Frederike Bemelman - Academia.edu (original) (raw)

Papers by Frederike Bemelman

Research paper thumbnail of Histological characteristics of Acute Tubular Injury during Delayed Graft Function predict renal function after renal transplantation

Physiological Reports, 2019

Research paper thumbnail of Rationale and design of the OPTIMIZE trial: OPen label multicenter randomized trial comparing standard IMmunosuppression with tacrolimus and mycophenolate mofetil with a low exposure tacrolimus regimen In combination with everolimus in de novo renal transplantation in Elderly patients

BMC Nephrology, 2021

BackgroundIn 2019, more than 30 % of all newly transplanted kidney transplant recipients in The N... more BackgroundIn 2019, more than 30 % of all newly transplanted kidney transplant recipients in The Netherlands were above 65 years of age. Elderly patients are less prone to rejection, and death censored graft loss is less frequent compared to younger recipients. Elderly recipients do have increased rates of malignancy and infection-related mortality. Poor kidney transplant function in elderly recipients may be related to both pre-existing (i.e. donor-derived) kidney damage and increased susceptibility to nephrotoxicity of calcineurin inhibitors (CNIs) in kidneys from older donors. Hence, it is pivotal to shift the focus from prevention of rejection to preservation of graft function and prevention of over-immunosuppression in the elderly. The OPTIMIZE study will test the hypothesis that reduced CNI exposure in combination with everolimus will lead to better kidney transplant function, a reduced incidence of complications and improved health-related quality of life for kidney transplant...

Research paper thumbnail of T-Cell Epitopes Shared Between Immunizing HLA and Donor HLA Associate With Graft Failure After Kidney Transplantation

Frontiers in Immunology, 2021

CD4+T-helper cells play an important role in alloimmune reactions following transplantation by st... more 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...

Research paper thumbnail of Niertransplantaties in de nacht

Nederlands Tijdschrift voor Geneeskunde, 2014

In renal transplantation, prolonged cold ischaemia time (CIT) increases the risk of delayed graft... more In renal transplantation, prolonged cold ischaemia time (CIT) increases the risk of delayed graft function, rejection and graft failure. To minimise CIT, renal transplantations are performed directly upon graft availability and often take place during the night. Night-time surgery is supposedly associated with an increased risk of surgical complications compared with daytime operations. The aim of this study was to assess the consequences of night-time renal transplantation on surgical complications and graft function. 384 adult recipients of deceased-donor renal transplantations performed between January 2007 and June 2012 were retrospectively examined. Night-time renal transplantations were defined as surgery between 11 PM and 6 AM. The primary outcome was the occurrence of surgical complications. The secondary outcome was graft function. No differences in surgical complications or graft function were observed among daytime and night-time groups. CIT was significantly increased in...

Research paper thumbnail of Oxygenated versus standard cold perfusion preservation in kidney transplantation (COMPARE): a randomised, double-blind, paired, phase 3 trial

The Lancet, 2020

Background Deceased donor kidneys are preserved in cold hypoxic conditions. Providing oxygen duri... more Background Deceased donor kidneys are preserved in cold hypoxic conditions. Providing oxygen during preservation might improve post-transplant outcomes, particularly for kidneys subjected to greater degrees of preservation injury. This study aimed to investigate whether supplemental oxygen during hypothermic machine perfusion (HMP) could improve the outcome of kidneys donated after circulatory death. Methods This randomised, double-blind, paired, phase 3 trial was done in 19 European transplant centres. Kidney pairs from donors aged 50 years or older, donated after circulatory death, were eligible if both kidneys were transplanted into two different recipients. One kidney from each donor was randomly assigned using permuted blocks to oxygenated hypothermic machine perfusion (HMPO 2), the other to HMP without oxygenation. Perfusion was maintained from organ retrieval to implantation. The primary outcome was 12-month estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration equation in pairs of donated kidneys in which both transplanted kidneys were functioning at the end of follow-up. Safety outcomes were reported for all transplanted kidneys. Intentionto-treat analyses were done. This trial is registered with the ISRCTN Registry, ISRCTN32967929, and is now closed.

Research paper thumbnail of Antibodies against ARHGDIB are associated with long-term kidney graft loss

American Journal of Transplantation, 2019

This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmerc... more This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Research paper thumbnail of Allocation to highly sensitized patients based on acceptable mismatches results in low rejection rates comparable to nonsensitized patients

American Journal of Transplantation, 2019

Allocation to highly sensitized patients based on acceptable mismatches results in low rejection ... more Allocation to highly sensitized patients based on acceptable mismatches results in low rejection rates comparable to non-sensitized patients

Research paper thumbnail of Clinicopathological characteristics of T-cell non-Hodgkin lymphoma arising in patients with immunodeficiencies: a single-center case series of 25 patients and a review of the literature

Research paper thumbnail of A paired kidney analysis on the impact of pre-transplant anti-HLA antibodies on graft survival

Nephrology Dialysis Transplantation, 2018

Background. Pre-transplant donor-specific anti-human leucocyte antigen (HLA) antibodies (DSAs) ar... more 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 singleantigen 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%, P¼0.0001). 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 ¼ 0.79). Only in patients with both nDSAs Class I and II was there a trend towards a lower graft survival (58%, P ¼ 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 (P¼0.11). Conclusion. This paired kidney analysis confirms that the presence of pre-transplant DSAs in deceased donor transplantations

Research paper thumbnail of Effect of initial immunosuppression on long-term kidney transplant outcome in immunological low-risk patients

Nephrology Dialysis Transplantation, 2018

Background Few studies have evaluated the effect of different immunosuppressive strategies on lon... more Background Few studies have evaluated the effect of different immunosuppressive strategies on long-term kidney transplant outcomes. Moreover, as they were usually based on historical data, it was not possible to account for the presence of pretransplant donor-specific human-leukocyte antigen antibodies (DSA), a currently recognized risk marker for impaired graft survival. The aim of this study was to evaluate to what extent frequently used initial immunosuppressive therapies increase graft survival in immunological low-risk patients. Methods We performed an analysis on the PROCARE cohort, a Dutch multicentre study including all transplantations performed in the Netherlands between 1995 and 2005 with available pretransplant serum (n = 4724). All sera were assessed for the presence of DSA by a luminex single-antigen bead assay. Patients with a previous kidney transplantation, pretransplant DSA or receiving induction therapy were excluded from the analysis. Results Three regimes were u...

Research paper thumbnail of Differential effects of donor-specific HLA antibodies in living versus deceased donor transplant

American Journal of Transplantation, 2018

Research paper thumbnail of Early Steroid Withdrawal Compared With Standard Immunosuppression in Kidney Transplantation - Interim Analysis of the Amsterdam-Leiden-Groningen Randomized Controlled Trial

Transplantation direct, 2018

The optimal immunosuppressive regimen in kidney transplant recipients, delivering maximum efficac... more The optimal immunosuppressive regimen in kidney transplant recipients, delivering maximum efficacy with minimal toxicity, is unknown. The Amsterdam, LEiden, GROningen trial is a randomized, multicenter, investigator-driven, noninferiority, open-label trial in 305 kidney transplant recipients, in which 2 immunosuppression minimization strategies-one consisting of early steroid withdrawal, the other of tacrolimus minimization 6 months after transplantation-were compared with standard immunosuppression with basiliximab, corticosteroids, tacrolimus, and mycophenolic acid. The primary endpoint was kidney function. Secondary endpoints included death, primary nonfunction, graft failure, rejection, discontinuation of study medication, and a combined endpoint of treatment failure. An interim analysis was scheduled at 6 months, that is, just before tacrolimus minimization. This interim analysis revealed no significant differences in Modification of Diet in Renal Disease between the early ster...

Research paper thumbnail of PIRCHE-II Is Related to Graft Failure after Kidney Transplantation

Frontiers in immunology, 2018

Individual HLA mismatches may differentially impact graft survival after kidney transplantation. ... more 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 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, = 0.003]. When analyzing a subgroup of patients who had their first transpl...

Research paper thumbnail of Strategy to achieve biomarker-driven immunosuppression after solid organ transplantation by an academic-industry partnership within the European BIO-DrIM consortium

Advances in Precision Medicine, 2016

Solid organ transplantation has emerged as the “gold standard” therapy for end-stage organ failur... more Solid organ transplantation has emerged as the “gold standard” therapy for end-stage organ failure as it improves both quality of life and survival. Despite the progress in short-term graft survival, that is closely associated with the impressive reduction of acute rejections within the first year, long-term graft and patient survival remain almost un-changed and unsatisfactory. Incomplete control of chronic allograft injury but particularly the adverse effects of long-term immunosuppression, such as graft toxicity, diabetes, cardiovascular events, infections, and tumours continue to challenge the long-term success. In general, immunosuppression is applied as one-size-fits-all strategy. This can result in over- and under-immunosuppression of patients with low and high alloresponsiveness, respectively. Trial- and -error strategies to minimize or even completely wean of immunosuppression have a high failure rate. Consequently, there is an unmet medical need to develop biomarkers allow...

Research paper thumbnail of Exploring genetic and non-genetic risk factors for delayed graft function, acute and subclinical rejection in renal transplant recipients

British Journal of Clinical Pharmacology, 2016

This study aimed at identifying pharmacological factors such as pharmacogenetics and drug exposur... more This study aimed at identifying pharmacological factors such as pharmacogenetics and drug exposure as new predictive biomarkers for delayed graft function (DGF), acute rejection (AR) and/or subclinical rejection (SCR). METHODS Adult renal transplant recipients (n = 361) on cyclosporine-based immunosuppression were followed for the first 6 months after transplantation. The incidence of DGF and AR were documented as well as the prevalence of SCR at 6 months in surveillance biopsies. Demographic, transplant-related factors, pharmacological and pharmacogenetic factors (ABCB1, CYP3A5, CYP3A4, CYP2C8, NR1I2, PPP3CA and PPP3CB) were analysed in a combined approach in relation to the occurrence of DGF, AR and prevalence of SCR at month 6 using a proportional odds model and time to event model. RESULTS Fourteen per cent of the patients experienced at least one clinical rejection episode and only DGF showed a significant effect on the time to AR. The incidence of DGF correlated with a deceased donor kidney transplant (27% vs. 0.6% of living donors). Pharmacogenetic factors were not associated with risk for DGF, AR or SCR. A deceased donor kidney and acute rejection history were the most important determinants for SCR, resulting in a 52% risk of SCR at 6 months (vs. 11% average). In a sub-analysis of the patients with AR, those treated with rejection treatment including ATG, significantly less frequent SCR was found in the 6month biopsy (13% vs. 50%). CONCLUSIONS Transplant-related factors remain the most important determinants of DGF, AR and SCR. Furthermore, rejection treatment with depleting antibodies effectively prevented SCR in 6-month surveillance biopsies.

Research paper thumbnail of Intragraft Blood Dendritic Cell Antigen-1-Positive Myeloid Dendritic Cells Increase during BK Polyomavirus-Associated Nephropathy

Journal of the American Society of Nephrology : JASN, Jan 23, 2015

Although both polyomavirus infection and T cell-mediated rejection (TCMR) are characterized by tu... more Although both polyomavirus infection and T cell-mediated rejection (TCMR) are characterized by tubulointerstitial inflammation in the renal allograft, these conditions are treated with opposing therapeutic regimens. To gain more insight into the differences between antiviral and alloimmune responses, we performed a case-control study, in which we immunophenotyped the inflammatory infiltrates in renal biopsy specimens with BK polyomavirus-associated nephropathy (BKPyVAN) and specimens with TCMR. Compared with TCMR, BKPyVAN was diagnosed later after transplantation; therefore, BKPyVAN specimens showed more chronic damage than TCMR specimens showed. However, TCMR and BKPyVAN specimens had comparable levels of tubulointerstitial inflammation. Adjustment for confounders in various multivariable models revealed more blood dendritic cell antigen-1(+) (BDCA-1(+)) myeloid dendritic cells (mDCs) present during BKPyVAN (odds ratio, 2.31; 95% confidence interval, 1.03 to 5.16; P=0.04) than duri...

Research paper thumbnail of The DESCARTES-Nantes survey of kidney transplant recipients displaying clinical operational tolerance identifies 35 new tolerant patients and 34 almost tolerant patients

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, Jun 12, 2016

Kidney recipients maintaining a prolonged allograft survival in the absence of immunosuppressive ... more 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. 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…

Research paper thumbnail of Renal and Urinary Levels of Endothelial Protein C Receptor Correlate with Acute Renal Allograft Rejection

PLoS ONE, 2013

The Endothelial Protein C Receptor (EPCR) is expressed on leukocytes, on endothelium of large blo... more The Endothelial Protein C Receptor (EPCR) is expressed on leukocytes, on endothelium of large blood vessels and to a lesser extent on capillaries. Membrane bound EPCR plays an important role in the activation of protein C which has anticoagulant, anti-inflammatory and cytoprotective effects. After cleavage by a protease EPCR is also found as a soluble protein. Acute rejection of kidney allografts can be divided in T-cell-mediated rejection (TCMR) and antibody-mediated (ABMR) rejection. The latter is characterized by strong activation of coagulation. Currently no reliable non-invasive biomarkers are available to monitor rejection. Renal biopsies were available from 81 renal transplant patients (33 without rejection, 26 TCMR and 22 ABMR), we had access to mRNA material, matched plasma and urine samples for a portion of this cohort. Renal EPCR expression was assessed by RT-PCR and immunostaining. Plasma and urine sEPCR levels were measured by ELISA. ABMR patients showed higher levels of EPCR mRNA than TCMR patients. EPCR expression on glomeruli was significantly elevated in ABMR patients than in TCMR or control patients. In the peritubular capillaries EPCR expression was higher in ABMR patients than in control patients. EPCR expression was higher in tubules and arteries of rejection patients than in control patients. Plasma sEPCR levels did not differ. Urine sEPCR levels were more elevated in the ABMR group than in patients with TCMR or without rejection. ROC analysis demonstrated that urinary sEPCR is appropriate to discriminate between ABMR patients and TCMR or control patients. We conclude that urinary sEPCR could be a novel non-invasive biomarker of antibody mediated rejection in renal transplantation.

Research paper thumbnail of Transplantation: clinical studies - A

Nephrology Dialysis Transplantation, 2013

Introduction and Aims: Endothelial dysfunction can be detected at early stages of chronic kidney ... more Introduction and Aims: Endothelial dysfunction can be detected at early stages of chronic kidney disease (CKD). Although endothelial functions improve after successful renal transplantation, renal transplant recipients have still worse endothelial functions compared to healthy subjects. Recent trials showed that vitamin D deficiency and high fibroblast growth factor-23 (FGF-23) levels may have a role on endothelial dysfunction in CKD patients besides their well-known effects on calcium and phosphorus metabolism. Aim of this study is to investigate the association between endothelial functions, vitamin D and FGF 23 levels in renal transplant recipients. Methods: One hundred-nine renal transplant recipients (71 male, 38 female) underwent brachial flow mediated vasodilatation (FMD), serum 25 OH vitamin D and FGF-23 level measurements. Patients were divided into two groups based on endothelial functions. Vitamin D and FGF-23 levels were compared between patients with normal and abnormal endothelial functions. Correlations between amount of FMD, vitamin D level and FGF-23 were also investigated. Results: Mean ages of the patients was 40.4±11.5 years, mean duration after transplantation date was 74.7±69.5 months. Endothelial functions were abnormal in 79 patients (72.5%). Prevalence of vitamin D deficiency (<15 mcg/L) was 65.1%. Patients with normal endothelial functions and endothelial dysfunction had similar demographic, clinical characteristics and laboratory values. itamin D levels were significantly lower in patients with endothelial dysfunction compared to patients with normal endothelial functions (12.6± 6.6 mcg/L vs 17.3±10.0 mcg/L respectively, p=0.02). FGF-23 levels were not different between two groups. Vitamin D levels had a significant positive correlation with amount of FMD (r=0.218 and p=0.02). Conclusions: Vitamin D deficiency is one of the causes of endothelial dysfunction in renal transplant recipients. Further studies are needed to clarify whether FGF-23 is a marker or a potential initiation for endothelial dysfunction and the effect of vitamin D replacement on endothelial functions in these patients.

Research paper thumbnail of Intragraft Toll-like receptor profiling in acute renal allograft rejection

Nephrology Dialysis Transplantation, 2010

Background. Experimental studies have shown potential for Toll-like receptor (TLR) profiling in r... more Background. Experimental studies have shown potential for Toll-like receptor (TLR) profiling in renal allograft in predicting renal outcome after transplantation. Our goal was to determine if profiling of TLR1-10 and TLR-related genes could be used as a prognostic value for renal function and late clinical outcome after transplantation. Methods. TLR1-10, CD14, MD-2 and negative regulators Toll-interacting protein (TOLLIP) and single immunoglobulin domain IL-1R-related receptor were analysed in 36 biopsies from renal transplant recipients with acute rejection (AR) and in 14 biopsies from renal transplant recipients without rejection (NR). Analysis was performed by multiplex ligation-dependent probe amplification. TLR (-related) genes were correlated to Banff'07 classification, cellular influx, response to conventional anti-rejection therapy, renal function 12 and 24 months after rejection and graft loss. Results. mRNA levels of most TLRs were significantly higher in acute rejection while TOLLIP mRNA level was decreased. mRNA levels of TLR1/2/4/7/8 were highly accurate in distinguishing AR from NR. TLR mRNA levels correlated to inflammatory parameters according to the Banff '07 classification and to cellular influx. Elevated mRNA level of TLR3 in acute rejection was independent from infiltrating leukocytes. TLR (-related) genes were not correlated with response to conventional anti-rejection therapy. Splice variant TLR4r3 was associated with poor renal function 24 months after transplantation, and TLR1 appeared to be associated with graft loss. Conclusion. The elevated mRNA levels of several TLRs in association with reduced mRNA levels of TOLLIP in renal transplant biopsies of patients with acute rejection indicate a pro-inflammatory state, which may contribute to uncontrolled inflammation.

Research paper thumbnail of Histological characteristics of Acute Tubular Injury during Delayed Graft Function predict renal function after renal transplantation

Physiological Reports, 2019

Research paper thumbnail of Rationale and design of the OPTIMIZE trial: OPen label multicenter randomized trial comparing standard IMmunosuppression with tacrolimus and mycophenolate mofetil with a low exposure tacrolimus regimen In combination with everolimus in de novo renal transplantation in Elderly patients

BMC Nephrology, 2021

BackgroundIn 2019, more than 30 % of all newly transplanted kidney transplant recipients in The N... more BackgroundIn 2019, more than 30 % of all newly transplanted kidney transplant recipients in The Netherlands were above 65 years of age. Elderly patients are less prone to rejection, and death censored graft loss is less frequent compared to younger recipients. Elderly recipients do have increased rates of malignancy and infection-related mortality. Poor kidney transplant function in elderly recipients may be related to both pre-existing (i.e. donor-derived) kidney damage and increased susceptibility to nephrotoxicity of calcineurin inhibitors (CNIs) in kidneys from older donors. Hence, it is pivotal to shift the focus from prevention of rejection to preservation of graft function and prevention of over-immunosuppression in the elderly. The OPTIMIZE study will test the hypothesis that reduced CNI exposure in combination with everolimus will lead to better kidney transplant function, a reduced incidence of complications and improved health-related quality of life for kidney transplant...

Research paper thumbnail of T-Cell Epitopes Shared Between Immunizing HLA and Donor HLA Associate With Graft Failure After Kidney Transplantation

Frontiers in Immunology, 2021

CD4+T-helper cells play an important role in alloimmune reactions following transplantation by st... more 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...

Research paper thumbnail of Niertransplantaties in de nacht

Nederlands Tijdschrift voor Geneeskunde, 2014

In renal transplantation, prolonged cold ischaemia time (CIT) increases the risk of delayed graft... more In renal transplantation, prolonged cold ischaemia time (CIT) increases the risk of delayed graft function, rejection and graft failure. To minimise CIT, renal transplantations are performed directly upon graft availability and often take place during the night. Night-time surgery is supposedly associated with an increased risk of surgical complications compared with daytime operations. The aim of this study was to assess the consequences of night-time renal transplantation on surgical complications and graft function. 384 adult recipients of deceased-donor renal transplantations performed between January 2007 and June 2012 were retrospectively examined. Night-time renal transplantations were defined as surgery between 11 PM and 6 AM. The primary outcome was the occurrence of surgical complications. The secondary outcome was graft function. No differences in surgical complications or graft function were observed among daytime and night-time groups. CIT was significantly increased in...

Research paper thumbnail of Oxygenated versus standard cold perfusion preservation in kidney transplantation (COMPARE): a randomised, double-blind, paired, phase 3 trial

The Lancet, 2020

Background Deceased donor kidneys are preserved in cold hypoxic conditions. Providing oxygen duri... more Background Deceased donor kidneys are preserved in cold hypoxic conditions. Providing oxygen during preservation might improve post-transplant outcomes, particularly for kidneys subjected to greater degrees of preservation injury. This study aimed to investigate whether supplemental oxygen during hypothermic machine perfusion (HMP) could improve the outcome of kidneys donated after circulatory death. Methods This randomised, double-blind, paired, phase 3 trial was done in 19 European transplant centres. Kidney pairs from donors aged 50 years or older, donated after circulatory death, were eligible if both kidneys were transplanted into two different recipients. One kidney from each donor was randomly assigned using permuted blocks to oxygenated hypothermic machine perfusion (HMPO 2), the other to HMP without oxygenation. Perfusion was maintained from organ retrieval to implantation. The primary outcome was 12-month estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration equation in pairs of donated kidneys in which both transplanted kidneys were functioning at the end of follow-up. Safety outcomes were reported for all transplanted kidneys. Intentionto-treat analyses were done. This trial is registered with the ISRCTN Registry, ISRCTN32967929, and is now closed.

Research paper thumbnail of Antibodies against ARHGDIB are associated with long-term kidney graft loss

American Journal of Transplantation, 2019

This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmerc... more This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Research paper thumbnail of Allocation to highly sensitized patients based on acceptable mismatches results in low rejection rates comparable to nonsensitized patients

American Journal of Transplantation, 2019

Allocation to highly sensitized patients based on acceptable mismatches results in low rejection ... more Allocation to highly sensitized patients based on acceptable mismatches results in low rejection rates comparable to non-sensitized patients

Research paper thumbnail of Clinicopathological characteristics of T-cell non-Hodgkin lymphoma arising in patients with immunodeficiencies: a single-center case series of 25 patients and a review of the literature

Research paper thumbnail of A paired kidney analysis on the impact of pre-transplant anti-HLA antibodies on graft survival

Nephrology Dialysis Transplantation, 2018

Background. Pre-transplant donor-specific anti-human leucocyte antigen (HLA) antibodies (DSAs) ar... more 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 singleantigen 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%, P¼0.0001). 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 ¼ 0.79). Only in patients with both nDSAs Class I and II was there a trend towards a lower graft survival (58%, P ¼ 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 (P¼0.11). Conclusion. This paired kidney analysis confirms that the presence of pre-transplant DSAs in deceased donor transplantations

Research paper thumbnail of Effect of initial immunosuppression on long-term kidney transplant outcome in immunological low-risk patients

Nephrology Dialysis Transplantation, 2018

Background Few studies have evaluated the effect of different immunosuppressive strategies on lon... more Background Few studies have evaluated the effect of different immunosuppressive strategies on long-term kidney transplant outcomes. Moreover, as they were usually based on historical data, it was not possible to account for the presence of pretransplant donor-specific human-leukocyte antigen antibodies (DSA), a currently recognized risk marker for impaired graft survival. The aim of this study was to evaluate to what extent frequently used initial immunosuppressive therapies increase graft survival in immunological low-risk patients. Methods We performed an analysis on the PROCARE cohort, a Dutch multicentre study including all transplantations performed in the Netherlands between 1995 and 2005 with available pretransplant serum (n = 4724). All sera were assessed for the presence of DSA by a luminex single-antigen bead assay. Patients with a previous kidney transplantation, pretransplant DSA or receiving induction therapy were excluded from the analysis. Results Three regimes were u...

Research paper thumbnail of Differential effects of donor-specific HLA antibodies in living versus deceased donor transplant

American Journal of Transplantation, 2018

Research paper thumbnail of Early Steroid Withdrawal Compared With Standard Immunosuppression in Kidney Transplantation - Interim Analysis of the Amsterdam-Leiden-Groningen Randomized Controlled Trial

Transplantation direct, 2018

The optimal immunosuppressive regimen in kidney transplant recipients, delivering maximum efficac... more The optimal immunosuppressive regimen in kidney transplant recipients, delivering maximum efficacy with minimal toxicity, is unknown. The Amsterdam, LEiden, GROningen trial is a randomized, multicenter, investigator-driven, noninferiority, open-label trial in 305 kidney transplant recipients, in which 2 immunosuppression minimization strategies-one consisting of early steroid withdrawal, the other of tacrolimus minimization 6 months after transplantation-were compared with standard immunosuppression with basiliximab, corticosteroids, tacrolimus, and mycophenolic acid. The primary endpoint was kidney function. Secondary endpoints included death, primary nonfunction, graft failure, rejection, discontinuation of study medication, and a combined endpoint of treatment failure. An interim analysis was scheduled at 6 months, that is, just before tacrolimus minimization. This interim analysis revealed no significant differences in Modification of Diet in Renal Disease between the early ster...

Research paper thumbnail of PIRCHE-II Is Related to Graft Failure after Kidney Transplantation

Frontiers in immunology, 2018

Individual HLA mismatches may differentially impact graft survival after kidney transplantation. ... more 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 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, = 0.003]. When analyzing a subgroup of patients who had their first transpl...

Research paper thumbnail of Strategy to achieve biomarker-driven immunosuppression after solid organ transplantation by an academic-industry partnership within the European BIO-DrIM consortium

Advances in Precision Medicine, 2016

Solid organ transplantation has emerged as the “gold standard” therapy for end-stage organ failur... more Solid organ transplantation has emerged as the “gold standard” therapy for end-stage organ failure as it improves both quality of life and survival. Despite the progress in short-term graft survival, that is closely associated with the impressive reduction of acute rejections within the first year, long-term graft and patient survival remain almost un-changed and unsatisfactory. Incomplete control of chronic allograft injury but particularly the adverse effects of long-term immunosuppression, such as graft toxicity, diabetes, cardiovascular events, infections, and tumours continue to challenge the long-term success. In general, immunosuppression is applied as one-size-fits-all strategy. This can result in over- and under-immunosuppression of patients with low and high alloresponsiveness, respectively. Trial- and -error strategies to minimize or even completely wean of immunosuppression have a high failure rate. Consequently, there is an unmet medical need to develop biomarkers allow...

Research paper thumbnail of Exploring genetic and non-genetic risk factors for delayed graft function, acute and subclinical rejection in renal transplant recipients

British Journal of Clinical Pharmacology, 2016

This study aimed at identifying pharmacological factors such as pharmacogenetics and drug exposur... more This study aimed at identifying pharmacological factors such as pharmacogenetics and drug exposure as new predictive biomarkers for delayed graft function (DGF), acute rejection (AR) and/or subclinical rejection (SCR). METHODS Adult renal transplant recipients (n = 361) on cyclosporine-based immunosuppression were followed for the first 6 months after transplantation. The incidence of DGF and AR were documented as well as the prevalence of SCR at 6 months in surveillance biopsies. Demographic, transplant-related factors, pharmacological and pharmacogenetic factors (ABCB1, CYP3A5, CYP3A4, CYP2C8, NR1I2, PPP3CA and PPP3CB) were analysed in a combined approach in relation to the occurrence of DGF, AR and prevalence of SCR at month 6 using a proportional odds model and time to event model. RESULTS Fourteen per cent of the patients experienced at least one clinical rejection episode and only DGF showed a significant effect on the time to AR. The incidence of DGF correlated with a deceased donor kidney transplant (27% vs. 0.6% of living donors). Pharmacogenetic factors were not associated with risk for DGF, AR or SCR. A deceased donor kidney and acute rejection history were the most important determinants for SCR, resulting in a 52% risk of SCR at 6 months (vs. 11% average). In a sub-analysis of the patients with AR, those treated with rejection treatment including ATG, significantly less frequent SCR was found in the 6month biopsy (13% vs. 50%). CONCLUSIONS Transplant-related factors remain the most important determinants of DGF, AR and SCR. Furthermore, rejection treatment with depleting antibodies effectively prevented SCR in 6-month surveillance biopsies.

Research paper thumbnail of Intragraft Blood Dendritic Cell Antigen-1-Positive Myeloid Dendritic Cells Increase during BK Polyomavirus-Associated Nephropathy

Journal of the American Society of Nephrology : JASN, Jan 23, 2015

Although both polyomavirus infection and T cell-mediated rejection (TCMR) are characterized by tu... more Although both polyomavirus infection and T cell-mediated rejection (TCMR) are characterized by tubulointerstitial inflammation in the renal allograft, these conditions are treated with opposing therapeutic regimens. To gain more insight into the differences between antiviral and alloimmune responses, we performed a case-control study, in which we immunophenotyped the inflammatory infiltrates in renal biopsy specimens with BK polyomavirus-associated nephropathy (BKPyVAN) and specimens with TCMR. Compared with TCMR, BKPyVAN was diagnosed later after transplantation; therefore, BKPyVAN specimens showed more chronic damage than TCMR specimens showed. However, TCMR and BKPyVAN specimens had comparable levels of tubulointerstitial inflammation. Adjustment for confounders in various multivariable models revealed more blood dendritic cell antigen-1(+) (BDCA-1(+)) myeloid dendritic cells (mDCs) present during BKPyVAN (odds ratio, 2.31; 95% confidence interval, 1.03 to 5.16; P=0.04) than duri...

Research paper thumbnail of The DESCARTES-Nantes survey of kidney transplant recipients displaying clinical operational tolerance identifies 35 new tolerant patients and 34 almost tolerant patients

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, Jun 12, 2016

Kidney recipients maintaining a prolonged allograft survival in the absence of immunosuppressive ... more 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. 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…

Research paper thumbnail of Renal and Urinary Levels of Endothelial Protein C Receptor Correlate with Acute Renal Allograft Rejection

PLoS ONE, 2013

The Endothelial Protein C Receptor (EPCR) is expressed on leukocytes, on endothelium of large blo... more The Endothelial Protein C Receptor (EPCR) is expressed on leukocytes, on endothelium of large blood vessels and to a lesser extent on capillaries. Membrane bound EPCR plays an important role in the activation of protein C which has anticoagulant, anti-inflammatory and cytoprotective effects. After cleavage by a protease EPCR is also found as a soluble protein. Acute rejection of kidney allografts can be divided in T-cell-mediated rejection (TCMR) and antibody-mediated (ABMR) rejection. The latter is characterized by strong activation of coagulation. Currently no reliable non-invasive biomarkers are available to monitor rejection. Renal biopsies were available from 81 renal transplant patients (33 without rejection, 26 TCMR and 22 ABMR), we had access to mRNA material, matched plasma and urine samples for a portion of this cohort. Renal EPCR expression was assessed by RT-PCR and immunostaining. Plasma and urine sEPCR levels were measured by ELISA. ABMR patients showed higher levels of EPCR mRNA than TCMR patients. EPCR expression on glomeruli was significantly elevated in ABMR patients than in TCMR or control patients. In the peritubular capillaries EPCR expression was higher in ABMR patients than in control patients. EPCR expression was higher in tubules and arteries of rejection patients than in control patients. Plasma sEPCR levels did not differ. Urine sEPCR levels were more elevated in the ABMR group than in patients with TCMR or without rejection. ROC analysis demonstrated that urinary sEPCR is appropriate to discriminate between ABMR patients and TCMR or control patients. We conclude that urinary sEPCR could be a novel non-invasive biomarker of antibody mediated rejection in renal transplantation.

Research paper thumbnail of Transplantation: clinical studies - A

Nephrology Dialysis Transplantation, 2013

Introduction and Aims: Endothelial dysfunction can be detected at early stages of chronic kidney ... more Introduction and Aims: Endothelial dysfunction can be detected at early stages of chronic kidney disease (CKD). Although endothelial functions improve after successful renal transplantation, renal transplant recipients have still worse endothelial functions compared to healthy subjects. Recent trials showed that vitamin D deficiency and high fibroblast growth factor-23 (FGF-23) levels may have a role on endothelial dysfunction in CKD patients besides their well-known effects on calcium and phosphorus metabolism. Aim of this study is to investigate the association between endothelial functions, vitamin D and FGF 23 levels in renal transplant recipients. Methods: One hundred-nine renal transplant recipients (71 male, 38 female) underwent brachial flow mediated vasodilatation (FMD), serum 25 OH vitamin D and FGF-23 level measurements. Patients were divided into two groups based on endothelial functions. Vitamin D and FGF-23 levels were compared between patients with normal and abnormal endothelial functions. Correlations between amount of FMD, vitamin D level and FGF-23 were also investigated. Results: Mean ages of the patients was 40.4±11.5 years, mean duration after transplantation date was 74.7±69.5 months. Endothelial functions were abnormal in 79 patients (72.5%). Prevalence of vitamin D deficiency (<15 mcg/L) was 65.1%. Patients with normal endothelial functions and endothelial dysfunction had similar demographic, clinical characteristics and laboratory values. itamin D levels were significantly lower in patients with endothelial dysfunction compared to patients with normal endothelial functions (12.6± 6.6 mcg/L vs 17.3±10.0 mcg/L respectively, p=0.02). FGF-23 levels were not different between two groups. Vitamin D levels had a significant positive correlation with amount of FMD (r=0.218 and p=0.02). Conclusions: Vitamin D deficiency is one of the causes of endothelial dysfunction in renal transplant recipients. Further studies are needed to clarify whether FGF-23 is a marker or a potential initiation for endothelial dysfunction and the effect of vitamin D replacement on endothelial functions in these patients.

Research paper thumbnail of Intragraft Toll-like receptor profiling in acute renal allograft rejection

Nephrology Dialysis Transplantation, 2010

Background. Experimental studies have shown potential for Toll-like receptor (TLR) profiling in r... more Background. Experimental studies have shown potential for Toll-like receptor (TLR) profiling in renal allograft in predicting renal outcome after transplantation. Our goal was to determine if profiling of TLR1-10 and TLR-related genes could be used as a prognostic value for renal function and late clinical outcome after transplantation. Methods. TLR1-10, CD14, MD-2 and negative regulators Toll-interacting protein (TOLLIP) and single immunoglobulin domain IL-1R-related receptor were analysed in 36 biopsies from renal transplant recipients with acute rejection (AR) and in 14 biopsies from renal transplant recipients without rejection (NR). Analysis was performed by multiplex ligation-dependent probe amplification. TLR (-related) genes were correlated to Banff'07 classification, cellular influx, response to conventional anti-rejection therapy, renal function 12 and 24 months after rejection and graft loss. Results. mRNA levels of most TLRs were significantly higher in acute rejection while TOLLIP mRNA level was decreased. mRNA levels of TLR1/2/4/7/8 were highly accurate in distinguishing AR from NR. TLR mRNA levels correlated to inflammatory parameters according to the Banff '07 classification and to cellular influx. Elevated mRNA level of TLR3 in acute rejection was independent from infiltrating leukocytes. TLR (-related) genes were not correlated with response to conventional anti-rejection therapy. Splice variant TLR4r3 was associated with poor renal function 24 months after transplantation, and TLR1 appeared to be associated with graft loss. Conclusion. The elevated mRNA levels of several TLRs in association with reduced mRNA levels of TOLLIP in renal transplant biopsies of patients with acute rejection indicate a pro-inflammatory state, which may contribute to uncontrolled inflammation.