.06). In conclusion, the IPV did not decrease after switching from IR-tacrolimus to either ER-tacrolimus or LCP-tacrolimus. These results provide no arguments to switch kidney transplant recipients from twice-daily (IR) tacrolimus formulations to once-daily (modified-release) tacrolimus formulations when the aim is to lower the IPV.
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- 2022
6. Donor characteristics and their impact on kidney transplantation outcomes: Results from two nationwide instrumental variable analyses based on outcomes of donor kidney pairs accepted for transplantation
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Schaapherder, Alexander F., Kaisar, Maria, Mumford, Lisa, Robb, Matthew, Johnson, Rachel, Kok, Michele J.C. de, Baas, M.C., Ploeg, Rutger J., Lindeman, Jan H.N., Schaapherder, Alexander F., Kaisar, Maria, Mumford, Lisa, Robb, Matthew, Johnson, Rachel, Kok, Michele J.C. de, Baas, M.C., Ploeg, Rutger J., and Lindeman, Jan H.N.
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Contains fulltext : 253049.pdf (Publisher’s version ) (Open Access)
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- 2022
7. T-Cell Epitopes Shared Between Immunizing HLA and Donor HLA Associate With Graft Failure After Kidney Transplantation
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Peereboom, E.T.M., Matern, B.M., Tomosugi, T., Niemann, M., Drylewicz, J., Joosten, I., Allebes, W.A., Meer, A. van der, Hilbrands, L.B., Baas, M.C., Reekum, F.E. van, Verhaar, M.C., Kamburova, E.G., Seelen, M.A., Sanders, J.S., Hepkema, B.G., Lambeck, A.J.A., Bungener, L.B., Roozendaal, C., Tilanus, M.G., Voorter, C.E.M., Wieten, L., Duijnhoven, E.M. van, Gelens, M., Christiaans, M.H., Ittersum, F.J. van, Nurmohamed, A., Lardy, N.M., Swelsen, W., Pant, Karlijn A.M.I. van der, Weerd, N.C. van der, Berge, I.J. Ten, Bemelman, F.J., Vries, A.P.J de, Fijter, J.W. de, Betjes, M. G. H., Roelen, D.L., Claas, F.H.J., Otten, H.G., Heidt, S., Zuilen, A.D. van, Kobayashi, T., Geneugelijk, K., Spierings, E, Peereboom, E.T.M., Matern, B.M., Tomosugi, T., Niemann, M., Drylewicz, J., Joosten, I., Allebes, W.A., Meer, A. van der, Hilbrands, L.B., Baas, M.C., Reekum, F.E. van, Verhaar, M.C., Kamburova, E.G., Seelen, M.A., Sanders, J.S., Hepkema, B.G., Lambeck, A.J.A., Bungener, L.B., Roozendaal, C., Tilanus, M.G., Voorter, C.E.M., Wieten, L., Duijnhoven, E.M. van, Gelens, M., Christiaans, M.H., Ittersum, F.J. van, Nurmohamed, A., Lardy, N.M., Swelsen, W., Pant, Karlijn A.M.I. van der, Weerd, N.C. van der, Berge, I.J. Ten, Bemelman, F.J., Vries, A.P.J de, Fijter, J.W. de, Betjes, M. G. H., Roelen, D.L., Claas, F.H.J., Otten, H.G., Heidt, S., Zuilen, A.D. van, Kobayashi, T., Geneugelijk, K., and Spierings, E
- Abstract
Contains fulltext : 241482.pdf (Publisher’s version ) (Open Access), CD4(+) T-helper cells play an important role in alloimmune reactions following transplantation by stimulating humoral as well as cellular responses, which might lead to failure of the allograft. CD4(+) memory T-helper cells from a previous immunizing event can potentially be reactivated by exposure to HLA mismatches that share T-cell epitopes with the initial immunizing HLA. Consequently, reactivity of CD4(+) memory T-helper cells toward T-cell epitopes that are shared between immunizing HLA and donor HLA could increase the risk of alloimmunity following transplantation, thus affecting transplant outcome. In this study, the amount of T-cell epitopes shared between immunizing and donor HLA was used as a surrogate marker to evaluate the effect of donor-reactive CD4(+) memory T-helper cells on the 10-year risk of death-censored kidney graft failure in 190 donor/recipient combinations using the PIRCHE-II algorithm. The T-cell epitopes of the initial theoretical immunizing HLA and the donor HLA were estimated and the number of shared PIRCHE-II epitopes was calculated. We show that the natural logarithm-transformed PIRCHE-II overlap score, or Shared T-cell EPitopes (STEP) score, significantly associates with the 10-year risk of death-censored kidney graft failure, suggesting that the presence of pre-transplant donor-reactive CD4(+) memory T-helper cells might be a strong indicator for the risk of graft failure following kidney transplantation.
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- 2021
8. Delayed graft function and rejection are risk factors for cytomegalovirus breakthrough infection in kidney transplant recipients
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Kleinherenbrink, W., Baas, M.C., Nakhsbandi, Gizal, Hesselink, D.A., Roodnat, J.I., Winter, B.C. de, Hilbrands, L.B., Gelder, T. van, Kleinherenbrink, W., Baas, M.C., Nakhsbandi, Gizal, Hesselink, D.A., Roodnat, J.I., Winter, B.C. de, Hilbrands, L.B., and Gelder, T. van
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Item does not contain fulltext
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- 2021
9. ABO-incompatible kidney transplantation in perspective of deceased donor transplantation and induction strategies: a propensity-matched analysis
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Weerd, A.E. de, Brand, J. van den, Bouwsma, H., Vries, A.P.J de, Dooper, I.M.M., Sanders, J.F., Christiaans, M.H., Reekum, F.E. van, Zuilen, A.D. van, Bemelman, F.J., Nurmohamed, A.S., Agteren, M. van, Betjes, M. G. H., Jong, M.F.C. de, Baas, M.C., Weerd, A.E. de, Brand, J. van den, Bouwsma, H., Vries, A.P.J de, Dooper, I.M.M., Sanders, J.F., Christiaans, M.H., Reekum, F.E. van, Zuilen, A.D. van, Bemelman, F.J., Nurmohamed, A.S., Agteren, M. van, Betjes, M. G. H., Jong, M.F.C. de, and Baas, M.C.
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Contains fulltext : 245148.pdf (Publisher’s version ) (Open Access), Kidney transplant candidates are blood group incompatible with roughly one out of three potential living donors. We compared outcomes after ABO-incompatible (ABOi) kidney transplantation with matched ABO-compatible (ABOc) living and deceased donor transplantation and analyzed different induction regimens. We performed a retrospective study with propensity matching and compared patient and death-censored graft survival after ABOi versus ABOc living donor and deceased donor kidney transplantation in a nationwide registry from 2006 till 2019. 296 ABOi were compared with 1184 center and propensity-matched ABOc living donor and 1184 deceased donor recipients (matching: recipient age, sex, blood group, and PRA). Patient survival was better compared with deceased donor [hazard ratio (HR) for death of HR 0.69 (0.49-0.96)] and non-significantly different from ABOc living donor recipients [HR 1.28 (0.90-1.81)]. Rate of graft failure was higher compared with ABOc living donor transplantation [HR 2.63 (1.72-4.01)]. Rejection occurred in 47% of 140 rituximab versus 22% of 50 rituximab/basiliximab, and 4% of 92 alemtuzumab-treated recipients (P < 0.001). ABOi kidney transplantation is superior to deceased donor transplantation. Rejection rate and graft failure are higher compared with matched ABOc living donor transplantation, underscoring the need for further studies into risk stratification and induction therapy [NTR7587, www.trialregister.nl].
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- 2021
10. Improving outcomes for donation after circulatory death kidney transplantation: Science of the times
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Kok, Michele J.C. de, Schaapherder, Alexander F.M., Alwayn, Ian P.J., Bemelman, Frederike J., Wetering, Jacqueline van de, Zuilen, Arjan D. van, Baas, M.C., Vries, Aiko P.J. de, Lindeman, Jan H.N., Kok, Michele J.C. de, Schaapherder, Alexander F.M., Alwayn, Ian P.J., Bemelman, Frederike J., Wetering, Jacqueline van de, Zuilen, Arjan D. van, Baas, M.C., Vries, Aiko P.J. de, and Lindeman, Jan H.N.
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Contains fulltext : 221518.pdf (publisher's version ) (Open Access)
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- 2020
11. Should kidney allografts from old donors be allocated only to old recipients?
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Süsal, C., Kumru, G., Döhler, B., Morath, C., Baas, M.C., Lutz, J., Unterrainer, C., Arns, W., Aubert, O., Bara, C., Beiras-Fernandez, A., Böhmig, G.A., Bösmüller, C., Diekmann, F., Dutkowski, P., Hauser, I., Legendre, C., Lozanovski, V.J., Mehrabi, A., Melk, A., Minor, T., Mueller, T.F., Pisarski, P., Rostaing, L., Schemmer, P., Schneeberger, S., Schwenger, V., Sommerer, C., Tönshoff, B., Viebahn, R., Viklicky, O., Weimer, R., Weiss, K.H., Zeier, M., Živčić-Ćosić, S., Heemann, U., Süsal, C., Kumru, G., Döhler, B., Morath, C., Baas, M.C., Lutz, J., Unterrainer, C., Arns, W., Aubert, O., Bara, C., Beiras-Fernandez, A., Böhmig, G.A., Bösmüller, C., Diekmann, F., Dutkowski, P., Hauser, I., Legendre, C., Lozanovski, V.J., Mehrabi, A., Melk, A., Minor, T., Mueller, T.F., Pisarski, P., Rostaing, L., Schemmer, P., Schneeberger, S., Schwenger, V., Sommerer, C., Tönshoff, B., Viebahn, R., Viklicky, O., Weimer, R., Weiss, K.H., Zeier, M., Živčić-Ćosić, S., and Heemann, U.
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Item does not contain fulltext, In several deceased donor kidney allocation systems, organs from elderly donors are allocated primarily to elderly recipients. The Eurotransplant Senior Program (ESP) was implemented in 1999, and since then, especially in Europe, the use of organs from elderly donors has steadily increased. The proportion of ≥60-year-old donors reported to the Collaborative Transplant Study (CTS) by European centers has doubled, from 21% in 2000-2001 to 42% in 2016-2017. Therefore, in the era of organ shortage it is a matter of debate whether kidney organs from elderly donors should only be allocated to elderly recipients or whether <65-year-old recipients can also benefit from these generally as "marginal" categorized organs. To discuss this issue, a European Consensus Meeting was organized by the CTS on April 12, 2018, in Heidelberg, in which 36 experts participated. Based on available evidence, it was unanimously concluded that kidney organs from 65- to 74-year-old donors can also be allocated to 55- to 64-year-old recipients, especially if these organs are from donors with no history of hypertension, no increased creatinine, no cerebrovascular death, and no other reasons for defining a marginal donor, such as diabetes or cancer.
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- 2020
12. A nationwide evaluation of deceased donor kidney transplantation indicates detrimental consequences of early graft loss
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Kok, Michele J. de, Schaapherder, Alexander F., Mensink, Jacobus W., Vries, Aiko P. de, Reinders, Marlies E., Konijn, Cynthia, Baas, M.C., Alwayn, Ian P., Lindeman, Jan H., Kok, Michele J. de, Schaapherder, Alexander F., Mensink, Jacobus W., Vries, Aiko P. de, Reinders, Marlies E., Konijn, Cynthia, Baas, M.C., Alwayn, Ian P., and Lindeman, Jan H.
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Contains fulltext : 220255pub.pdf (Publisher’s version ) (Closed access) Contains fulltext : 220255pre.pdf (Author’s version preprint ) (Open Access)
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- 2020
13. Improving outcomes for donation after circulatory death kidney transplantation: Science of the times
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de Kok, M.J.C. (Michèle J C), Schaapherder, A.F.M. (Alexander), Alwayn, I.P.J. (Ian), Bemelman, F.J. (Fréderike), Wetering, J. (Jacqueline) van de, van Zuilen, A.D. (Arjan D.), Christiaans, M.H. (Maarten), Baas, M.C. (Marije), Nurmohamed, A.S. (Azam S.), Berger, S.P. (Stefan P.), Bastiaannet, E. (Esther), Ploeg, R.J. (Rutger), de Vries, A.P.J. (Aiko P J), Lindeman, J. (J.), de Kok, M.J.C. (Michèle J C), Schaapherder, A.F.M. (Alexander), Alwayn, I.P.J. (Ian), Bemelman, F.J. (Fréderike), Wetering, J. (Jacqueline) van de, van Zuilen, A.D. (Arjan D.), Christiaans, M.H. (Maarten), Baas, M.C. (Marije), Nurmohamed, A.S. (Azam S.), Berger, S.P. (Stefan P.), Bastiaannet, E. (Esther), Ploeg, R.J. (Rutger), de Vries, A.P.J. (Aiko P J), and Lindeman, J. (J.)
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The use of kidneys donated after circulatory death (DCD) remains controversial due to concerns with regard to high incidences of early graft loss, delayed graft function (DGF), and impaired graft survival. As these concerns are mainly based on data from historical cohorts, they are prone to time-related effects and may therefore not apply to the current timeframe. To assess the impact of time on outcomes, we performed a time-dependent comparative analysis of outcomes of DCD and donation after brain death (DBD) kidney transplantations. Data of all 11,415 deceased-donor kidney transplantations performed in The Netherlands between 1990-2018 were collected. Based on the incidences of early graft loss, two eras were defined (1998-2008 [n = 3,499] and 2008-2018 [n = 3,781]), and potential time-related effects on outcomes evaluated. Multivariate analyses were applied to examine associations between donor type and outcomes. Interaction tests were used to explore presence of effect modification. Results show clear time-related effects on posttransplant outcomes. The 1998-2008 interval showed compromised outcomes for DCD procedures (higher incidences of DGF and early graft loss, impaired 1-year renal function, and inferior graft survival), whereas DBD and DCD outcome equivalence was observed for the 2008-2018 interval. This occurred despite persistently high incidences of DGF in DCD grafts, and more adverse recipient and donor risk profiles (recipients were 6 years older and the KDRI increased from 1.23 to 1.39 and from 1.35 to 1.49 for DBD and DCD donors). In contrast, the median cold ischaemic period dec
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- 2020
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14. Toward a Sensible Single-antigen Bead Cutoff Based on Kidney Graft Survival
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Wisse, B.W., Kamburova, E.G., Joosten, I., Allebes, W.A., Meer, A. van der, Hilbrands, L.B., Baas, M.C., Spierings, E., Hack, C.E., Reekum, F.E. van, Zuilen, A.D. van, Verhaar, M.C., Bots, M.L., Drop, A., Plaisier, L., Seelen, M.A., Stephan Sanders, J., Hepkema, B.G., Lambeck, A.J.A., Bungener, L.B., Roozendaal, C., Tilanus, M.G., Voorter, C.E.M., Wieten, L., van Duijnhoven, E.M., Gelens, M., Christiaans, M.H., van Ittersum, F.J., Nurmohamed, S.A., Lardy, N.M., Swelsen, W., Pant, K. van der, Weerd, N.C. van der, Berge, I.J. ten, Bemelman, F.J., Hoitsma, A.J., Boog, P.J. van der, Fijter, J.W. de, Betjes, M.G., Heidt, S., Roelen, D.L., Claas, F.H., Otten, H.G., Wisse, B.W., Kamburova, E.G., Joosten, I., Allebes, W.A., Meer, A. van der, Hilbrands, L.B., Baas, M.C., Spierings, E., Hack, C.E., Reekum, F.E. van, Zuilen, A.D. van, Verhaar, M.C., Bots, M.L., Drop, A., Plaisier, L., Seelen, M.A., Stephan Sanders, J., Hepkema, B.G., Lambeck, A.J.A., Bungener, L.B., Roozendaal, C., Tilanus, M.G., Voorter, C.E.M., Wieten, L., van Duijnhoven, E.M., Gelens, M., Christiaans, M.H., van Ittersum, F.J., Nurmohamed, S.A., Lardy, N.M., Swelsen, W., Pant, K. van der, Weerd, N.C. van der, Berge, I.J. ten, Bemelman, F.J., Hoitsma, A.J., Boog, P.J. van der, Fijter, J.W. de, Betjes, M.G., Heidt, S., Roelen, D.L., Claas, F.H., and Otten, H.G.
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Contains fulltext : 204258.pdf (publisher's version ) (Open Access), BACKGROUND: There is no consensus in the literature on the interpretation of single-antigen bead positive for a specific HLA antibody. METHODS: To inform the debate, we studied the relationship between various single-antigen bead positivity algorithms and the impact of resulting donor-specific HLA antibody (DSA) positivity on long-term kidney graft survival in 3237 deceased-donor transplants. RESULTS: First, we showed that the interassay variability can be greatly reduced when working with signal-to-background ratios instead of absolute median fluorescence intensities (MFIs). Next, we determined pretransplant DSA using various MFI cutoffs, signal-to-background ratios, and combinations thereof. The impact of the various cutoffs was studied by comparing the graft survival between the DSA-positive and DSA-negative groups. We did not observe a strong impact of various cutoff levels on 10-year graft survival. A stronger relationship between the cutoff level and 1-year graft survival for DSA-positive transplants was found when using signal-to-background ratios, most pronounced for the bead of the same HLA locus with lowest MFI taken as background. CONCLUSIONS: With respect to pretransplant risk stratification, we propose a signal-to-background ratio-6 (using the bead of the same HLA-locus with lowest MFI as background) cutoff of 15 combined with an MFI cutoff of 500, resulting in 8% and 21% lower 1- and 10-year graft survivals, respectively, for 8% DSA-positive transplants.
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- 2019
15. Allocation to highly sensitized patients based on acceptable mismatches results in low rejection rates comparable to nonsensitized patients
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Heidt, S., Haasnoot, G.W., Witvliet, M.D., Linden-van Oevelen, M.J.H. van der, Kamburova, E.G., Wisse, B.W., Joosten, I., Allebes, W.A., Meer, A. van der, Hilbrands, L.B., Baas, M.C., Spierings, E., Hack, C.E., Reekum, F.E. van, Zuilen, A.D. van, Verhaar, M.C., Bots, M.L., Drop, A., Plaisier, L., Seelen, M.A., Sanders, J.S., Hepkema, B.G., Lambeck, A.J.A., Bungener, L.B., Roozendaal, C., Tilanus, M.G., Voorter, C.E.M., Wieten, L., Duijnhoven, E.M. van, Gelens, M., Christiaans, M.H., Ittersum, F.J. van, Nurmohamed, S.A., Lardy, N.M., Swelsen, W., Pant, K. van der, Weerd, N.C. van der, Berge, I.J. Ten, Bemelman, F.J., Hoitsma, A., Boog, P.J. van der, Fijter, J.W. de, Betjes, M.G., Otten, H.G., Roelen, D.L., Claas, F.H., Heidt, S., Haasnoot, G.W., Witvliet, M.D., Linden-van Oevelen, M.J.H. van der, Kamburova, E.G., Wisse, B.W., Joosten, I., Allebes, W.A., Meer, A. van der, Hilbrands, L.B., Baas, M.C., Spierings, E., Hack, C.E., Reekum, F.E. van, Zuilen, A.D. van, Verhaar, M.C., Bots, M.L., Drop, A., Plaisier, L., Seelen, M.A., Sanders, J.S., Hepkema, B.G., Lambeck, A.J.A., Bungener, L.B., Roozendaal, C., Tilanus, M.G., Voorter, C.E.M., Wieten, L., Duijnhoven, E.M. van, Gelens, M., Christiaans, M.H., Ittersum, F.J. van, Nurmohamed, S.A., Lardy, N.M., Swelsen, W., Pant, K. van der, Weerd, N.C. van der, Berge, I.J. Ten, Bemelman, F.J., Hoitsma, A., Boog, P.J. van der, Fijter, J.W. de, Betjes, M.G., Otten, H.G., Roelen, D.L., and Claas, F.H.
- Abstract
Contains fulltext : 208426.pdf (publisher's version ) (Open Access), Whereas regular allocation avoids unacceptable mismatches on the donor organ, allocation to highly sensitized patients within the Eurotransplant Acceptable Mismatch (AM) program is based on the patient's HLA phenotype plus acceptable antigens. These are HLA antigens to which the patient never made antibodies, as determined by extensive laboratory testing. AM patients have superior long-term graft survival compared with highly sensitized patients in regular allocation. Here, we questioned whether the AM program also results in lower rejection rates. From the PROCARE cohort, consisting of all Dutch kidney transplants in 1995-2005, we selected deceased donor single transplants with a minimum of 1 HLA mismatch and determined the cumulative 6-month rejection incidence for patients in AM or regular allocation. Additionally, we determined the effect of minimal matching criteria of 1 HLA-B plus 1 HLA-DR, or 2 HLA-DR antigens on rejection incidence. AM patients showed significantly lower rejection rates than highly immunized patients in regular allocation, comparable to nonsensitized patients, independent of other risk factors for rejection. In contrast to highly sensitized patients in regular allocation, minimal matching criteria did not affect rejection rates in AM patients. Allocation based on acceptable antigens leads to relatively low-risk transplants for highly sensitized patients with rejection rates similar to those of nonimmunized individuals.
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- 2019
16. A paired kidney analysis on the impact of pre-transplant anti-HLA antibodies on graft survival
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Michielsen, L.A., Wisse, B.W., Kamburova, E.G., Verhaar, M.C., Joosten, I., Allebes, W.A., Meer, A. van der, Hilbrands, L.B., Baas, M.C., Spierings, E, Hack, C.E., Reekum, F.E. van, Bots, M.L., Drop, A., Plaisier, L., Seelen, M.A., Sanders, J.F., Hepkema, B.G., Lambeck, A.J.A., Bungener, L.B., Roozendaal, C., Tilanus, M.G., Voorter, C.E.M., Wieten, L., Duijnhoven, E.M. van, Gelens, M., Christiaans, M.H., Ittersum, F.J. van, Nurmohamed, S.A., Lardy, N.M., Swelsen, W., Pant, K.A. van der, Weerd, N.C. van der, Berge, I.J. ten, Bemelman, F.J., Hoitsma, A.J., Boog, P.J. van der, Fijter, J.W. de, Betjes, M.G., Heidt, S., Roelen, D.L., Claas, F.H., Otten, H.G., Zuilen, A.D. van, Michielsen, L.A., Wisse, B.W., Kamburova, E.G., Verhaar, M.C., Joosten, I., Allebes, W.A., Meer, A. van der, Hilbrands, L.B., Baas, M.C., Spierings, E, Hack, C.E., Reekum, F.E. van, Bots, M.L., Drop, A., Plaisier, L., Seelen, M.A., Sanders, J.F., Hepkema, B.G., Lambeck, A.J.A., Bungener, L.B., Roozendaal, C., Tilanus, M.G., Voorter, C.E.M., Wieten, L., Duijnhoven, E.M. van, Gelens, M., Christiaans, M.H., Ittersum, F.J. van, Nurmohamed, S.A., Lardy, N.M., Swelsen, W., Pant, K.A. van der, Weerd, N.C. van der, Berge, I.J. ten, Bemelman, F.J., Hoitsma, A.J., Boog, P.J. van der, Fijter, J.W. de, Betjes, M.G., Heidt, S., Roelen, D.L., Claas, F.H., Otten, H.G., and Zuilen, A.D. van
- Abstract
Item does not contain fulltext, BACKGROUND: Pre-transplant donor-specific anti-human leucocyte antigen (HLA) antibodies (DSAs) are associated with impaired kidney graft survival while the clinical relevance of non-donor-specific anti-HLA antibodies (nDSAs) is more controversial. The aim of the present paired kidney graft study was to compare the clinical relevance of DSAs and nDSAs. METHODS: To eliminate donor and era-dependent factors, a post hoc paired kidney graft analysis was performed as part of a Dutch multicentre study evaluating all transplantations between 1995 and 2005 with available pre-transplant serum samples. Anti-HLA antibodies were detected with a Luminex single-antigen bead assay. RESULTS: Among 3237 deceased donor transplantations, we identified 115 recipient pairs receiving a kidney from the same donor with one recipient being DSA positive and the other without anti-HLA antibodies. Patients with pre-transplant DSAs had a significantly lower 10-year death-censored graft survival (55% versus 82%, P=0.0001). We identified 192 pairs with one recipient as nDSA positive (against Class I and/or II) and the other without anti-HLA antibodies. For the patients with nDSAs against either Class I or II, graft survival did not significantly differ compared with patients without anti-HLA antibodies (74% versus 77%, P = 0.79). Only in patients with both nDSAs Class I and II was there a trend towards a lower graft survival (58%, P = 0.06). Lastly, in a small group of 42 recipient pairs, 10-year graft survival in recipients with DSAs was 49% compared with 68% in recipients with nDSAs (P=0.11). CONCLUSION: This paired kidney analysis confirms that the presence of pre-transplant DSAs in deceased donor transplantations is a risk marker for graft loss, whereas nDSAs in general are not associated with a lower graft survival. Subgroup analysis indicated that only in broadly sensitized patients with nDSAs against Class I and II, nDSAs may be a risk marker for graft loss in the long term.
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- 2019
17. Effect of initial immunosuppression on long-term kidney transplant outcome in immunological low-risk patients
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Michielsen, L.A., Zuilen, A.D. van, Verhaar, M.C., Wisse, B.W., Kamburova, Elena G., Joosten, I., Allebes, W.A., Meer, A. van der, Baas, M.C., Hoitsma, A.J., Otten, Henderikus G., Hilbrands, L.B., Michielsen, L.A., Zuilen, A.D. van, Verhaar, M.C., Wisse, B.W., Kamburova, Elena G., Joosten, I., Allebes, W.A., Meer, A. van der, Baas, M.C., Hoitsma, A.J., Otten, Henderikus G., and Hilbrands, L.B.
- Abstract
Item does not contain fulltext
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- 2019
18. Antibodies against ARHGDIB are associated with long-term kidney graft loss
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Kamburova, E.G., Gruijters, M.L., Kardol-Hoefnagel, T., Wisse, B.W., Joosten, I., Allebes, W.A., Meer, A. van der, Hilbrands, L.B., Baas, M.C., Spierings, E., Hack, C.E., Reekum, F.E. van, Zuilen, A.D. van, Verhaar, M.C., Bots, M.L., Drop, A., Plaisier, L., Melchers, R.C., Seelen, M.A., Sanders, J.S., Hepkema, B.G., Lambeck, A.J.A., Bungener, L.B., Roozendaal, C., Tilanus, M.G., Voorter, C.E.M., Wieten, L., Duijnhoven, E.M. van, Gelens, M., Christiaans, M.H., Ittersum, F.J. van, Nurmohamed, S.A., Lardy, N.M., Swelsen, W., Pant, K. van der, Weerd, N.C. van der, Berge, I.J. Ten, Hoitsma, A., Boog, P.J. van der, Fijter, J.W. de, Betjes, M.G., Heidt, S., Roelen, D.L., Claas, F.H., Bemelman, F.J., Otten, H.G., Kamburova, E.G., Gruijters, M.L., Kardol-Hoefnagel, T., Wisse, B.W., Joosten, I., Allebes, W.A., Meer, A. van der, Hilbrands, L.B., Baas, M.C., Spierings, E., Hack, C.E., Reekum, F.E. van, Zuilen, A.D. van, Verhaar, M.C., Bots, M.L., Drop, A., Plaisier, L., Melchers, R.C., Seelen, M.A., Sanders, J.S., Hepkema, B.G., Lambeck, A.J.A., Bungener, L.B., Roozendaal, C., Tilanus, M.G., Voorter, C.E.M., Wieten, L., Duijnhoven, E.M. van, Gelens, M., Christiaans, M.H., Ittersum, F.J. van, Nurmohamed, S.A., Lardy, N.M., Swelsen, W., Pant, K. van der, Weerd, N.C. van der, Berge, I.J. Ten, Hoitsma, A., Boog, P.J. van der, Fijter, J.W. de, Betjes, M.G., Heidt, S., Roelen, D.L., Claas, F.H., Bemelman, F.J., and Otten, H.G.
- Abstract
Contains fulltext : 215571.pdf (publisher's version ) (Open Access), The clinical significance of non-HLA antibodies on renal allograft survival is a matter of debate, due to differences in reported results and lack of large-scale studies incorporating analysis of multiple non-HLA antibodies simultaneously. We developed a multiplex non-HLA antibody assay against 14 proteins highly expressed in the kidney. In this study, the presence of pretransplant non-HLA antibodies was correlated to renal allograft survival in a nationwide cohort of 4770 recipients transplanted between 1995 and 2006. Autoantibodies against Rho GDP-dissociation inhibitor 2 (ARHGDIB) were significantly associated with graft loss in recipients transplanted with a deceased-donor kidney (N = 3276) but not in recipients of a living-donor kidney (N = 1496). At 10 years after deceased-donor transplantation, recipients with anti-ARHGDIB antibodies (94/3276 = 2.9%) had a 13% lower death-censored covariate-adjusted graft survival compared to the anti-ARHGDIB-negative (3182/3276 = 97.1%) population (hazard ratio 1.82; 95% confidence interval, 1.32-2.53; P = .0003). These antibodies occur independently from donor-specific anti-HLA antibodies (DSA) or other non-HLA antibodies investigated. No significant relations with graft loss were found for the other 13 non-HLA antibodies. We suggest that pretransplant risk assessment can be improved by measuring anti-ARHGDIB antibodies in all patients awaiting deceased-donor transplantation.
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- 2019
19. Allocation to highly sensitized patients based on acceptable mismatches results in low rejection rates comparable to nonsensitized patients
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Heidt, P.J. (Peter), Haasnoot, G.W. (Geert), Witvliet, M.D. (Marian), van der Linden-van Oevelen, M.J.H. (Marissa J. H.), Kamburova, E.G., Wisse, B.W., Joosten, I. (Irma), Allebes, W.A. (Wil), van der Meer, A., Hilbrands, L.B. (Luuk), Baas, M.C. (Marije), Spierings, E. (E.), Hack, C.E. (Erik), van Reekum, F., van Zuilen, A.D. (Arjan D.), Verhaar, M.C. (Marianne), Bots, M.L. (Michiel), Drop, A.C.A.D., Plaisier, L., Seelen, M.A.J., Sanders, J.S.F., Hepkema, B.G. (Bouke), Lambeck, A.J.A. (Annechien J.A.), Bungener, L.B., Roozendaal, C., Tilanus, M.G.J. (Marcel), Voorter, C.E.M. (C. E M), Wieten, L., van Duijnhoven, E., Gelens, M., Christiaans, M.H. (Maarten), van Ittersum, F., Nurmohamed, S.A. (Shaikh Azam), Lardy, N.M. (Neubury), Swelsen, W.T., van der Pant, K.A., Weerd, N.C. (Neelke) van der, Berge, I.J.M. (Ineke) ten, Bemelman, F.J. (Fréderike), Hoitsma, A.J. (Andries), van der Boog, P.J.M., Fijter, J.W. (Johan) de, Betjes, M.G.H. (Michiel), Otten, H.G. (Henderikus), Roelen, D.L. (Dave), Claas, F.H.J. (Frans), Heidt, P.J. (Peter), Haasnoot, G.W. (Geert), Witvliet, M.D. (Marian), van der Linden-van Oevelen, M.J.H. (Marissa J. H.), Kamburova, E.G., Wisse, B.W., Joosten, I. (Irma), Allebes, W.A. (Wil), van der Meer, A., Hilbrands, L.B. (Luuk), Baas, M.C. (Marije), Spierings, E. (E.), Hack, C.E. (Erik), van Reekum, F., van Zuilen, A.D. (Arjan D.), Verhaar, M.C. (Marianne), Bots, M.L. (Michiel), Drop, A.C.A.D., Plaisier, L., Seelen, M.A.J., Sanders, J.S.F., Hepkema, B.G. (Bouke), Lambeck, A.J.A. (Annechien J.A.), Bungener, L.B., Roozendaal, C., Tilanus, M.G.J. (Marcel), Voorter, C.E.M. (C. E M), Wieten, L., van Duijnhoven, E., Gelens, M., Christiaans, M.H. (Maarten), van Ittersum, F., Nurmohamed, S.A. (Shaikh Azam), Lardy, N.M. (Neubury), Swelsen, W.T., van der Pant, K.A., Weerd, N.C. (Neelke) van der, Berge, I.J.M. (Ineke) ten, Bemelman, F.J. (Fréderike), Hoitsma, A.J. (Andries), van der Boog, P.J.M., Fijter, J.W. (Johan) de, Betjes, M.G.H. (Michiel), Otten, H.G. (Henderikus), Roelen, D.L. (Dave), and Claas, F.H.J. (Frans)
- Abstract
Whereas regular allocation avoids unacceptable mismatches on the donor organ, allocation to highly sensitized patients within the Eurotransplant Acceptable Mismatch (AM) program is based on the patient's HLA phenotype plus acceptable antigens. These are HLA antigens to which the patient never made antibodies, as determined by extensive laboratory testing. AM patients have superior long-term graft survival compared with highly sensitized patients in regular allocation. Here, we questioned whether the AM program also results in lower rejection rates. From the PROCARE cohort, consisting of all Dutch kidney transplants in 1995-2005, we selected deceased donor single transplants with a minimum of 1 HLA mismatch and determined the cumulative 6-month rejection incidence for patients in AM or regular allocation. Additionally, we determined the effect of minimal matching criteria of 1 HLA-B plus 1 HLA-DR, or 2 HLA-DR antigens on rejection incidence. AM patients showed significantly lower rejection rates than highly immunized patients in regular allocation, comparable to nonsensitized patients, independent of other risk factors for rejection. In contrast to highly sensitized patients in regular allocation, minimal matching criteria did not affect rejection rates in AM patients. Allocation based on acceptable antigens leads to relatively low-risk transplants for highly sensitized patients with rejection rates similar to those of nonimmunized individuals.
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- 2019
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20. Development and Validation of a Multiplex Non-HLA Antibody Assay for the Screening of Kidney Transplant Recipients
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Kamburova, Elena G., Kardol-Hoefnagel, Tineke, Wisse, B.W., Joosten, I., Allebes, W.A., Meer, A. van der, Hilbrands, L.B., Baas, M.C., Claas, Frans H., Otten, Henny G., Kamburova, Elena G., Kardol-Hoefnagel, Tineke, Wisse, B.W., Joosten, I., Allebes, W.A., Meer, A. van der, Hilbrands, L.B., Baas, M.C., Claas, Frans H., and Otten, Henny G.
- Abstract
Contains fulltext : 199461.pdf (publisher's version ) (Open Access)
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- 2018
21. PIRCHE-II Is Related to Graft Failure after Kidney Transplantation
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Geneugelijk, Kirsten, Niemann, Matthias, Drylewicz, Julia, Zuilen, A.D. van, Joosten, I., Allebes, W.A., Meer, A. van der, Hilbrands, L.B., Baas, M.C., Hoitsma, A.J., Otten, H.G., Spierings, E., Geneugelijk, Kirsten, Niemann, Matthias, Drylewicz, Julia, Zuilen, A.D. van, Joosten, I., Allebes, W.A., Meer, A. van der, Hilbrands, L.B., Baas, M.C., Hoitsma, A.J., Otten, H.G., and Spierings, E.
- Abstract
Contains fulltext : 190044.pdf (publisher's version ) (Open Access)
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- 2018
22. PIRCHE-II is related to graft failure after kidney transplantation
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Geneugelijk, K. (Kirsten), Niemann, M. (Matthias), Drylewicz, J. (Julia), van Zuilen, A.D. (Arjan D.), Joosten, I. (Irma), Allebes, W.A. (Wil), van der Meer, A., Hilbrands, L.B. (Luuk), Baas, M.C. (Marije), Hack, C.E. (Erik), van Reekum, F., Verhaar, M.C. (Marianne), Kamburova, E.G., Bots, M.L. (Michiel L.), Seelen, M.A.J., Sanders, J.S.F., Hepkema, B.G. (Bouke), Lambeck, A.J.A. (Annechien J.A.), Bungener, L.B., Roozendaal, C., Tilanus, M.G.J. (Marcel), Vanderlocht, J. (Joris), Voorter, C.E.M. (C. E M), Wieten, L., van Duijnhoven, E., Gelens, M., Christiaans, M.H. (Maarten), van Ittersum, F., Nurmohamed, A., Lardy, J.N.M. (Junior N.M.), Swelsen, W.T., van der Pant, K.A., Weerd, N.C. (Neelke) van der, Berge, I.J.M. (Ineke) ten, Bemelman, F.J. (Fréderike), Hoitsma, A.J. (Andries), van der Boog, P.J.M., Fijter, J.W. (Johan) de, Betjes, M.G.H. (Michiel), Heidt, P.J. (Peter), Roelen, D.L. (Dave), Claas, F.H.J. (Frans), Otten, H.G. (Henderikus), Spierings, E. (E.), Geneugelijk, K. (Kirsten), Niemann, M. (Matthias), Drylewicz, J. (Julia), van Zuilen, A.D. (Arjan D.), Joosten, I. (Irma), Allebes, W.A. (Wil), van der Meer, A., Hilbrands, L.B. (Luuk), Baas, M.C. (Marije), Hack, C.E. (Erik), van Reekum, F., Verhaar, M.C. (Marianne), Kamburova, E.G., Bots, M.L. (Michiel L.), Seelen, M.A.J., Sanders, J.S.F., Hepkema, B.G. (Bouke), Lambeck, A.J.A. (Annechien J.A.), Bungener, L.B., Roozendaal, C., Tilanus, M.G.J. (Marcel), Vanderlocht, J. (Joris), Voorter, C.E.M. (C. E M), Wieten, L., van Duijnhoven, E., Gelens, M., Christiaans, M.H. (Maarten), van Ittersum, F., Nurmohamed, A., Lardy, J.N.M. (Junior N.M.), Swelsen, W.T., van der Pant, K.A., Weerd, N.C. (Neelke) van der, Berge, I.J.M. (Ineke) ten, Bemelman, F.J. (Fréderike), Hoitsma, A.J. (Andries), van der Boog, P.J.M., Fijter, J.W. (Johan) de, Betjes, M.G.H. (Michiel), Heidt, P.J. (Peter), Roelen, D.L. (Dave), Claas, F.H.J. (Frans), Otten, H.G. (Henderikus), and Spierings, E. (E.)
- Abstract
Individual HLA mismatches may differentially impact graft survival after kidney transplantation. Therefore, there is a need for a reliable tool to define permissible HLA mismatches in kidney transplantation. We previously demonstrated that donor-derived Predicted Indirectly ReCognizable HLA Epitopes presented by recipient HLA class II (PIRCHE-II) play a role in de novo donor-specific HLA antibodies formation after kidney transplantation. In the present Dutch multi-center study, we evaluated the possible association between PIRCHE-II and kidney graft failure in 2,918 donor-recipient couples that were transplanted between 1995 and 2005. For these donors-recipients couples, PIRCHE-II numbers were related to graft survival in univariate and multivariable analyses. Adjusted for confounders, the natural logarithm of PIRCHE-II was associated with a higher risk for graft failure [hazard ratio (HR): 1.13, 95% CI: 1.04-1.23, p = 0.003]. When analyzing a subgroup of patients who had their first transplantation, the HR of graft failure for ln(PIRCHE-II) was higher compared with the overall cohort (HR: 1.22, 95% CI: 1.10-1.34, p < 0.001). PIRCHE-II demonstrated both early and late effects on graft failure in this subgroup. These data suggest that the PIRCHE-II may impact graft survival after kidney transplantation. Inclusion of PIRCHE-II in donor-selection criteria may eventually lead to an improved kidney graft survival.
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- 2018
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23. Pretransplant C3d-Fixing Donor-Specific Anti-HLA Antibodies Are Not Associated with Increased Risk for Kidney Graft Failure
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Kamburova, E.G., Wisse, B.W., Joosten, I., Allebes, W.A., Meer, A. van der, Hilbrands, L.B., Baas, M.C., Spierings, E., Hack, C.E., Reekum, F.E. van, Zuilen, A.D. van, Verhaar, M.C., Bots, M.L., Drop, A.C., Plaisier, L., Seelen, M.A., Sanders, J.S., Hepkema, B.G., Lambeck, A.J.A., Bungener, L.B., Roozendaal, C., Tilanus, M.G., Voorter, C.E.M., Wieten, L., Duijnhoven, E.M. van, Gelens, M.A., Christiaans, M.H., Ittersum, F.J. van, Nurmohamed, S.A., Lardy, N.M., Swelsen, W., Pant, Karlijn A.M.I. van der, Weerd, N.C. van der, Berge, I.J. Ten, Bemelman, F.J., Hoitsma, A.J., Boog, P.J. van der, Fijter, J.W. de, Betjes, M.G., Heidt, S., Roelen, D.L., Claas, F.H., Otten, H.G., Kamburova, E.G., Wisse, B.W., Joosten, I., Allebes, W.A., Meer, A. van der, Hilbrands, L.B., Baas, M.C., Spierings, E., Hack, C.E., Reekum, F.E. van, Zuilen, A.D. van, Verhaar, M.C., Bots, M.L., Drop, A.C., Plaisier, L., Seelen, M.A., Sanders, J.S., Hepkema, B.G., Lambeck, A.J.A., Bungener, L.B., Roozendaal, C., Tilanus, M.G., Voorter, C.E.M., Wieten, L., Duijnhoven, E.M. van, Gelens, M.A., Christiaans, M.H., Ittersum, F.J. van, Nurmohamed, S.A., Lardy, N.M., Swelsen, W., Pant, Karlijn A.M.I. van der, Weerd, N.C. van der, Berge, I.J. Ten, Bemelman, F.J., Hoitsma, A.J., Boog, P.J. van der, Fijter, J.W. de, Betjes, M.G., Heidt, S., Roelen, D.L., Claas, F.H., and Otten, H.G.
- Abstract
Item does not contain fulltext
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- 2018
24. PIRCHE-II: A NOVEL TOOL TO IDENTIFY PERMISSIBLE HLA MISMATCHES IN KIDNEY TRANSPLANTATION
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Geneugelijk, K., Niemann, M., Drylewicz, J., Zuilen, A.D. van, Joosten, I., Allebes, W.A., Meer, A. van der, Hilbrands, L.B., Baas, M.C., Hack, C.E., Reekum, F.E. van, Verhaar, M., Kamburova, E.G., Bots, M.L., Seelen, M.A.J., Sanders, J.S.F., Hepkema, B.G., Lambeck, A.J., Bungener, L.B., Roozendaal, C., Tilanus, M.G.J., Vanderlocht, J., Voorter, C.E.M., Wieten, L., Duijnhoven, E.M. van, Gelens, M., Christiaans, M.H.L., Ittersum, F.J. van, Nurmohamed, A., Lardy, N.M., Swelsen, W., Pant, K.A. van der, Weerd, N.C. van der, Berge, I.J.M. ten, Bemelman, F.D.J., Hoitsma, A., Boog, P.J.M. van der, Fijter, J.W. de, Betjes, M.G.H., Heidt, S., Roelen, D.L., Claas, F.H.J., Otten, H.G., and Spierings, E.
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- 2017
25. DIFFERENTIAL EFFECT OF DONOR-SPECIFIC HLA ANTIBODIES IN LIVING VERSUS DECEASED DONOR KIDNEY TRANSPLANTATION
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Kamburova, E.G., Wisse, B.W., Joosten, I., Allebes, W.A., Meer, A. van der, Hilbrands, L.B., Baas, M.C., Spierings, E., Hack, C.E., Reekum, F. van, Zuilen, A. van, Verhaar, M.C., Bots, M.L., Drop, A.C.A.D., Plaisier, L., Seelen, M.A.J., Sanders, J.S.F., Hepkema, B.G., Lambeck, A.J., Bungener, L.B., Roozendaal, C., Tilanus, M.G.J., Voorter, C.E.M., Wieten, L., Duijnhoven, E.M. van, Gelens, M., Christiaans, M.H.L., Ittersum, F.J. van, Nurmohamed, A., Lardy, N.M., Swelsen, W., Pant, K.A. van der, Weerd, N.C. van der, Berge, I.J.M. ten, Bemelman, F.J., Hoitsma, A., Boog, P.J.M. van der, Fijter, H. de, Betjes, M.G.H., Heidt, S., Roelen, D.L., Claas, F.H.J., and Otten, H.G.
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- 2017
26. Absence of Intragraft B Cells in Rejection Biopsies After Rituximab Induction Therapy: Consequences for Clinical Outcome
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Hoogen, M.W.F. van den, Steenbergen, E.J., Baas, M.C., Florquin, S., Hilbrands, L.B., Hoogen, M.W.F. van den, Steenbergen, E.J., Baas, M.C., Florquin, S., and Hilbrands, L.B.
- Abstract
Contains fulltext : 174159.pdf (publisher's version ) (Open Access), BACKGROUND: The pathophysiological role of intragraft B cells during renal allograft rejection is unclear. METHODS: We studied B-cell infiltration during acute rejection in 53 patients who participated in a clinical trial in which adult renal transplant patients were randomized between a single intraoperative dose of rituximab (375 mg/m2) or placebo as induction therapy. Two independent pathologists scored all biopsies in a blinded fashion according to the Banff classification and scored for the presence of B cells and plasma cells using CD79a and CD138 as markers. RESULTS: The majority of acute rejections were T cell-mediated. The proportion of acute rejections with an antibody-mediated component tended to be lower in rituximab-treated patients (4/23, 17.4%) than in placebo-treated patients (11/30, 36.7%; P = 0.14). Biopsies of rituximab-treated patients had significantly lower scores for B cells (0.00; range, 0.00-0.50 vs 1.70; range, 0.60-3.30; P < 0.0001) and plasma cells (0.10; range, 0.00-1.90 vs 0.40; range, 0.00-7.50; P = 0.006). During acute rejection, intragraft clusters of B cells were not observed after rituximab induction therapy. However, the depletion of intragraft B cells during acute rejection did not affect steroid resistance, proteinuria, graft function at 2 years follow-up, or patient and graft survival at a median follow-up of 4.1 years (range, 2.0-6.2 years). CONCLUSIONS: These data do not support a harmful influence of intragraft B cells present during acute allograft rejection on the clinical course within the first few years after renal transplantation.
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- 2017
27. Peri- and Postoperative Treatment with the Interleukin-1 Receptor Antagonist Anakinra Is Safe in Patients Undergoing Renal Transplantation: Case Series and Review of the Literature
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Mulders-Manders, C.M., Baas, M.C., Molenaar, F.M., Simon, A., Mulders-Manders, C.M., Baas, M.C., Molenaar, F.M., and Simon, A.
- Abstract
Contains fulltext : 174156.pdf (publisher's version ) (Open Access), In patients undergoing solid organ transplantation, the presence of an interleukin-1 (IL-1) driven disease may require the addition of IL-1 inhibiting drugs to the standard immunosuppressive regimen to protect against inflammation and negative graft outcome. Three patients undergoing renal transplantation were treated perioperatively with the interleukin-1 receptor antagonist anakinra. Kidney function increased rapidly in all three and the only complications seen were minor infections. In vitro studies report associations between serum and urinary levels of IL-1beta and IL-1 receptor antagonist and negative graft outcome, and studies in animals and two small human trials illustrate a possible protective effect of anti-IL-1 therapy after solid organ transplantation. Peri- and postoperative use of anakinra is safe and effective in patients undergoing renal transplantation.
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- 2017
28. The Induction and Maintenance of Transplant Tolerance Engages Both Regulatory and Anergic CD4+ T cells
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Besancon, A., Baas, M.C., Goncalves, T., Valette, F., Waldmann, H., Chatenoud, L., You, S., Besancon, A., Baas, M.C., Goncalves, T., Valette, F., Waldmann, H., Chatenoud, L., and You, S.
- Abstract
Contains fulltext : 174171.pdf (publisher's version ) (Open Access), Therapeutic tolerance to self-antigens or foreign antigens is thought to depend on constant vigilance by Foxp3+ regulatory T cells (Tregs). Previous work using a pancreatic islet allograft model and a short pulse of CD3 antibody therapy has shown that CD8+ T cells become anergic and use TGFbeta and coinhibitory signaling as their contribution to the tolerance process. Here, we examine the role of CD4+ T cells in tolerization by CD3 antibodies. We show that both Foxp3+ Tregs and CD4+ T cell anergy play a role in the induction of tolerance and its maintenance. Foxp3+ Tregs resisted CD3 antibody-mediated depletion, unlike intragraft Th1 CD4+ lymphocytes coexpressing granzyme B and Tbx21, which were selectively eliminated. Tregs were mandatory for induction of tolerance as their depletion at the time of CD3 antibody therapy or for a short time thereafter, by an antibody to CD25 (PC61), led to graft rejection. Early treatment with CTLA-4 antibody gave the same outcome. In contrast, neither PC61 nor anti-CTLA-4 given late, at day 100 posttransplant, reversed tolerance once established. Ablation of Foxp3 T cells after diphtheria toxin injection in tolerant Foxp3DTR recipient mice provided the same outcome. Alloreactive T cells had been rendered intrinsically unresponsive as total CD4+ or Treg-deprived CD4+ T cells from tolerant recipients were unable to mount donor-specific IFN-gamma responses. In addition, intragraft Treg-deprived CD4+ T cells lacked proliferative capacities, expressed high levels of the inhibitory receptor PD-1, and exhibited a CD73hiFR4hi phenotype, thus reflecting a state of T cell anergy. We conclude that Tregs play a substantive and critical role in guiding the immune system toward tolerance of the allograft, when induced by CD3 antibody, but are less important for maintenance of the tolerant state, where T cell anergy appears sufficient.
- Published
- 2017
29. How can we reduce costs of solid-phase multiplex-bead assays used to determine anti-HLA antibodies?
- Author
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Kamburova, E.G., Wisse, B.W., Joosten, I., Allebes, W.A., Meer, A. van der, Hilbrands, L.B., Baas, M.C., Spierings, E., Hack, C.E., Reekum, F.E. van, Zuilen, A.D. van, Verhaar, M., Bots, M.L., Drop, A.C.A.D., Plaisier, L., Seelen, M.A.J., Sanders, J.S.F., Hepkema, B.G., Lambeck, A.J., Bungener, L.B., Roozendaal, C., Tilanus, M.G.J., Vanderlocht, J., Voorter, C.E., Wieten, L., Duijnhoven, E.M. van, Gelens, M., Christiaans, M.H.L., Ittersum, F.J. van, Nurmohamed, A., Lardy, N.M., Swelsen, W., Pant, K.A. van der, Weerd, N.C. van der, Berge, I.J.M. ten, Bemelman, F.J., Hoitsma, A., Boog, P.J.M. van der, Fijter, J.W. de, Betjes, M.G.H., Heidt, S., Roelen, D.L., Claas, F.H., Otten, H.G., RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Interne Geneeskunde, MUMC+: DA Transplantatie Immunologie (5), MUMC+: DA TI Staf (9), MUMC+: DA TI Laboratorium (9), MUMC+: MA Nefrologie (9), RS: NUTRIM - R3 - Chronic inflammatory disease and wasting, Internal medicine, Nephrology, ICaR - Ischemia and repair, Internal Medicine, Other departments, AII - Amsterdam institute for Infection and Immunity, Groningen Institute for Organ Transplantation (GIOT), and Groningen Kidney Center (GKC)
- Subjects
CLINICAL-RELEVANCE ,KIDNEY-TRANSPLANTATION ,Immunology ,Other Research Radboud Institute for Molecular Life Sciences [Radboudumc 0] ,Sensitivity and Specificity ,HLA Antigens ,Isoantibodies ,Genetics ,Journal Article ,Immunology and Allergy ,Humans ,Alleles ,Automation, Laboratory ,Immunoassay ,Observer Variation ,ALLOANTIBODIES ,Histocompatibility Testing ,Immune Sera ,Reproducibility of Results ,human leukocyte antigen antibodies ,Kidney Transplantation ,single antigen ,solid-phase multiplex-bead assays ,luminex ,Reagent Kits, Diagnostic ,Renal disorders Radboud Institute for Health Sciences [Radboudumc 11] ,Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5] - Abstract
Item does not contain fulltext Solid-phase multiplex-bead assays are widely used in transplantation to detect anti-human leukocyte antigen (HLA) antibodies. These assays enable high resolution detection of low levels of HLA antibodies. However, multiplex-bead assays are costly and yield variable measurements that limit the comparison of results between laboratories. In the context of a Dutch national Consortium study we aimed to determine the inter-assay and inter-machine variability of multiplex-bead assays, and we assessed how to reduce the assay reagents costs. Fifteen sera containing a variety of HLA antibodies were used yielding in total 7092 median fluorescence intensities (MFI) values. The inter-assay and inter-machine mean absolute relative differences (MARD) of the screening assay were 12% and 13%, respectively. The single antigen bead (SAB) inter-assay MARD was comparable, but showed a higher lot-to-lot variability. Reduction of screening assay reagents to 50% or 40% of manufacturers' recommendations resulted in MFI values comparable to 100% of the reagents, with an MARD of 12% or 14%, respectively. The MARD of the 50% and 40% SAB assay reagent reductions were 11% and 22%, respectively. From this study, we conclude that the reagents can be reliably reduced at least to 50% of manufacturers' recommendations with virtually no differences in HLA antibody assignments.
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- 2016
30. PRE-TRANSPLANT DONOR SPECIFIC HLA ANTIBODIES IN 4386 RENAL TRANSPLANT RECIPIENTS: A PRELIMINARY ANALYSIS OF THE PROCARE COHORT
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Kamburova, E.G., Wisse, B.W., Joosten, I., Allebes, W.A., Meer, A. van der, Hilbrands, L.B., Baas, M.C., Spierings, E., Hack, C.E., Reekum, F. van, Zuilen, A.D. van, Verhaar, M.C., Bots, M.L., Drop, A.C.A.D., Plaisier, L., Seelen, M.A.J., Sanders, J.S.F., Hepkema, B.G., Lambeck, A.J., Bungener, L.B., Roozendaal, C., Tilanus, M.G.J., Vanderlocht, J., Voorter, C.E., Wieten, L., Duijnhoven, E. van, Gelens, M., Christiaans, M., Ittersum, F. van, Nurmohamed, A., Lardy, N.M., Swelsen, W.T., Pant, K.A.M.I. van der, Weerd, N.C. van der, Berge, I.J.M. ten, Bemelman, F.J., Hoitsma, A.J., Fijter, J.W. de, Betjes, M.G.H., Roelen, D.L., Claas, F.H.J., and Otten, H.G.
- Published
- 2016
31. The DESCARTES-Nantes survey of kidney transplant recipients displaying clinical operational tolerance identifies 35 new tolerant patients and 34 almost tolerant patients
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Massart, A., Pallier, A., Pascual, J., Viklicky, O., Budde, K., Spasovski, G., Klinger, M., Sever, M.S., Sorensen, S.S., Hadaya, K., Oberbauer, R., Dudley, C., Fijter, J.W. de, Yussim, A., Hazzan, M., Wekerle, T., Berglund, D., Biase, C. De, Perez-Saez, M.J., Muhlfeld, A., Orlando, G., Clemente, K., Lai, Q., Pisani, F., Kandus, A., Baas, M.C., Bemelman, F., Ponikvar, J.B., Mazouz, H., Stratta, P., Subra, J.F., Villemain, F., Hoitsma, A., Braun, L., Cantarell, M.C., Colak, H., Courtney, A., Frasca, G.M., Howse, M., Naesens, M., Reischig, T., Seron, D., Seyahi, N., Tugmen, C., Hernandez, A., Bena, L., Biancone, L., Cuna, V., Diaz-Corte, C., Dufay, A., Gaasbeek, A., Garnier, A., Gatault, P., Gentil Govantes, M.A., Glowacki, F., Gross, O., Hurault de Ligny, B., Huynh-Do, U., Janbon, B., Jimenez Del Cerro, L.A., Keller, F., Manna, G. La, Lauzurica, R., Monies De Sagazan, H. Le, Thaiss, F., Legendre, C., Martin, S., Moal, M.C., Noel, C., Pillebout, E., Piredda, G.B., Puga, A.R., Sulowicz, W., Tuglular, S., Prokopova, M., Chesneau, M., Moine, A. Le, Guerif, P., Soulillou, J.P., Abramowicz, M., Giral, M., Racape, J., Maggiore, U., Brouard, S., Abramowicz, D., Massart, A., Pallier, A., Pascual, J., Viklicky, O., Budde, K., Spasovski, G., Klinger, M., Sever, M.S., Sorensen, S.S., Hadaya, K., Oberbauer, R., Dudley, C., Fijter, J.W. de, Yussim, A., Hazzan, M., Wekerle, T., Berglund, D., Biase, C. De, Perez-Saez, M.J., Muhlfeld, A., Orlando, G., Clemente, K., Lai, Q., Pisani, F., Kandus, A., Baas, M.C., Bemelman, F., Ponikvar, J.B., Mazouz, H., Stratta, P., Subra, J.F., Villemain, F., Hoitsma, A., Braun, L., Cantarell, M.C., Colak, H., Courtney, A., Frasca, G.M., Howse, M., Naesens, M., Reischig, T., Seron, D., Seyahi, N., Tugmen, C., Hernandez, A., Bena, L., Biancone, L., Cuna, V., Diaz-Corte, C., Dufay, A., Gaasbeek, A., Garnier, A., Gatault, P., Gentil Govantes, M.A., Glowacki, F., Gross, O., Hurault de Ligny, B., Huynh-Do, U., Janbon, B., Jimenez Del Cerro, L.A., Keller, F., Manna, G. La, Lauzurica, R., Monies De Sagazan, H. Le, Thaiss, F., Legendre, C., Martin, S., Moal, M.C., Noel, C., Pillebout, E., Piredda, G.B., Puga, A.R., Sulowicz, W., Tuglular, S., Prokopova, M., Chesneau, M., Moine, A. Le, Guerif, P., Soulillou, J.P., Abramowicz, M., Giral, M., Racape, J., Maggiore, U., Brouard, S., and Abramowicz, D.
- Abstract
Item does not contain fulltext, BACKGROUND: Kidney recipients maintaining a prolonged allograft survival in the absence of immunosuppressive drugs and without evidence of rejection are supposed to be exceptional. The ERA-EDTA-DESCARTES working group together with Nantes University launched a European-wide survey to identify new patients, describe them and estimate their frequency for the first time. METHODS: Seventeen coordinators distributed a questionnaire in 256 transplant centres and 28 countries in order to report as many 'operationally tolerant' patients (TOL; defined as having a serum creatinine <1.7 mg/dL and proteinuria <1 g/day or g/g creatinine despite at least 1 year without any immunosuppressive drug) and 'almost tolerant' patients (minimally immunosuppressed patients (MIS) receiving low-dose steroids) as possible. We reported their number and the total number of kidney transplants performed at each centre to calculate their frequency. RESULTS: One hundred and forty-seven questionnaires were returned and we identified 66 TOL (61 with complete data) and 34 MIS patients. Of the 61 TOL patients, 26 were previously described by the Nantes group and 35 new patients are presented here. Most of them were noncompliant patients. At data collection, 31/35 patients were alive and 22/31 still operationally tolerant. For the remaining 9/31, 2 were restarted on immunosuppressive drugs and 7 had rising creatinine of whom 3 resumed dialysis. Considering all patients, 10-year death-censored graft survival post-immunosuppression weaning reached 85% in TOL patients and 100% in MIS patients. With 218 913 kidney recipients surveyed, cumulative incidences of operational tolerance and almost tolerance were estimated at 3 and 1.5 per 10 000 kidney recipients, respectively. CONCLUSIONS: In kidney transplantation, operational tolerance and almost tolerance are infrequent findings associated with excellent long-term death-censored graft survival.
- Published
- 2016
32. TGFbeta-dependent expression of PD-1 and PD-L1 controls CD8(+) T cell anergy in transplant tolerance
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Baas, M.C., Besancon, A., Goncalves, T., Valette, F., Yagita, H., Sawitzki, B., Volk, H.D., Waeckel-Enee, E., Rocha, B., Chatenoud, L., You, S., Baas, M.C., Besancon, A., Goncalves, T., Valette, F., Yagita, H., Sawitzki, B., Volk, H.D., Waeckel-Enee, E., Rocha, B., Chatenoud, L., and You, S.
- Abstract
Contains fulltext : 171603.pdf (publisher's version ) (Open Access), CD8(+) T cell anergy is a critical mechanism of peripheral tolerance, poorly investigated in response to immunotherapy. Here, using a pancreatic islet allograft model and CD3 antibody therapy, we showed, by single cell gene profiling, that intragraft CD8(+) lymphocytes coexpressing granzyme B and perforin were selectively depleted through the Fas/FasL pathway. This step led to long-standing anergy of the remaining CD8(+) T cells marked by the absence of cytotoxic/inflammatory gene expression also confirmed by transcriptome analysis. This sustained unresponsiveness required the presence of the alloantigens. Furthermore, tissue-resident CD8(+) lymphocytes produced TGFbeta and expressed the inhibitory receptors PD-1 and PD-L1. Blockade of TGFbeta downregulated PD-1 and PD-L1 expression and precipitated graft rejection. Neutralizing PD-1, PD-L1 or TGFbetaRII signaling in T cells also abrogated CD3 antibody-induced tolerance. These studies unravel novel mechanisms underlying CD8(+) T cell anergy and reveal a cell intrinsic regulatory link between the TGFbeta and the PD-1/PD-L1 pathways.
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- 2016
33. Rituximab as induction therapy after renal transplantation: a randomized, double-blind, placebo-controlled study of efficacy and safety
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Hoogen, M.W.F. van den, Kamburova, E.G., Baas, M.C., Steenbergen, E., Florquin, S., Koenen, H.J.P.M., Joosten, I., Hilbrands, L.B., Hoogen, M.W.F. van den, Kamburova, E.G., Baas, M.C., Steenbergen, E., Florquin, S., Koenen, H.J.P.M., Joosten, I., and Hilbrands, L.B.
- Abstract
Item does not contain fulltext, We evaluated the efficacy and safety of rituximab as induction therapy in renal transplant patients. In a double-blind, placebo-controlled study, 280 adult renal transplant patients were randomized between a single dose of rituximab (375 mg/m(2)) or placebo during transplant surgery. Patients were stratified according to panel-reactive antibody (PRA) value and rank number of transplantation. Maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil and steroids. The primary endpoint was the incidence of biopsy proven acute rejection (BPAR) within 6 months after transplantation. The incidence of BPAR was comparable between rituximab-treated (23/138, 16.7%) and placebo-treated patients (30/142, 21.2%, p = 0.25). Immunologically high-risk patients (PRA >6% or re-transplant) not receiving rituximab had a significantly higher incidence of rejection (13/34, 38.2%) compared to other treatment groups (rituximab-treated immunologically high-risk patients, and rituximab- or placebo-treated immunologically low-risk (PRA = 6% or first transplant) patients (17.9%, 16.4% and 15.7%, p = 0.004). Neutropenia (<1.5 x 10(9) /L) occurred more frequently in rituximab-treated patients (24.3% vs. 2.2%, p < 0.001). After 24 months, the cumulative incidence of infections and malignancies was comparable. A single dose of rituximab as induction therapy did not reduce the overall incidence of BPAR, but might be beneficial in immunologically high-risk patients. Treatment with rituximab was safe.
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- 2015
34. Cytokine Release After Treatment With Rituximab in Renal Transplant Recipients
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Kamburova, E.G., Hoogen, M.W.F. van den, Koenen, H.J.P.M., Baas, M.C., Hilbrands, L.B., Joosten, I., Kamburova, E.G., Hoogen, M.W.F. van den, Koenen, H.J.P.M., Baas, M.C., Hilbrands, L.B., and Joosten, I.
- Abstract
Item does not contain fulltext, BACKGROUND: Treatment with rituximab may be accompanied by a systemic cytokine release. We studied the effects of a single dose of rituximab on cytokine levels in transplant patients and examined the underlying mechanism. METHODS: Twenty renal transplant recipients (10 rituximab-treated, 10 placebo-treated) were recruited from a randomized clinical trial. Rituximab or placebo was infused during surgery, and blood samples were taken before, during, and after surgery and analyzed for interleukin (IL)-2, IL-4, IL-6, IL-10, IL-12, IL-17, interferon-gamma, macrophage inflammatory protein (MIP)-1beta, transforming growth factor-beta, and tumor necrosis factor-alpha. in vitro, healthy donor peripheral blood mononuclear cells, purified B cells, monocytes, natural killer (NK) cells, or combinations thereof were incubated with rituximab, rituximab-F(ab')2, or medium and MIP-1beta, IL-10, interferon-gamma, and tumor necrosis factor-alpha levels were measured in the supernatant. RESULTS: Rituximab-treated patients had higher serum levels of IL-10 (101 +/- 35 pg/mL vs 41 +/- 9 pg/mL; P < 0.01) and MIP-1beta (950 +/- 418 pg/mL vs 125 +/- 32 pg/mL; P < 0.001) compared to placebo-treated patients at 2 hours after start of infusion. There was no difference in the level of other cytokines. In vitro, the addition of rituximab, but not rituximab-F(ab')2 fragments, only led to significantly increased levels of MIP-1beta in co-cultures of B and NK cells. Levels of MIP-1beta were higher in patients with a high affinity Fc-receptor compared to those with a lower affinity FcgammaRIIIa (1356 +/- 184 pg/mL vs 679 +/- 273 pg/mL; P < 0.01). CONCLUSIONS: In addition to B-cell depletion, rituximab can modulate the immune response by inducing cytokine secretion, especially IL-10 and MIP-1beta. Rituximab-induced MIP-1beta secretion depends on the combined presence of B cells and FcR-bearing cells, especially NK cells.
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- 2015
35. Anti-T and anti-B cell therapy in renal transplantation
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Hilbrands, L.B., Hoitsma, A.J., Baas, M.C., Hoogen, M.W.F. van den, Hilbrands, L.B., Hoitsma, A.J., Baas, M.C., and Hoogen, M.W.F. van den
- Abstract
Radboud Universiteit Nijmegen, 3 juli 2015, Promotores : Hilbrands, L.B., Hoitsma, A.J. Co-promotor : Baas, M.C., Contains fulltext : 141368.pdf (publisher's version ) (Open Access)
- Published
- 2015
36. GFR meets mTOR: value of different methods to measure and estimate GFR & (side) effects of mTOR inhibition in renal transplantation
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Baas, M.C., ten Berge, R.J.M., Bemelman, F.J., and Faculteit der Geneeskunde
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urogenital system ,urologic and male genital diseases - Abstract
The subject of this thesis is twofold: where GFR and mTOR meet. Precise measurement of kidney function is difficult and cumbersome and many, simpler alternatives have been developed to determine GFR. Determination of GFR remains an approximation since the GFR itself is not a static phenomenon. This should be kept in mind when interpreting GFR results. mTOR inhibitors are a new class of immunosuppressive drugs and increasingly used in renal transplantation. They seem to be most promising due to their lack of nephrotoxicity, their potential anti-atherosclerotic effects and their anti-oncogenic effects. However, with the increased use side effects are becoming more clear. Individual tailoring of the immunosuppressive regimen will be the answer to decrease adverse effects and to benefit the most from the advantages of inhibition of the mTOR pathway.
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- 2011
37. Anti-B-cell therapy in renal Transplantation: B aware!
- Author
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Joosten, I., Hilbrands, L.B., Koenen, H.J.P.M., Baas, M.C., Kamburova, E.G., Joosten, I., Hilbrands, L.B., Koenen, H.J.P.M., Baas, M.C., and Kamburova, E.G.
- Abstract
Radboud Universiteit Nijmegen, 25 september 2014, Promotores : Joosten, I., Hilbrands, L.B. Co-promotores : Koenen, H.J.P.M., Baas, M.C., Contains fulltext : 129678.pdf (publisher's version ) (Open Access)
- Published
- 2014
38. Longitudinal Analysis of T and B Cell Phenotype and Function in Renal Transplant Recipients with or without Rituximab Induction Therapy
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Kamburova, E.G., Koenen, H.J.P.M., Hoogen, M.W.F. van den, Baas, M.C., Joosten, I., Hilbrands, L.B., Kamburova, E.G., Koenen, H.J.P.M., Hoogen, M.W.F. van den, Baas, M.C., Joosten, I., and Hilbrands, L.B.
- Abstract
Contains fulltext : 138913.pdf (publisher's version ) (Open Access), BACKGROUND: Prevention of rejection after renal transplantation requires treatment with immunosuppressive drugs. Data on their in vivo effects on T- and B-cell phenotype and function are limited. METHODS: In a randomized double-blind placebo-controlled study to prevent renal allograft rejection, patients were treated with tacrolimus, mycophenolate mofetil (MMF), steroids, and a single dose of rituximab or placebo during transplant surgery. In a subset of patients, we analyzed the number and phenotype of peripheral T and B cells by multiparameter flow cytometry before transplantation, and at 3, 6, 12, and 24 months after transplantation. RESULTS: In patients treated with tacrolimus/MMF/steroids the proportion of central memory CD4+ and CD8+ T cells was higher at 3 months post-transplant compared to pre-transplant levels. In addition, the ratio between the percentage of central memory CD4+ and CD4+ regulatory T cells was significantly higher up to 24 months post-transplant compared to pre-transplant levels. Interestingly, treatment with tacrolimus/MMF/steroids resulted in a shift toward a more memory-like B-cell phenotype post-transplant. Addition of a single dose of rituximab resulted in a long-lasting B-cell depletion. At 12 months post-transplant, the small fraction of repopulated B cells consisted of a high percentage of transitional B cells. Rituximab treatment had no effect on the T-cell phenotype and function post-transplant. CONCLUSIONS: Renal transplant recipients treated with tacrolimus/MMF/steroids show an altered memory T and B-cell compartment post-transplant. Additional B-cell depletion by rituximab leads to a relative increase of transitional and memory-like B cells, without affecting T-cell phenotype and function. TRIAL REGISTRATION: ClinicalTrials.gov NCT00565331.
- Published
- 2014
39. Combining autologous dendritic cell therapy with CD3 antibodies promotes regulatory T cells and permanent islet allograft acceptance
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Baas, M.C., Kuhn, C., Valette, F., Mangez, C., Duarte, M.S., Hill, M., Besancon, A., Chatenoud, L., Cuturi, M.C., You, S., Baas, M.C., Kuhn, C., Valette, F., Mangez, C., Duarte, M.S., Hill, M., Besancon, A., Chatenoud, L., Cuturi, M.C., and You, S.
- Abstract
Item does not contain fulltext, Cell therapy and the use of mAbs that interfere with T cell effector functions constitute promising approaches for the control of allograft rejection. In the current study, we investigated a novel approach combining administration of autologous tolerogenic dendritic cells with short-term treatment with CD3-specific Abs. Permanent acceptance of pancreatic islet allografts was achieved in mice treated with the combination therapy the day before transplantation but not in recipients treated with either therapy alone. The combination treatment induced a marked decrease in T cells infiltrating the allografts and a sustained reduction of antidonor responses. Importantly, CD4(+)Foxp3(+) regulatory T cells appeared to play a crucial role in the long-term graft acceptance. Their frequency increased significantly in the spleen, draining lymph nodes, and transplanted islets and remained elevated over the long term; they exhibited increased donor-specific suppressive functions; and their removal at the time of transplantation abrogated the therapeutic effect of the combined therapy. These results support the therapeutic potential of protocols combining autologous dendritic cells and low-dose CD3 Abs, both currently in clinical development, and that act in synergy to control allogeneic immune responses and favor graft survival in a full-mismatch situation.
- Published
- 2014
40. Interstitial pneumonitis caused by everolimus: a case-cohort study in renal transplant recipients
- Author
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Baas, M.C., Struijk, G.H., Moes, D.J., Berk, I.A.H. van den, Jonkers, R.E., Fijter, J.W. de, Heide, J.J. van der, Dijk, M. van, Berge, I.J. Ten, Bemelman, F.J., Baas, M.C., Struijk, G.H., Moes, D.J., Berk, I.A.H. van den, Jonkers, R.E., Fijter, J.W. de, Heide, J.J. van der, Dijk, M. van, Berge, I.J. Ten, and Bemelman, F.J.
- Abstract
Item does not contain fulltext, The use of inhibitors of the mammalian target of rapamycin (mTORi) in renal transplantation is associated with many side effects, the potentially most severe being interstitial pneumonitis. Several papers have reported on sirolimus-induced pneumonitis, but less is published on everolimus-induced pneumonitis (EIP). Data on risk factors for contracting EIP are even more scarce. In the present case-cohort study in renal transplant recipients (RTR), we aimed to assess the incidence and risk factors of EIP after renal transplantation. This study is a retrospective substudy of a multicenter randomized controlled trial. All patients included in the original trial and treated with prednisolone/everolimus were included in this substudy. RTR who developed EIP were identified as cases. RTR without pulmonary symptoms served as controls. Thirteen of 102 patients (12.7%) developed EIP. We did not find any predisposing factors, especially no correlation with everolimus concentration. On pulmonary CT scan, EIP presented with an organizing pneumonia-like pattern, a nonspecific interstitial pneumonitis-like pattern, or both. Median time (range) to the development of EIP after start of everolimus was 162 (38-407) days. In conclusion, EIP is common in RTR, presenting with an organizing pneumonia, a nonspecific interstitial pneumonitis-like pattern, or both. No predisposing factors could be identified (Trial registration number: NTR567 (www.trialregister.nl), ISRCTN69188731).
- Published
- 2014
41. Anti-B cell therapy with rituximab as induction therapy in renal transplantation
- Author
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Joosten, I., Baas, M.C., Kamburova, E.G., Hoogen, M.W.F. van den, Koenen, H.J.P.M., Hilbrands, L.B., Joosten, I., Baas, M.C., Kamburova, E.G., Hoogen, M.W.F. van den, Koenen, H.J.P.M., and Hilbrands, L.B.
- Abstract
Item does not contain fulltext, Traditionally, antirejection therapy in organ transplantation has mainly been directed at T cells. During recent years, the role of B cells in acute rejection has attracted more attention. In the Radboud University Medical Center (Nijmegen, The Netherlands) we performed a randomized, placebo controlled study to assess the efficacy and safety of rituximab as induction therapy after renal transplantation. In parallel we investigated the effects of rituximab on the numbers and function of B and T cells. An overview of the results, which have largely been published in peer reviewed papers, is presented below.
- Published
- 2014
42. Anti-B cell therapy with rituximab as induction therapy in renal transplantation
- Author
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Joosten, I., primary, Baas, M.C., additional, Kamburova, E.G., additional, van den Hoogen, M.W.F., additional, Koenen, H.J.P.M., additional, and Hilbrands, L.B., additional
- Published
- 2014
- Full Text
- View/download PDF
43. Intragraft mechanisms associated with the immunosuppressive versus the tolerogenic effect of CD3 antibodies in a mouse model of islet allografts
- Author
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Baas, M.C., Besancon, A., Sawitzki, B., Mangez, C., Valette, F., Chatenoud, L., You, S., Baas, M.C., Besancon, A., Sawitzki, B., Mangez, C., Valette, F., Chatenoud, L., and You, S.
- Abstract
Item does not contain fulltext, We previously demonstrated the ability of CD3-specific antibodies (Abs) to induce tolerance of fully mismatched pancreatic islets when administered at the time of effector T-cell priming (day +7). When administered on day -1, CD3 Abs only displayed an immunosuppressive effect with no permanent acceptance. Here we show that rejection correlates with progressive migration of CD4(+) and CD8(+) T cells into the graft. In contrast, the day +7 CD3 Ab tolerogenic effect is associated with absence of de novo accumulation of CD8(+) T cells within the allograft while CD4(+) T-cell migration is not altered. Furthermore, the increased proportion in T-regulatory cells, observed both in the draining lymph nodes and in the transplanted islets, was more pronounced after the delayed (day +7) than the early (day -1) CD3 Ab course. Last, tolerance-promoting (day +7), but not immunosuppressive (day -1) CD3 Ab treatment was associated with an elevated in situ Foxp3/alpha-1,2-mannosidase gene expression ratio, identified as a biomarker predicting tolerance in renal transplant patients. In conclusion, intragraft-enhanced regulation over effector function after the delayed but not the early CD3 antibody therapy discriminates between the tolerance-promoting and immunosuppressive effect of CD3 Ab treatment and further highlights the importance of the therapeutic window.
- Published
- 2013
44. Treatment with everolimus is associated with a procoagulant state
- Author
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Baas, M.C., Gerdes, V.E., Berge, I.J. Ten, Heutinck, K.M., Florquin, S., Meijers, J.C., Bemelman, F.J., Baas, M.C., Gerdes, V.E., Berge, I.J. Ten, Heutinck, K.M., Florquin, S., Meijers, J.C., and Bemelman, F.J.
- Abstract
Item does not contain fulltext, INTRODUCTION: Renal transplant recipients are at increased risk of venous thromboembolic events, which is in part caused by their treatment with maintenance immunosuppressive drugs. Because we observed an increased incidence of venous thromboembolic events in renal transplant recipients treated with the mTOR inhibitor (mTORi) everolimus, we aimed to identify prothrombotic mechanisms of this immunosuppressive drug. MATERIALS AND METHODS: In a single center study, nested in a multi-center randomized controlled trial, we measured parameters of coagulation, anti-coagulation and fibrinolysis in renal transplant recipients, receiving the mTORi everolimus (n=16, mTOR group) and compared them to a similar patient group, receiving a calcineurin inhibitor and/or mycophenolate sodium (n=20, non-mTOR group). All patients were at least 6months following transplantation with a stable transplant function. RESULTS: The use of an mTORi was associated with significantly higher levels of von Willebrand factor, prothrombin fragment 1+2, thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 as compared to a non-mTORi based immunosuppressive regimen. CONCLUSIONS: Treatment with an mTORi leads to increased endothelial activation, thrombin formation and impaired fibrinolysis in renal transplant recipients. This suggests an increased risk of thrombotic events in renal transplant recipients treated with mTOR inhibitors. A prospective study to establish the precise risk of thrombotic events in these patients is urgently needed.
- Published
- 2013
45. Cyclosporine versus everolimus: effects on the glomerulus
- Author
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Baas, M.C., Kers, J., Florquin, S., Fijter, J.W. de, Heide, J.J. van der, Weerman, M.A. van den Bergh, Berge, I.J. Ten, Bemelman, F.J., Baas, M.C., Kers, J., Florquin, S., Fijter, J.W. de, Heide, J.J. van der, Weerman, M.A. van den Bergh, Berge, I.J. Ten, and Bemelman, F.J.
- Abstract
Item does not contain fulltext, Inhibitors of the mammalian target of rapamycin (mTOR) have been associated with proteinuria. We studied the development of proteinuria in renal transplant recipients (RTR) treated with the mTOR inhibitor everolimus in comparison with a calcineurin inhibitor. We related the presence of proteinuria to histopathological glomerular findings in two-yr protocol biopsies. In a single-center study, nested in a multicenter randomized controlled trial, we determined eGFR, proteinuria, and renal biopsy data (light- and electron microscopy) of RTR receiving prednisolone/everolimus (P/EVL) (n = 16) in comparison with patients treated with prednisolone/cyclosporine A (P/CsA) (n = 7). All patients had been on the above-described maintenance immunosuppression for 18 months. Renal function at two yr after transplantation did not differ between patients receiving P/EVL or P/CsA (eGFR 45.5 vs. 45.7 mL/min/1.73 m(2)). Proteinuria was slightly increased in P/EVL vs. P/CsA group (0.29 vs. 0.14 g/24 h, p = 0.06). There were no differences in light- or electron microscopic findings. We could not demonstrate increased podocyte effacement or changes in glomerular basement membrane (GBM) thickness in P/EVL-treated patients. In conclusion, long-term treatment with everolimus leaves the GBM and podocytes unaffected.
- Published
- 2013
46. Induction of allograft tolerance by monoclonal CD3 antibodies: a matter of timing
- Author
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You, S., Zuber, J., Kuhn, C., Baas, M.C., Valette, F., Sauvaget, V., Sarnacki, S., Sawitzki, B., Bach, J.F., Volk, H.D., Chatenoud, L., You, S., Zuber, J., Kuhn, C., Baas, M.C., Valette, F., Sauvaget, V., Sarnacki, S., Sawitzki, B., Bach, J.F., Volk, H.D., and Chatenoud, L.
- Abstract
Item does not contain fulltext, Despite remarkable progress in organ transplantation through the development of a wealth of immunosuppressive drugs highly effective at controlling acute rejection, two major problems still remain, the loss of transplants due to chronic rejection and the growing number of sensitized recipients due to previous transplants, transfusions or pregnancies. Induction of immune tolerance appears to be the only way to curb this complex situation. Here we describe that a therapy, already successfully used to restore immune tolerance to self-antigens in overt autoimmunity, is effective at promoting transplant tolerance. We demonstrate that a short low-dose course with CD3 antibodies started after transplantation, at the time of effector T cell priming to alloantigens, induces permanent acceptance of fully mismatched islet allografts. Mechanistic studies revealed that antigen-specific regulatory and effector T cells are differentially affected by the treatment. CD3 antibody treatment preferentially induces apoptosis of activated alloreactive T cells which is mandatory for tolerance induction. In contrast, regulatory T cells are relatively spared from CD3 antibody-induced depletion and can transfer antigen-specific tolerance thus arguing for their prominent role in sustaining long-term graft survival.
- Published
- 2012
47. Intragraft Mechanisms Associated With the Immunosuppressive Versus the Tolerogenic Effect of CD3 Antibodies in a Mouse Model of Islet Allografts
- Author
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Baas, M.C., primary, Besançon, A., additional, Sawitzki, B., additional, Mangez, C., additional, Valette, F., additional, Chatenoud, L., additional, and You, S., additional
- Published
- 2013
- Full Text
- View/download PDF
48. Mumps: Not an Innocent Bystander in Solid Organ Transplantation
- Author
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Baas, M.C, primary, Donselaar, K.A.M.I, additional, Florquin, S., additional, Binnendijk, R.S., additional, ten Berge, I.J.M, additional, and Bemelman, F.J, additional
- Published
- 2009
- Full Text
- View/download PDF
49. Anti-T and anti-B cell therapy in renal transplantation
- Author
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Hoogen, M.W.F. van den, Hilbrands, L.B., Hoitsma, A.J., Baas, M.C., and Radboud University Nijmegen
- Subjects
Renal disorders Radboud Institute for Health Sciences [Radboudumc 11] ,GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) - Abstract
Contains fulltext : 141368.pdf (Publisher’s version ) (Open Access) Radboud Universiteit Nijmegen, 03 juli 2015 Promotores : Hilbrands, L.B., Hoitsma, A.J. Co-promotor : Baas, M.C.
- Published
- 2015
50. Anti-B-cell therapy in renal Transplantation: B aware!
- Author
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Kamburova, E.G., Joosten, I., Hilbrands, L.B., Koenen, H.J.P.M., Baas, M.C., and Radboud University Nijmegen
- Subjects
GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) ,Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5] - Abstract
Contains fulltext : 129678.pdf (Publisher’s version ) (Open Access) Radboud Universiteit Nijmegen, 25 september 2014 Promotores : Joosten, I., Hilbrands, L.B. Co-promotores : Koenen, H.J.P.M., Baas, M.C.
- Published
- 2014
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