135 results on '"Jan-Stephan F Sanders"'
Search Results
2. Prospective monitoring of in vitro produced PR3-ANCA does not improve relapse prediction in granulomatosis with polyangiitis.
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Judith Land, Wayel H Abdulahad, Suzanne Arends, Jan-Stephan F Sanders, Coen A Stegeman, Peter Heeringa, and Abraham Rutgers
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Medicine ,Science - Abstract
Patients with granulomatosis with polyangiitis (GPA) are prone to disease relapse. Currently, no good biomarkers are available to predict relapses in individual patients. This study aimed to determine whether patients at risk for relapse can be distinguished based on increased in vitro autoantibody production.Eighty-four proteinase 3 (PR3) anti-neutrophil cytoplasmic antibody (ANCA) positive GPA outpatients were prospectively monitored for up to two years and 32 healthy controls were included. At periodic intervals peripheral blood mononuclear cells were isolated, cultured and in vitro production of total and PR3-ANCA-specific IgG was determined. Moreover, serum ANCA titers were measured by indirect immunofluorescence.Sixteen patients (21%) relapsed during the follow-up period. At time of inclusion no significant differences were present for ANCA production between relapsing and non-relapsing patients. Samples before relapse exhibited increased serum ANCA titers and in vitro PR3-ANCA IgG levels compared with inclusion samples from non-relapsing patients. When evaluating changes over time, increasing serum ANCA titers were observed prior to relapse compared to a 1-year follow-up from non-relapsing patients. No significant change in in vitro PR3-ANCA levels occurred prior to relapse, compared to non-relapse patients.While differences were observed for the serum ANCA titer in relapsing and non-relapsing patients, monitoring in vitro PR3-ANCA IgG production does not improve relapse prediction in GPA patients.
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- 2017
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3. Post COVID-19 condition imposes significant burden in patients with advanced chronic kidney disease: A nested case-control study
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Pim Bouwmans, S.Reshwan K. Malahe, A. Lianne Messchendorp, Priya Vart, Céline Imhof, Jan-Stephan F. Sanders, Ron T. Gansevoort, Aiko P.J. de Vries, Alferso C. Abrahams, Frederike J. Bemelman, Johanna P.M. Vervoort, Luuk B. Hilbrands, Marc A.G.J. ten Dam, René M.A. van den Dorpel, Theo Rispens, Maurice Steenhuis, Marlies E.J. Reinders, and Marc H. Hemmelder
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Post COVID-19 condition ,Long-COVID ,Chronic kidney disease ,Dialysis ,Kidney transplant recipient ,Solid organ transplant recipient ,Infectious and parasitic diseases ,RC109-216 - Abstract
Background: The burden of post COVID-19 condition (PCC) is not well studied in patients with advanced kidney disease. Methods: A large prospective cohort of SARS-CoV-2 vaccinated patients with chronic kidney disease stages G4–G5 (CKD G4/5), on dialysis, and kidney transplant recipients (KTR) were included. Antibody levels were determined after vaccination. Presence of long-lasting symptoms was assessed in patients with and without prior COVID-19 and compared using logistic regression. In patients with prior COVID-19, PCC was defined according to the WHO definition. Results: Two hundred sixteen CKD G4/5 patients, 375 dialysis patients, and 2005 KTR were included. Long-lasting symptoms were reported in 204/853 (24%) patients with prior COVID-19 and in 297/1743 (17%) patients without prior COVID-19 (aOR: 1.45 (1.17–1.78)], P < 0.001). PCC was prevalent in 29% of CKD G4/5 patients, 21% of dialysis patients, and 24% of KTR. In addition, 69% of patients with PCC reported (very) high symptom burden. Odds of PCC was lower per 10-fold increase in antibody level after vaccination (aOR 0.82 [0.70–0.96], P = 0.01) and higher in case of COVID-19 related hospital admission (aOR 4.64 [2.61–8.25], P = 0.003). Conclusions: CKD G4/5 patients, dialysis patients, and KTR are at risk for PCC with high symptom burden after SARS-CoV-2 vaccination, especially if antibody levels are low and in case of hospitalization due to COVID-19.
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- 2024
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4. Kidney Transplantation Improves Health-Related Quality of Life in Older Recipients
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Silke E. de Boer, Tim. J. Knobbe, Daan Kremer, Barbara C. van Munster, Gertrude J. Nieuwenhuijs-Moeke, Robert A. Pol, Stephan J. L. Bakker, Stefan P. Berger, and Jan Stephan F. Sanders
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elderly ,health-related quality of life ,kidney transplantation ,immunosuppression ,patient reported outcome measures ,side-effects ,Specialties of internal medicine ,RC581-951 - Abstract
Kidney transplantation is the best treatment for kidney failure in older patients. However, little is known regarding changes in health-related quality of life (HRQoL) from before to after transplantation and determinants of HRQoL in older kidney transplant recipients (KTR). We studied both, using data of older (≥65 years) patients waitlisted for kidney transplantation and older KTR 1 year after transplantation from the TransplantLines Biobank and Cohort Study. HRQoL was assessed using the SF-36 questionnaire. We included 145 older waitlisted patients (68% male, age 70 ± 4 years) and 115 older KTR at 1 year after transplantation (73% male, age 70 ± 4 years). Both mental (48.5 ± 8.4 versus 51.2 ± 7.7, p = 0.009) and physical (47.4 ± 8.5 versus 52.1 ± 7.2, p < 0.001) HRQoL were higher among included KTR, compared to the waitlisted patients. In paired analyses among 46 patients with HRQoL-data both before and after transplantation, there was a trend towards increased mental HRQoL (49.1 ± 8.4 to 51.6 ± 7.5, p = 0.054), and significantly increased physical HRQoL (48.1 ± 8.0 to 52.4 ± 6.7, p = 0.001) after transplantation. Among all assessed factors, the number of patient-reported immunosuppressive drug-related side effects was most strongly negatively associated with both mental and physical HRQoL. In conclusion, HRQoL is significantly higher among older KTR after kidney transplantation compared to older waitlisted patients.
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- 2024
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5. Incidence and Severity of COVID-19 in Relation to Anti-Receptor-Binding Domain IgG Antibody Level after COVID-19 Vaccination in Kidney Transplant Recipients
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A. Lianne Messchendorp, Jan-Stephan F. Sanders, Alferso C. Abrahams, Frederike J. Bemelman, Pim Bouwmans, René M. A. van den Dorpel, Luuk B. Hilbrands, Céline Imhof, Marlies E. J. Reinders, Theo Rispens, Maurice Steenhuis, Marc A. G. J. ten Dam, Priya Vart, Aiko P. J. de Vries, Marc H. Hemmelder, Ron T. Gansevoort, and RECOVAC Investigators
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COVID-19 ,COVID-19 vaccination ,kidney transplantation ,efficiency ,Microbiology ,QR1-502 - Abstract
Kidney transplant recipients (KTRs) elicit an impaired immune response after COVID-19 vaccination; however, the exact clinical impact remains unclear. We therefore analyse the relationship between antibody levels after vaccination and the risk of COVID-19 in a large cohort of KTRs. All KTRs living in the Netherlands were invited to send a blood sample 28 days after their second COVID-19 vaccination for measurement of their IgG antibodies against the receptor-binding domain of the SARS-CoV-2 spike protein (anti-RBD IgG). Information on COVID-19 was collected from the moment the blood sample was obtained until 6 months thereafter. Multivariable Cox and logistic regression analyses were performed to analyse which factors affected the occurrence and severity (i.e., hospitalization and/or death) of COVID-19. In total, 12,159 KTRs were approached, of whom 2885 were included in the analyses. Among those, 1578 (54.7%) became seropositive (i.e., anti-RBD IgG level >50 BAU/mL). Seropositivity was associated with a lower risk for COVID-19, also after adjusting for multiple confounders, including socio-economic status and adherence to COVID-19 restrictions (HR 0.37 (0.19–0.47), p = 0.005). When studied on a continuous scale, we observed a log-linear relationship between antibody level and the risk for COVID-19 (HR 0.52 (0.31–0.89), p = 0.02). Similar results were found for COVID-19 severity. In conclusion, antibody level after COVID-19 vaccination is associated in a log-linear manner with the occurrence and severity of COVID-19 in KTRs. This implies that if future vaccinations are indicated, the aim should be to reach for as high an antibody level as possible and not only seropositivity to protect this vulnerable patient group from disease.
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- 2024
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6. High-Density Lipoprotein Particles and Torque Teno Virus in Stable Outpatient Kidney Transplant Recipients
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Jip Jonker, Caecilia S. E. Doorenbos, Daan Kremer, Edmund J. Gore, Hubert G. M. Niesters, Coretta van Leer-Buter, Philippe Bourgeois, Margery A. Connelly, Robin P. F. Dullaart, Stefan P. Berger, Jan-Stephan F. Sanders, and Stephan J. L. Bakker
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torque teno virus ,kidney transplantation ,immunosuppression ,immune system ,high-density lipoprotein ,Microbiology ,QR1-502 - Abstract
Torque teno virus (TTV) is emerging as a potential marker for monitoring immune status. In transplant recipients who are immunosuppressed, higher TTV DNA loads are observed than in healthy individuals. TTV load measurement may aid in optimizing immunosuppressive medication dosing in solid organ transplant recipients. Additionally, there is a growing interest in the role of HDL particles in immune function; therefore, assessment of both HDL concentrations and TTV load may be of interest in transplant recipients. The objective of this study was to analyze TTV loads and HDL parameters in serum samples collected at least one year post-transplantation from 656 stable outpatient kidney transplant recipients (KTRs), enrolled in the TransplantLines Food and Nutrition Cohort (Groningen, the Netherlands). Plasma HDL particles and subfractions were measured using nuclear magnetic resonance spectroscopy. Serum TTV load was measured using a quantitative real-time polymerase chain reaction. Associations between HDL parameters and TTV load were examined using univariable and multivariable linear regression. The median age was 54.6 [IQR: 44.6 to 63.1] years, 43.3% were female, the mean eGFR was 52.5 (±20.6) mL/min/1.73 m2 and the median allograft vintage was 5.4 [IQR: 2.0 to 12.0] years. A total of 539 participants (82.2%) had a detectable TTV load with a mean TTV load of 3.04 (±1.53) log10 copies/mL, the mean total HDL particle concentration was 19.7 (±3.4) μmol/L, and the mean HDL size was 9.1 (±0.5) nm. The univariable linear regression revealed a negative association between total HDL particle concentration and TTV load (st.β = −0.17, 95% CI st.β: −0.26 to −0.09, p < 0.001). An effect modification of smoking behavior influencing the association between HDL particle concentration and TTV load was observed (Pinteraction = 0.024). After adjustment for age, sex, alcohol intake, hemoglobin, eGFR, donor age, allograft vintage and the use of calcineurin inhibitors, the negative association between HDL particle concentration and TTV load remained statistically significant in the non-smoking population (st.β = −0.14, 95% CI st.β: −0.23 to −0.04, p = 0.006). Furthermore, an association between small HDL particle concentration and TTV load was found (st.β = −0.12, 95% CI st.β: −0.22 to −0.02, p = 0.017). Higher HDL particle concentrations were associated with a lower TTV load in kidney transplant recipients, potentially indicative of a higher immune function. Interventional studies are needed to provide causal evidence on the effects of HDL on the immune system.
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- 2024
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7. Smoking, Alcohol Intake and Torque Teno Virus in Stable Kidney Transplant Recipients
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Caecilia S. E. Doorenbos, Jip Jonker, Jiasi Hao, Edmund J. Gore, Daan Kremer, Tim J. Knobbe, Anoek A. E. de Joode, Jan Stephan F. Sanders, Olivier Thaunat, Hubert G. M. Niesters, Coretta C. Van Leer-Buter, and Stephan J. L. Bakker
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Torque Teno Virus ,smoking ,alcohol ,immunosuppression ,kidney transplantation ,Microbiology ,QR1-502 - Abstract
Torque Teno Virus (TTV) is a non-pathogenic virus that is highly prevalent among kidney transplant recipients (KTRs). Its circulating load is associated with an immunological status in KTR and is considered a promising tool for guiding immunosuppression. To allow for optimal guidance, it is important to identify other determinants of TTV load. We aimed to investigate the potential association of smoking and alcohol intake with TTV load. For this cross-sectional study, serum TTV load was measured using PCR in stable kidney transplant recipients at ≥1 year after transplantation, and smoking status and alcohol intake were assessed through questionnaires and measurements of urinary cotinine and ethyl glucuronide. A total of 666 KTRs were included (57% male). A total of 549 KTR (82%) had a detectable TTV load (3.1 ± 1.5 log10 copies/mL). In KTR with a detectable TTV load, cyclosporin and tacrolimus use were positively associated with TTV load (St. β = 0.46, p < 0.001 and St. β = 0.66, p < 0.001, respectively), independently of adjustment for potential confounders. Current smoking and alcohol intake of >20 g/day were negatively associated with TTV load (St. β = −0.40, p = 0.004 and St. β = −0.33, p = 0.009, respectively), independently of each other and of adjustment for age, sex, kidney function, time since transplantation and calcineurin inhibitor use. This strong association of smoking and alcohol intake with TTV suggests a need to account for the smoking status and alcohol intake when applying TTV guided immunosuppression in KTR.
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- 2023
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8. The impact of pre-transplantation nephrectomy on quality of life in patients with autosomal dominant polycystic kidney disease
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Paul Geertsema, Ron T. Gansevoort, Lisanne P. J. Brenkman, Shosha E. I. Dekker, Damia V. P. Eleveld, Johan W. de Fijter, Anna M. Leliveld, Maya Levy, Esther Meijer, Robert A. Pol, Emmelien E. M. Schillern, Jan-Stephan F. Sanders, Niek F. Casteleijn, Cardiovascular Centre (CVC), Groningen Kidney Center (GKC), Groningen Institute for Organ Transplantation (GIOT), and Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE)
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Urology - Abstract
Purpose In selected ADPKD patients, a nephrectomy is required in the work-up for a kidney transplantation. Because the impact of this procedure is unknown, we investigated the effect of pre-transplantation nephrectomy on quality of life in this group. Methods In this retrospective cohort study all ADPKD patients, ≥ 18 years, who received a kidney transplantation in 2 ADPKD expertise centers between January 2000 and January 2016, were asked to participate. Quality of life was assessed using three validated questionnaires on three time points. Nephrectomy was performed in preparation for transplantation. Results Two hundred seventy-six ADPKD patients (53 ± 9 years, 56.2% male) were included. 98 patients (35.5%) underwent native nephrectomy in preparation for transplantation, of which 43 underwent bilateral nephrectomy. Pre-transplantation, ADPKD-IS scores were worse in the nephrectomy group vs. no-nephrectomy group (physical: 2.9 vs. 2.3, p p = 0.03; fatigue: 3.0 vs. 2.3, p = 0.01). Post-transplantation and post-nephrectomy, ADPKD-IS scores improved significantly in both groups, with a significantly higher improvement in the nephrectomy group. During follow-up, all scores were still better compared to pre-transplantation. Observed physical QoL (ADPKD-IS physical 1.3 vs. 1.7, p = 0.04; SF-36 physical 50.0 vs. 41.3, p = 0.03) was better post-transplantation after bilateral nephrectomy compared to unilateral nephrectomy. In retrospect, 19.7% of patients would have liked to undergo a nephrectomy, while the decision not to perform nephrectomy was made by the treating physician. Conclusion This study shows that pre-transplantation nephrectomy improves quality of life in selected ADPKD patients. Bilateral nephrectomy may be preferred, although the risk of additional complications should be weighted.
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- 2023
9. Kidney utilization in the Netherlands - do we optimally use our donor organs?
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Rianne Schutter, Willemijn A L Vrijlandt, Gelske M Weima, Robert A Pol, Jan-Stephan F Sanders, Meindert J Crop, Henri G D Leuvenink, Cyril Moers, Groningen Kidney Center (GKC), Groningen Institute for Organ Transplantation (GIOT), and Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE)
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Transplantation ,Nephrology - Abstract
BackgroundTo ensure optimal utilization of deceased donor kidneys, it is important to understand the precise reasons why kidneys are discarded. In this study we aimed to obtain a comprehensive overview of kidney utilization and discard during the entire donation process in the Netherlands.MethodsIn this retrospective cohort study we analysed kidney utilization of 3856 kidneys in the Netherlands between 1 January 2015 and 31 December 2020. For every kidney that was not transplanted, we determined the moment of and reason for discard through a unique case-by-case assessment.ResultsKidney discard according to the traditional definition (procured but not transplanted) was 7.8%. However, when kidneys that seemed medically suitable at the beginning of the donation process were also included, many more potential donor kidneys were lost and the total non-utilization was 24.4%. Subjectively presumed impaired organ quality was responsible for 34.2% of all discarded kidneys. Two-thirds of kidneys discarded due to acute kidney injury (AKI) had only AKI stage 1 or 2.ConclusionThe classical definition of organ discard underestimates the non-utilization of deceased donor kidneys. Strategies to improve kidney utilization could be a revision of the maximum allowed agonal time in donation after circulatory death, careful consideration in reporting and accepting kidneys from donors with AKI and a prospectively filled registry of detailed organ discard reasons, including the ‘silent’ non-utilization before procurement.
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- 2023
10. Alternative strategies to increase the immunogenicity of COVID-19 vaccines in kidney transplant recipients not responding to two or three doses of an mRNA vaccine (RECOVAC)
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Marcia M L Kho, A Lianne Messchendorp, Sophie C Frölke, Celine Imhof, Vera JCH Koomen, S Reshwan K Malahe, Priya Vart, Daryl Geers, Rory D de Vries, Corine H GeurtsvanKessel, Carla C Baan, Renate G van der Molen, Dimitri A Diavatopoulos, Ester B M Remmerswaal, Debbie van Baarle, Rob van Binnendijk, Gerco den Hartog, Aiko P J de Vries, Ron T Gansevoort, Frederike J Bemelman, Marlies E J Reinders, Jan-Stephan F Sanders, Luuk B Hilbrands, Alferso C. Abrahams, Marije C. Baas, Pim Bouwmans, Marc A.G.J. ten Dam, Lennert Gommers, Dorien Standaar, Marieke van der Heiden, Yvonne M.R. Adema, Marieken J. Boer-Verschragen, Wouter B. Mattheussens, Ria H.L.A. Philipsen, Djenolan van Mourik, Susanne Bogers, Laura L.A. van Dijk, Nynke Rots, Gaby Smits, Marjan Kuijer, Marc H. Hemmelder, Infectious diseases, Graduate School, Experimental Immunology, AII - Infectious diseases, AII - Inflammatory diseases, Nephrology, APH - Aging & Later Life, Translational Immunology Groningen (TRIGR), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), Internal Medicine, and Virology
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Infectious Diseases ,All institutes and research themes of the Radboud University Medical Center ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,SDG 3 - Good Health and Well-being ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Renal disorders Radboud Institute for Health Sciences [Radboudumc 11] ,Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5] - Abstract
BACKGROUND: An urgent need exists to improve the suboptimal COVID-19 vaccine response in kidney transplant recipients (KTRs). We aimed to compare three alternative strategies with a control single dose mRNA-1273 vaccination: a double vaccine dose, heterologous vaccination, and temporary discontinuation of mycophenolate mofetil or mycophenolic acid.METHODS: This open-label randomised trial, done in four university medical centres in the Netherlands, enrolled KTRs without seroconversion after two or three doses of an mRNA vaccine. Between Oct 20, 2021, and Feb 2, 2022, 230 KTRs were randomly assigned block-wise per centre by a web-based system in a 1:1:1 manner to receive 100 μg mRNA-1273, 2 × 100 μg mRNA-1273, or Ad26.COV2-S vaccination. In addition, 103 KTRs receiving 100 μg mRNA-1273, were randomly assigned 1:1 to continue (mycophenolate mofetil+) or discontinue (mycophenolate mofetil-) mycophenolate mofetil or mycophenolic acid treatment for 2 weeks. The primary outcome was the percentage of participants with a spike protein (S1)-specific IgG concentration of at least 10 binding antibody units per mL at 28 days after vaccination, assessed in all participants who had a baseline measurement and who completed day 28 after vaccination without SARS-CoV-2 infection. Safety was assessed as a secondary outcome in all vaccinated patients by incidence of solicited adverse events, acute rejection or other serious adverse events. This trial is registered with ClinicalTrials.gov, NCT05030974 and is closed.FINDINGS: Between April 23, 2021, and July 2, 2021, of 12 158 invited Dutch KTRs, 3828 with a functioning kidney transplant participated in a national survey for antibody measurement after COVID-19 vaccination. Of these patients, 1311 did not seroconvert after their second vaccination and another 761 not even after a third. From these seronegative patients, 345 agreed to participate in our repeated vaccination study. Vaccination with 2 × mRNA-1273 or Ad26.COV2-S was not superior to single mRNA-1273, with seroresponse rates of 49 (68%) of 72 (95% CI 56-79), 46 (63%) of 73 (51-74), and 50 (68%) of 73 (57-79), respectively. The difference with single mRNA-1273 was -0·4% (-16 to 15; p=0·96) for 2 × mRNA-1273 and -6% (-21 to 10; p=0·49) for Ad26.COV2-S. Mycophenolate mofetil- was also not superior to mycophenolate mofetil+, with seroresponse rates of 37 (80%) of 46 (66-91) and 31 (67%) of 46 (52-80), and a difference of 13% (-5 to 31; p=0·15). Local adverse events were more frequent after a single and double dose of mRNA-1273 than after Ad26.COV2-S (65 [92%] of 71, 67 [92%] of 73, and 38 [50%] of 76, respectively; pINTERPRETATION: Repeated vaccination increases SARS-CoV-2-specific antibodies in KTRs, without further enhancement by use of a higher dose, a heterologous vaccine, or 2 weeks discontinuation of mycophenolate mofetil or mycophenolic acid. To achieve a stronger response, possibly required to neutralise new virus variants, repeated booster vaccination is needed.FUNDING: The Netherlands Organization for Health Research and Development and the Dutch Kidney Foundation.
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- 2023
11. External ureteric stent versus internal double J stent in kidney transplantation: a retrospective analysis on the incidence of urological complications and urinary tract infections
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Ietje T. Hazenberg, Stephanie J. M. Middelkoop, Anoek A. E. de Joode, Juliette D. Rabbeljee, Robert A. Pol, Benjamin H. J. Doornweerd, Jan-Stephan F. Sanders, and Coen A. Stegeman
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IntroductionUrologic complications (UCs) and urinary tract infections (UTIs) are common after kidney transplantation. Intraoperative stent placement at the vesicoureteric anastomosis reduces UC risk, but increases UTI risk.MethodsIn 2014 our stenting protocol changed from external ureteric stent (ES) to internal double J stent (DJ). We retrospectively studied the occurrence of UCs and UTIs in relation to ES or DJ in 697 kidney recipients.MethodsAn ES was used in 403 patients (57.8%), in 294 (42.2%) a DJ. ES was removed 7-12 days and DJ 3-4 weeks post-operative. Induction immunosuppression was the same in both groups. Primary outcomes at 6 months follow-up were UC (urinary leakage/ureter stenosis) and UTI; they were related to stenting procedure and clinical and transplant characteristics. The incidence of UCs was similar for ES (8.4%) and DJ (6.8%), p=0.389. ES use was a significant risk factor for UTI (OR 1.69 (1.15-2.50), p=0.008). Post-transplant hospitalization was significantly shorter in the DJ group. Despite more acute rejection episodes with ES (ES/DJ: 16.4%/6.1%, pDiscussionA DJ is, compared to ES, associated with a lower incidence of UTIs and comparable occurrence of UCs and is therefore the preferred technique for stenting the vesicoureteric anastomosis.
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- 2023
12. Carboxypeptidase B2 gene polymorphisms in the donor associate with kidney allograft loss
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Felix Poppelaars, Siawosh K. Eskandari, Jeffrey Damman, Ashley Frazer-Abel, V. Michael Holers, Bradley P. Dixon, Mohamed R. Daha, Jan-Stephan F. Sanders, Marc A. Seelen, Bernardo Faria, Mariana Gaya da Costa, and Joshua M. Thurman
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IntroductionPlasma carboxypeptidase B2 (CPB2) is an enzyme that cleaves C-terminal amino acids from proteins, thereby regulating their activities. CPB2 has anti-inflammatory and anti-fibrinolytic properties and can therefore be protective or harmful in disease. We explored the impact of functional carboxypeptidase B2 gene (CPB2) polymorphisms on graft survival following kidney transplantation.MethodsWe performed a longitudinal cohort study to evaluate the association of functionalCPB2polymorphisms (rs2146881, rs3742264, rs1926447, rs3818477) and complement polymorphisms (rs2230199, rs17611) with long-term allograft survival in 1,271 kidney transplant pairs from the University Medical Center Groningen in The Netherlands.ResultsThe high-producingCPB2rs3742264 polymorphism in the donor was associated with a reduced risk of graft loss following kidney transplantation (hazard ratio, 0.71 for the A-allele; 95%-CI, 0.55–0.93;P=0.014). In fully adjusted models, the association between the CPB2 polymorphism in the donor and graft loss remained significant. The protective effect of the high-producingCPB2variant in the donor could be mitigated by the hazardous effect of gain-of-function complement polymorphisms. Additionally, we compiled a genetic risk score of the fourCPB2variants in the recipients and donors, which was independently associated with long-term allograft survival. Furthermore, this genetic risk score substantially improved risk prediction for graft loss beyond currently used clinical predictors.ConclusionKidney allografts from deceased donors possessing a high-producing CPB2 polymorphism are at a lower risk of graft loss after kidney transplantation. Furthermore, our findings suggest that CPB2 might have a protective effect on graft loss through its ability to inactivate complement anaphylatoxins.EssentialsCarboxypeptidase B2 (CPB2) is a metalloprotease with anti-fibrinolytic and anti-inflammatory properties.We investigated the impact ofCPB2polymorphisms on graft loss after kidney transplantation.The rs3742264-A SNP in the donor, linked to higher CPB2 levels, decreased the risk of graft loss.CPB2 could have a protective effect on graft survival by inactivating complement anaphylatoxins.
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- 2023
13. Plasma Lead Concentration and Risk of Late Kidney Allograft Failure
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Camilo G. Sotomayor, Flavia Giubergia, Dion Groothof, Catterina Ferreccio, Ilja M. Nolte, Gerjan J. Navis, Antonio W. Gomes-Neto, Daan Kremer, Tim J. Knobbe, Michele F. Eisenga, Ramón Rodrigo, Daan J. Touw, Stephan J.L. Bakker, Kevin Damman, Vincent E. de Meijer, Robert J. Porte, Marieke T. de Boer, Henri G.D. Leuvenink, Robert A. Pol, Coby Annema, Adelita V. Ranchor, Marion J. Siebelink, Willem S. Lexmond, Bouke G. Hepkema, L. Joost van Pelt, C. Tji Gan, Erik A.M. Verschuuren, Frank A.J.A. Bodewes, Gerard Dijkstra, Hans J. Blokzijl, Bert H.G.M. Niesters, Jan-Stephan F. Sanders, Heleen Grootjans, Rianne M. Douwes, António W. Gomes-Neto, Riemer H.J.A. Slart, Michiel E. Erasmus, Coretta van Leer-Buter, Marco van Londen, Wim Timens, Arjan Diepstra, Marius C. van den Heuvel, Joëlle C. Schutten, Cas Swarte, Rinse K. Weersma, Rebecca Heiner-Fokkema, Michel Vos, Frank Klont, Eelko Hak, Life Course Epidemiology (LCE), Value, Affordability and Sustainability (VALUE), Groningen Kidney Center (GKC), Pharmaceutical Analysis, Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), Medicinal Chemistry and Bioanalysis (MCB), Groningen Research Institute for Asthma and COPD (GRIAC), Biopharmaceuticals, Discovery, Design and Delivery (BDDD), and Groningen Institute for Organ Transplantation (GIOT)
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Graft Rejection ,Graft Survival ,Allografts ,Kidney ,Kidney Transplantation ,Arsenic ,Cohort Studies ,Lead ,Risk Factors ,Nephrology ,Humans ,Prospective Studies ,Renal Insufficiency ,Renal Insufficiency, Chronic ,Biological Specimen Banks ,Cadmium - Abstract
RATIONALE & OBJECTIVE: Heavy metals are known to induce kidney damage and recent studies have linked minor exposures to cadmium and arsenic with increased risk of kidney allograft failure, yet the potential association of lead (Pb) with late graft failure in kidney transplant recipients (KTR) remains unknown.STUDY DESIGN: Prospective cohort study in the Netherlands.SETTING & PARTICIPANTS: We studied outpatient KTR (n=670) with a functioning graft for ≥1 year recruited at a university setting (2008-2011, NCT02811835) and followed, on average, for 4.9 (IQR, 3.4‒5.5) years. Additionally, end-stage kidney disease patients (n=46) enrolled in the ongoing TransplantLines Cohort and Biobank Study (2016-2017, NCT03272841) were studied at admission for transplantation and at 3, 6, 12, and 24 months after transplantation.EXPOSURE: Plasma Pb was log2 transformed to estimate the association with outcomes per doubling of plasma Pb concentration and also considered categorically as tertiles of the Pb distribution.OUTCOME: Kidney graft failure (restart of dialysis or re-transplantation) with the competing event of death with a functioning graft.ANALYTICAL APPROACH: Multivariable-adjusted cause-specific hazards models where follow-up of KTR who died with a functioning graft was censored.RESULTS: Median baseline plasma Pb was 0.31 (IQR, 0.22─0.45) μg/L among all KTRs. During follow-up, 78 (12%) KTR developed graft failure. Higher plasma Pb was associated with increased risk of graft failure (HR 1.59, 95% CI 1.14‒2.21 per doubling; P=0.006) independent of age, sex, transplant characteristics, eGFR, proteinuria, smoking status, alcohol intake, and plasma concentrations of cadmium and arsenic. These findings remained materially unchanged after additional adjustment for dietary intake and were consistent with those of analyses examining Pb categorically. In serial measurements, plasma Pb was significantly higher at admission for transplantation than at 3-months post-transplant (P=0.001), after which it remained stable over 2 years of follow-up (P=0.2).LIMITATIONS: Observational study design.CONCLUSIONS: Pretransplant plasma Pb concentrations, which fall after transplantation, are associated with increased risk of late kidney allograft failure. These findings warrant further studies to evaluate whether preventive or therapeutic interventions to decrease plasma Pb may represent novel risk-management strategies to decrease the rate of kidney allograft failure.
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- 2022
14. Prediction of measured GFR after living kidney donation from pre-donation parameters
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Marco van Londen, Jessica van der Weijden, Robert S Niznik, Aidan F Mullan, Stephan J L Bakker, Stefan P Berger, Ilja M Nolte, Jan-Stephan F Sanders, Gerjan Navis, Andrew D Rule, Martin H de Borst, Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Life Course Epidemiology (LCE), and Value, Affordability and Sustainability (VALUE)
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Transplantation ,Nephrology - Abstract
Background One of the challenges in living kidney donor screening is to estimate remaining kidney function after donation. Here we developed a new model to predict post-donation measured glomerular filtration rate (mGFR) from pre-donation serum creatinine, age and sex. Methods In the prospective development cohort (TransplantLines, n = 511), several prediction models were constructed and tested for accuracy, precision and predictive capacity for short- and long-term post-donation 125I-iothalamate mGFR. The model with optimal performance was further tested in specific high-risk subgroups (pre-donation eGFR 65 years) and validated in internal (n = 509) and external (Mayo Clinic, n = 1087) cohorts. Results In the development cohort, pre-donation estimated GFR (eGFR) was 86 ± 14 mL/min/1.73 m2 and post-donation mGFR was 64 ± 11 mL/min/1.73 m2. Donors with a pre-donation eGFR ≥90 mL/min/1.73 m2 (present in 43%) had a mean post-donation mGFR of 69 ± 10 mL/min/1.73 m2 and 5% of these donors reached an mGFR 65 years of age [bias 0.003 mL/min/1.73 m2 (IQR 9)]. Conclusions We developed a novel post-donation mGFR prediction model based on pre-donation serum creatinine, age and sex.
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- 2022
15. Effect of Intravenous Ferric Carboxymaltose on Exercise Capacity After Kidney Transplantation (EFFECT-KTx): rationale and study protocol for a double-blind, randomised, placebo-controlled trial
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Joanna SJ Vinke, Michele F Eisenga, Jan-Stephan F Sanders, Stefan P Berger, Jacoba M Spikman, Wayel H Abdulahad, Stephan JL Bakker, Carlo A J M Gaillard, Arjan D van Zuilen, P van der Meer, Martin H de Borst, Groningen Kidney Center (GKC), Groningen Institute for Organ Transplantation (GIOT), Clinical Neuropsychology, Translational Immunology Groningen (TRIGR), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), and Cardiovascular Centre (CVC)
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Exercise Tolerance ,Treatment Outcome ,Double-Blind Method ,Iron ,Ferritins ,Quality of Life ,Humans ,Multicenter Studies as Topic ,General Medicine ,Iron Deficiencies ,Kidney Transplantation ,Randomized Controlled Trials as Topic - Abstract
IntroductionIron deficiency (ID) is common and has been associated with an excess mortality risk in kidney transplant recipients (KTRs). In patients with chronic heart failure and ID, intravenous iron improves exercise capacity and quality of life. Whether these beneficial effects also occur in KTRs is unknown. The main objective of this trial is to address whether intravenous iron improves exercise tolerance in iron-deficient KTRs.Methods and analysisThe Effect of Ferric Carboxymaltose on Exercise Capacity after Kidney Transplantation study is a multicentre, double-blind, randomised, placebo-controlled clinical trial that will include 158 iron-deficient KTRs. ID is defined as plasma ferritin 3+/mL, intravenously) or placebo (0.9% sodium chloride solution) every 6 weeks, four dosages in total. The primary endpoint is change in exercise capacity, as quantified by the 6 min walk test, between the first study visit and the end of follow-up, 24 weeks later. Secondary endpoints include changes in haemoglobin levels and iron status, quality of life, systolic and diastolic heart function, skeletal muscle strength, bone and mineral parameters, neurocognitive function and safety endpoints. Tertiary (explorative) outcomes are changes in gut microbiota and lymphocyte proliferation and function.Ethics and disseminationThe protocol of this study has been approved by the medical ethical committee of the University Medical Centre Groningen (METc 2018/482;) and is being conducted in accordance with the principles of the Declaration of Helsinki, the Standard Protocol Items: Recommendations for Interventional Trials checklist and the Good Clinical Practice guidelines provided by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. Study results will be disseminated through publications in peer-reviewed journals and conference presentations.Trial registration numberNCT03769441.
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- 2023
16. The RECOVAC Immune-response Study: The Immunogenicity, Tolerability, and Safety of COVID-19 Vaccination in Patients With Chronic Kidney Disease, on Dialysis, or Living With a Kidney Transplant
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Priya Vart, Wouter B Mattheussens, Marion Koopmans, Gerco den Hartog, Dimitri A. Diavatopoulos, Luuk B. Hilbrands, Marlies E J Reinders, Djenolan van Mourik, Renate G. van der Molen, Celine Imhof, Marieke van der Heiden, Daryl Geers, C. Baan, Frederike J. Bemelman, Rory D. de Vries, Marcia M L Kho, S Reshwan K Malahe, Debbie van Baarle, Rob van Binnendijk, Ester B. M. Remmerswaal, Jan-Stephan F. Sanders, Corine H. GeurtsvanKessel, Ron T. Gansevoort, Nynke Y. Rots, A. Lianne Messchendorp, Sophie C Frölke, Internal Medicine, Virology, Nephrology, AII - Inflammatory diseases, APH - Aging & Later Life, Infectious diseases, Graduate School, Experimental Immunology, Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Translational Immunology Groningen (TRIGR), and Cardiovascular Centre (CVC)
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medicine.medical_specialty ,COVID-19 Vaccines ,medicine.medical_treatment ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,All institutes and research themes of the Radboud University Medical Center ,SDG 3 - Good Health and Well-being ,Renal Dialysis ,Internal medicine ,Medicine ,Humans ,Prospective Studies ,Seroconversion ,Renal Insufficiency, Chronic ,Dialysis ,Transplantation ,Kidney ,business.industry ,Immunogenicity ,Vaccination ,Immunity ,COVID-19 ,medicine.disease ,Kidney Transplantation ,medicine.anatomical_structure ,Tolerability ,Cohort ,Renal disorders Radboud Institute for Health Sciences [Radboudumc 11] ,business ,Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5] ,Kidney disease ,2019-nCoV Vaccine mRNA-1273 - Abstract
BACKGROUND: In kidney patients COVID-19 is associated with severely increased morbidity and mortality. A comprehensive comparison of the immunogenicity, tolerability, and safety of COVID-19 vaccination in different cohorts of kidney patients and a control cohort is lacking.METHODS: This investigator driven, prospective, controlled multicenter study included 162 participants with chronic kidney disease (CKD) stages G4/5 (eGFR < 30 mL/min/1.73m2), 159 participants on dialysis, 288 kidney transplant recipients, and 191 controls. Participants received 2 doses of the mRNA-1273 COVID-19 vaccine (Moderna). The primary endpoint was seroconversion.RESULTS: Transplant recipients had a significantly lower seroconversion rate when compared with controls (56.9% versus 100%, P < 0.001), with especially mycophenolic acid, but also, higher age, lower lymphocyte concentration, lower eGFR, and shorter time after transplantation being associated with nonresponder state. Transplant recipients also showed significantly lower titers of neutralizing antibodies and T-cell responses when compared with controls. Although a high seroconversion rate was observed for participants with CKD G4/5 (100%) and on dialysis (99.4%), mean antibody concentrations in the CKD G4/5 cohort and dialysis cohort were lower than in controls (2405 [interquartile interval 1287-4524] and 1650 [698-3024] versus 3186 [1896-4911] BAU/mL, P = 0.06 and P < 0.001, respectively). Dialysis patients and especially kidney transplant recipients experienced less systemic vaccination related adverse events. No specific safety issues were noted.CONCLUSIONS: The immune response following vaccination in patients with CKD G4/5 and on dialysis is almost comparable to controls. In contrast, kidney transplant recipients have a poor response. In this latter, patient group development of alternative vaccination strategies are warranted.Supplemental visual abstract; http://links.lww.com/TP/C307.
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- 2022
17. Ferric carboxymaltose and SARS-CoV-2 vaccination-induced immunogenicity in kidney transplant recipients with iron deficiency: The COVAC-EFFECT randomized controlled trial
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Joanna Sophia J. Vinke, Dania H. A. Altulea, Michele F. Eisenga, Renate L. Jagersma, Tessa M. Niekolaas, Debbie van Baarle, Marieke van Der Heiden, Maurice Steenhuis, Theo Rispens, Wayel H. Abdulahad, Jan-Stephan F. Sanders, Martin H. De Borst, Landsteiner Laboratory, AII - Inflammatory diseases, Translational Immunology Groningen (TRIGR), Groningen Kidney Center (GKC), and Groningen Institute for Organ Transplantation (GIOT)
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iron deficiency ,randomized controlled (clinical) trial ,SARS-CoV-2 ,Immunology ,kidney transplantation ,Immunology and Allergy ,vaccination - Abstract
BackgroundKidney transplant recipients (KTRs) have an impaired immune response after vaccination against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Iron deficiency (ID) may adversely affect immunity and vaccine efficacy. We aimed to investigate whether ferric carboxymaltose (FCM) treatment improves humoral and cellular responses after SARS-CoV-2 vaccination in iron-deficient KTRs.MethodsWe randomly assigned 48 iron-deficient KTRs to intravenous FCM (1-4 doses of 500mg with six-week intervals) or placebo. Co-primary endpoints were SARS-CoV-2-specific anti-Receptor Binding Domain (RBD) Immunoglobulin G (IgG) titers and T-lymphocyte reactivity against SARS-CoV-2 at four weeks after the second vaccination with mRNA-1273 or mRNA-BNT162b2.ResultsAt four weeks after the second vaccination, patients receiving FCM had higher plasma ferritin and transferrin saturation (PP=0.07) and SARS-CoV-2-specific T-lymphocyte activation (FCM: 93.3 [0.85-342.5] IFN-ɣ spots per 106 peripheral blood mononuclear cells (PBMCs), placebo: 138.3 [0.0-391.7] IFN-ɣ spots per 106 PBMCs, P=0.83) were not significantly different among both arms. After the third vaccination, SARS-CoV-2-specific anti-RBD IgG titers remained similar between treatment groups (P=0.99).ConclusionsIntravenous iron supplementation efficiently restored iron status but did not improve the humoral or cellular immune response against SARS-CoV-2 after three vaccinations.
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- 2023
18. Proton Pump Inhibitor Use, Fatigue, and Health-Related Quality of Life in Kidney Transplant Recipients: Results From the TransplantLines Biobank and Cohort Study
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Tim J. Knobbe, Daan Kremer, Rianne M. Douwes, Michele F. Eisenga, António W. Gomes-Neto, Coby Annema, J. Casper Swarte, Frank Klont, Gerjan Navis, Stefan P. Berger, Stephan J.L. Bakker, Hans Blokzijl, Frank A.J.A. Bodewes, Marieke T. de Boer, Kevin Damman, Martin H. de Borst, Arjan Diepstra, Gerard Dijkstra, Caecilia S.E. Doorenbos, Michiel E. Erasmus, C. Tji Gan, Eelko Hak, Bouke G. Hepkema, Henri G.D. Leuvenink, Willem S. Lexmond, Vincent E. de Meijer, Hubert G.M. Niesters, L. Joost van Pelt, Robert A. Pol, Robert J. Porte, Adelta V. Ranchor, Jan Stephan F. Sanders, Marion J. Siebelink, Riemer J.H.J.A. Slart, Daan J. Touw, Marius C. van den Heuvel, Coretta van Leer-Buter, Marco van Londen, Erik A.M. Verschuuren, Michel J. Vos, Rinse K. Weersma, Faculteit Medische Wetenschappen/UMCG, Department of Health and Life Sciences, University of Groningen, PharmacoTherapy, -Epidemiology and -Economics, Value, Affordability and Sustainability (VALUE), Groningen Kidney Center (GKC), Groningen Institute for Organ Transplantation (GIOT), Cardiovascular Centre (CVC), Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Microbes in Health and Disease (MHD), Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Pharmaceutical Analysis, Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), Biopharmaceuticals, Discovery, Design and Delivery (BDDD), Groningen Research Institute for Asthma and COPD (GRIAC), and Medicinal Chemistry and Bioanalysis (MCB)
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side effects ,quality of life ,Nephrology ,kidney transplantation ,Gut-brain interaction ,patient-reported outcome measures ,tiredness - Abstract
Rationale & Objective: Prior studies report that the use of proton pump inhibitors (PPIs) can adversely affect gut microbiota and gastrointestinal uptake of micronutrients, in particular iron and magnesium, and are used frequently by kidney transplant recipients. Altered gut microbiota, iron deficiency, and magnesium deficiency have been implicated in the pathogenesis of chronic fatigue. Therefore, we hypothesized that PPI use may be an important and underappreciated cause of fatigue and reduced health-related quality of life (HRQoL) in this population. Study Design: Cross-sectional study. Setting & Participants: Kidney transplant recipients (≥1 year after transplantation) enrolled in the TransplantLines Biobank and Cohort Study. Exposure: PPI use, PPI type, PPI dosage, and duration of PPI use. Outcome: Fatigue and HRQoL, assessed using the validated Checklist Individual Strength 20 Revised questionnaire and Short Form-36 questionnaire. Analytical Approach: Logistic and linear regression. Results: We included 937 kidney transplant recipients (mean age 56 ± 13 years, 39% female) at a median of 3 (1-10) years after transplantation. PPI use was associated with fatigue severity (regression coefficient 4.02, 95% CI, 2.18 to 5.85, P < 0.001), a higher risk of severe fatigue (OR 2.05, 95% CI, 1.48 to 2.84, P < 0.001), lower physical HRQoL (regression coefficient −8.54, 95% CI, −11.54 to −5.54, P < 0.001), and lower mental HRQoL (regression coefficient −4.66, 95% CI, −7.15 to −2.17, P < 0.001). These associations were independent of potential confounders including age, time since transplantation, history of upper gastrointestinal disease, antiplatelet therapy, and the total number of medications. They were present among all individually assessed PPI types and were dose dependent. Duration of PPI exposure was only associated with fatigue severity. Limitations: Residual confounding and inability to assess causal relationships. Conclusions: PPI use is independently associated with fatigue and lower HRQoL among kidney transplant recipients. PPI use might be an easily accessible target for alleviating fatigue and improving HRQoL among kidney transplant recipients. Further studies examining the effect of PPI exposure in this population are warranted.
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- 2023
19. Comparative survival of elderly renal transplant recipients with a living donor versus a deceased donor
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Antonio W. Gomes Neto, Robert A. Pol, Stefan P Berger, Silke E de Boer, Hessel Peters-Sengers, Erzsi Tegzess, Jan-Stephan F. Sanders, Center of Experimental and Molecular Medicine, Epidemiology and Data Science, Nephrology, AII - Inflammatory diseases, Groningen Kidney Center (GKC), Groningen Institute for Organ Transplantation (GIOT), and Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE)
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Male ,HEMODIALYSIS ,medicine.medical_specialty ,KIDNEY-TRANSPLANTATION ,graft survival ,kidney transplantation ,living donor ,Kidney ,Single Center ,elderly patients ,PATIENT ,Living donor ,AGE ,patient survival ,QUALITY-OF-LIFE ,Internal medicine ,Living Donors ,medicine ,Humans ,Kidney transplantation ,Aged ,Retrospective Studies ,GRAFT-SURVIVAL ,OLDER ,Transplantation ,Deceased donor ,business.industry ,Patient survival ,Retrospective cohort study ,medicine.disease ,Tissue Donors ,Transplant Recipients ,Treatment Outcome ,medicine.anatomical_structure ,deceased donor ,Observational study ,business - Abstract
Increasing numbers of elderly (>= 65 years) patients are listed for kidney transplantation. This study compares the survival outcome between living (LDK), regularly allocated (ETKAS), and Eurotransplant Senior Program (ESP) donor kidneys in elderly recipients. This is a single-center retrospective cohort study of elderly kidney transplant recipients transplanted between 2005 and 2017. Primary outcome measures were nondeath-censored graft, death-censored graft, and patient survival. In total, 348 patients were transplanted, 109 recipients (31.3%) received an LDK, 100 (28.7%) an ETKAS, and 139 (40%) an ESP kidney. 62.5% were male, and median age was 68 years. LDK recipients had significantly better 5-year nondeath-censored graft survival compared with ETKAS and ESP (resp. 71.0% vs. 66.1% vs. 55.6%, P = 0.047). Death-censored graft survival after 1 year was significantly better in LDK recipients (99.1%) (ETKAS 90.8%; ESP 87.7%, P < 0.001). After 5 years, the difference remained significant (P < 0.001) with little additional graft loss (97.7% vs. 88.1% vs. 85.6). There was no significant difference in patient survival after 5 years (71.7% vs. 67.4% vs 61.9%, P = 0.480). In elderly recipients, the patient survival benefits of an LDK are limited, but there is decreased death-censored graft loss for LDK recipients. Nevertheless, graft survival in ETKAS and ESP remains satisfactory.
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- 2021
20. CD163 and CD206 expression define distinct macrophage subsets involved in active ANCA-associated glomerulonephritis
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Joop P. Aendekerk, William F. Jiemy, Elisabeth Raveling-Eelsing, Nele Bijnens, Myrurgia A. Abdul-Hamid, Inge M. Strating, Gerjan J. Dekkema, Jan-Stephan F. Sanders, Coen A. Stegeman, Jan G.M.C. Damoiseaux, Mark A. Little, Peter Heeringa, Pieter van Paassen, Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Translational Immunology Groningen (TRIGR), Interne Geneeskunde, RS: Carim - B02 Vascular aspects thrombosis and Haemostasis, MUMC+: DA Pat Pathologie (9), RS: GROW - R2 - Basic and Translational Cancer Biology, MUMC+: DA CDL Algemeen (9), RS: NUTRIM - R3 - Respiratory & Age-related Health, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Central Diagnostic Lab, MUMC+: MA Nefrologie (9), and MUMC+: MA Klinische Immunologie (9)
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Macrophages ,Immunology ,Humans ,Immunology and Allergy ,Antibodies, Antineutrophil Cytoplasmic ,Retrospective Studies - Abstract
INTRODUCTION: Macrophages are key players in the immunopathology of anti-neutrophil cytoplasmic antibody (ANCA) mediated-vasculitis (AAV) with glomerulonephritis (ANCA GN). Different macrophage phenotypes are expected to play distinct roles in ANCA GN. Macrophages expressing CD163 and CD206 are found in lesions associated with ANCA GN. Hence, we aimed to investigate the clinicopathological significance of CD206 and CD163 in ANCA GN in a multicenter retrospective cohort study.MATERIAL AND METHODS: Patients with ANCA-associated vasculitis, with clinical data, serum and urine samples were included from three cohorts. Serum soluble CD206 (ssCD206) and urinary soluble CD163 (usCD163) levels were measured. Human kidney tissue samples (n = 53) were stained for CD206 and CD163 using immunohistochemistry and immunofluorescence, and findings were correlated with clinical and pathological data.RESULTS: In total, 210 patients were included (i.e., ANCA GN, n = 134; AAV without GN, n = 24; AAV in remission n = 52). Increased levels of both ssCD206 and usCD163 were seen in ANCA GN. High levels of ssCD206 declined after reaching remission, however, ssCD206 did not improve the accuracy of usCD163 to detect ANCA GN. Soluble markers correlated with histopathological findings. CD163+CD206- macrophages were found in the glomerulus and may play pivotal roles in glomerulonephritis, whereas CD206+CD163- and CD206+CD163+ macrophages were located tubulointerstitially and likely play a more prominent role in ANCA-associated tubulointerstitial inflammation. In ANCA GN patients increasing levels of ssCD206 increased the risk for end-stage renal disease and mortality.CONCLUSIONS: Our results confirm and extend the notion that CD206+ and CD163+ macrophages are prominent components of the cellular infiltrate in ANCA GN. We found distinct macrophage phenotypes that may play distinct roles in the immunopathology of ANCA GN and elaborate on a potential mechanism underlying the findings of this study. usCD163 remains an excellent marker to detect active ANCA GN, whereas ssCD206 seems a more prominent marker for risk prediction.
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- 2022
21. Thiopurine methyltransferase genotype and activity cannot predict outcomes of azathioprine maintenance therapy for antineutrophil cytoplasmic antibody associated vasculitis: A retrospective cohort study.
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Arno C Hessels, Abraham Rutgers, Jan Stephan F Sanders, and Coen A Stegeman
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Medicine ,Science - Abstract
Azathioprine is a widely used immunosuppressive drug. Genetic polymorphisms and activity of the enzyme thiopurine methyltransferase (TPMT) have been associated with azathioprine efficacy and toxicity in several populations. We investigated whether these associations also exist for ANCA associated vasculitis (AAV) patients, who receive azathioprine maintenance therapy after remission induction with cyclophosphamide.207 AAV patients treated with cyclophosphamide induction and azathioprine maintenance therapy were included and followed for 60 months. TPMT genotype and tertiles of TPMT activity were compared to relapse free survival and occurrence of adverse events, particularly leukopenia. Multivariable regression was performed to account for confounders.In univariable analysis, relapse free survival was not significantly associated with TPMT genotype (P = 0.41) or TPMT activity (P = 0.07), although it tended to be longer in lower tertiles of TPMT activity. There was no significant association of TPMT genotype and activity with occurrence of any adverse event. In multiple regression, leukocyte counts at the end of cyclophosphamide induction were related to risk of leukopenia during azathioprine therapy [P
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- 2018
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22. Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases
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Frank Bridoux, David Jayne, Yusuke Suzuki, Amy Earley, Kelly A. Burdge, Marina Vivarelli, Zhihong Liu, Jai Radhakrishnan, Adrian Liew, Keisha L. Gibson, Marcello Tonelli, Richard J. Glassock, Sydney C.W. Tang, Sharon G. Adler, Jan-Stephan F. Sanders, H. Terence Cook, Jonathan C. Craig, Vladimir Tesar, Sanjeev Sethi, Jonathan Barratt, Pierre Ronco, Elizabeth M. Rave, Michael Cheung, Brad H. Rovin, David J. Tunnicliffe, Carla M. Nester, Juan M. Mejia-Vilet, Vivekanand Jha, Martin Howell, Fernando C. Fervenza, Tak Mao Chan, Lyubov Lytvyn, Jürgen Floege, Jack F.M. Wetzels, Heather N. Reich, Groningen Kidney Center (GKC), Groningen Institute for Organ Transplantation (GIOT), Jayne, David [0000-0002-1712-0637], and Apollo - University of Cambridge Repository
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Adult ,medicine.medical_specialty ,Evidence-based practice ,Kidney ,Glomerulonephritis, Membranous ,anti-GBM ,Nephropathy ,IgA vasculitis ,Glomerulonephritis ,Focal segmental glomerulosclerosis ,systematic review ,Membranous nephropathy ,evidence-based ,medicine ,Humans ,complement ,Minimal change disease ,C3 ,Child ,Intensive care medicine ,glomerular diseases ,infection-related glomerulonephritis ,KDIGO ,lupus nephritis ,ANCA ,nephrotic syndrome ,business.industry ,MPGN ,Nephrosis, Lipoid ,membranous nephropathy ,AAV ,Glomerulonephritis, IGA ,IgA nephropathy ,Guideline ,medicine.disease ,FSGS ,minimal change disease ,Systematic review ,Nephrology ,Renal disorders Radboud Institute for Health Sciences [Radboudumc 11] ,business ,guideline - Abstract
Kidney international 100(4), 753-779 (2021). doi:10.1016/j.kint.2021.05.015, Published by Elsevier, New York, NY
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- 2021
23. Net Endogenous Acid Excretion and Kidney Allograft Outcomes
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Stefan P Berger, Jan-Stephan F. Sanders, Martin H. de Borst, Gerjan Navis, Jenny E. Kootstra-Ros, Maryse C J Osté, Stanley M H Yeung, Else van den Berg, Juan Jesus Carrero, António W Gomes-Neto, Stephan J. L. Bakker, Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), and Value, Affordability and Sustainability (VALUE)
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medicine.medical_specialty ,Epidemiology ,Bicarbonate ,Urology ,Renal function ,Titratable acid ,Critical Care and Intensive Care Medicine ,Excretion ,chemistry.chemical_compound ,Renal Dialysis ,medicine ,Humans ,Kidney transplantation ,Transplantation ,Kidney ,business.industry ,Original Articles ,medicine.disease ,medicine.anatomical_structure ,chemistry ,Nephrology ,Fruit ,Net acid excretion ,Acidosis ,business - Abstract
BACKGROUND AND OBJECTIVES: High dietary acid load may accelerate a decline in kidney function. We prospectively investigated whether dietary acid load is associated with graft outcomes in kidney transplant recipients, and whether venous bicarbonate mediates this association.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used data from 642 kidney transplant recipients with a functioning graft ≥1 year after transplantation. Net endogenous acid production was estimated using food frequency questionnaires and, alternatively, 24-hour urinary urea and potassium excretion to estimate net endogenous acid production. We defined the composite kidney end point as a doubling of plasma creatinine or graft failure. Multivariable Cox regression analyses, adjusted for potential confounders, were used to study the associations of dietary acid load with the kidney end point. We evaluated potential mediation effects of venous bicarbonate, urinary bicarbonate excretion, urinary ammonium excretion, titratable acid excretion, and net acid excretion on the association between net endogenous acid production and the kidney end point.RESULTS: The median net endogenous acid production using food frequency questionnaires and net endogenous acid production using urinary excretion were 40 (interquartile range, 35-45) and 54 (interquartile range, 44-66) mEq/day, respectively. During a median follow-up of 5.3 years (interquartile range, 4.1-6.0), 121 (19%) participants reached the kidney end point. After multivariable adjustment, net endogenous acid production using food frequency questionnaires and net endogenous acid production using urinary excretion (per SD higher) were independently associated with higher risk for kidney end point (hazard ratio, 1.33; 95% confidence interval, 1.12 to 1.57, P=0.001 and hazard ratio, 1.44; 95% confidence interval, 1.24 to 1.69, PCONCLUSIONS: Higher dietary acid load was associated with a higher risk of doubling of plasma creatinine or graft failure, and this association was partly mediated by venous bicarbonate, urinary ammonium, and net acid excretion.
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- 2021
24. Gut microbiome dysbiosis is associated with increased mortality after solid organ transplantation
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J. Casper Swarte, Yanni Li, Shixian Hu, Johannes R. Björk, Ranko Gacesa, Arnau Vich Vila, Rianne M. Douwes, Valerie Collij, Alexander Kurilshikov, Adrian Post, Marjolein A. Y. Klaassen, Michele F. Eisenga, António W. Gomes-Neto, Daan Kremer, Bernadien H. Jansen, Tim J. Knobbe, Stefan P. Berger, Jan-Stephan F. Sanders, M. Rebecca Heiner-Fokkema, Robert J. Porte, Frans J. C. Cuperus, Vincent E. de Meijer, Cisca Wijmenga, Eleonora A. M. Festen, Alexandra Zhernakova, Jingyuan Fu, Hermie J. M. Harmsen, Hans Blokzijl, Stephan J. L. Bakker, Rinse K. Weersma, Groningen Kidney Center (GKC), Groningen Institute for Organ Transplantation (GIOT), Center for Liver, Digestive and Metabolic Diseases (CLDM), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), and Microbes in Health and Disease (MHD)
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Virulence Factors ,Hematopoietic Stem Cell Transplantation ,Dysbiosis ,Humans ,General Medicine ,Organ Transplantation ,Gastrointestinal Microbiome - Abstract
Organ transplantation is a life-saving treatment for patients with end-stage disease, but survival rates after transplantation vary considerably. There is now increasing evidence that the gut microbiome is linked to the survival of patients undergoing hematopoietic cell transplant, yet little is known about the role of the gut microbiome in solid organ transplantation. We analyzed 1370 fecal samples from 415 liver and 672 renal transplant recipients using shotgun metagenomic sequencing to assess microbial taxonomy, metabolic pathways, antibiotic resistance genes, and virulence factors. To quantify taxonomic and metabolic dysbiosis, we also analyzed 1183 age-, sex-, and body mass index–matched controls from the same population. In addition, a subset of 78 renal transplant recipients was followed longitudinally from pretransplantation to 24 months after transplantation. Our data showed that both liver and kidney transplant recipients suffered from gut dysbiosis, including lower microbial diversity, increased abundance of unhealthy microbial species, decreased abundance of important metabolic pathways, and increased prevalence and diversity of antibiotic resistance genes and virulence factors. These changes were found to persist up to 20 years after transplantation. Last, we demonstrated that the use of immunosuppressive drugs was associated with the observed dysbiosis and that the extent of dysbiosis was associated with increased mortality after transplantation. This study represents a step toward potential microbiome-targeted interventions that might influence the outcomes of recipients of solid organ transplantation.
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- 2022
25. Systemic and Renal Dynamics of Free Sulfhydryl Groups during Living Donor Kidney Transplantation
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Nora A. Spraakman, Annemieke M. Coester, Arno R. Bourgonje, Vincent B. Nieuwenhuijs, Jan-Stephan F. Sanders, Henri G. D. Leuvenink, Harry van Goor, Gertrude J. Nieuwenhuijs-Moeke, Groningen Institute for Organ Transplantation (GIOT), and Groningen Kidney Center (GKC)
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PLASMA ,Organic Chemistry ,ischemia-reperfusion injury ,free thiols ,kidney transplantation ,General Medicine ,Kidney ,THIOLS ,Catalysis ,Computer Science Applications ,Inorganic Chemistry ,ischemia–reperfusion injury ,oxidative stress ,redox ,Living Donors ,Humans ,Sulfhydryl Compounds ,REACTIVE OXYGEN ,Physical and Theoretical Chemistry ,REPERFUSION INJURY ,Molecular Biology ,Spectroscopy - Abstract
During ischemia–reperfusion injury (IRI), reactive oxygen species are produced that can be scavenged by free sulfhydryl groups (R-SH, free thiols). In this study, we hypothesized that R-SH levels decrease as a consequence of renal IRI and that R-SH levels reflect post-transplant graft function. Systemic venous, arterial, renal venous, and urinary samples were collected in donors and recipients before, during, and after transplantation. R-SH was measured colorimetrically. Systemic arterial R-SH levels in recipients increased significantly up to 30 sec after reperfusion (p < 0.001). In contrast, renal venous R-SH levels significantly decreased at 5 and 10 min compared to 30 sec after reperfusion (both p < 0.001). This resulted in a significant decrease in delta R-SH (defined as the difference between renal venous and systemic arterial R-SH levels) till 30 sec after reperfusion (p < 0.001), indicating a net decrease in R-SH levels across the transplanted kidney. Overall, these results suggest trans-renal oxidative stress as a consequence of IRI during kidney transplantation, reflected by systemic and renal changes in R-SH levels in transplant recipients.
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- 2022
26. Enhanced Humoral Immune Response After COVID-19 Vaccination in Elderly Kidney Transplant Recipients on Everolimus Versus Mycophenolate Mofetil-containing Immunosuppressive Regimens
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Silke E, de Boer, Stefan P, Berger, Coretta C, van Leer-Buter, Bart-Jan, Kroesen, Debbie, van Baarle, Jan-Stephan F, Sanders, Groningen Kidney Center (GKC), Groningen Institute for Organ Transplantation (GIOT), and Translational Immunology Groningen (TRIGR)
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Transplantation ,COVID-19 Vaccines ,Prednisolone ,Calcineurin Inhibitors ,Vaccination ,COVID-19 ,Mycophenolic Acid ,Kidney Transplantation ,Transplant Recipients ,Immunity, Humoral ,Humans ,Everolimus ,Immunosuppressive Agents ,Aged - Abstract
BACKGROUND: Elderly kidney transplant recipients (KTRs) represent almost one third of the total kidney transplant population. These patients have a very high coronavirus disease 2019 (COVID-19)-related mortality, whereas their response to COVID-19 vaccination is impaired. Finding ways to improve the COVID-19 vaccination response in this vulnerable population is of uttermost importance.METHODS: In the OPTIMIZE trial, we randomly assign elderly KTRs to an immunosuppressive regimen with standard-exposure calcineurin inhibitor (CNI), mycophenolate mofetil, and prednisolone or an adapted regimen with low dose CNI, everolimus, and prednisolone. In this substudy, we measured the humoral response after 2 (N = 32) and 3 (N = 22) COVID-19 mRNA vaccinations and the cellular response (N = 15) after 2 vaccinations.RESULTS: . The seroconversion rates of elderly KTRs on a standard immunosuppressive regimen were only 13% and 38% after 2 and 3 vaccinations, respectively, whereas the response rates of KTRs on the everolimus regimen were significantly higher at 56% (P = 0.009) and 100% (P = 0.006). Levels of severe acute respiratory syndrome coronaVirus 2 IgG antibodies were significantly higher at both time points in the everolimus group (P = 0.004 and P < 0.001). There were no differences in cellular response after vaccination.CONCLUSION: . An immunosuppressive regimen without mycophenolate mofetil, a lower CNI dose, and usage of everolimus is associated with a higher humoral response rate after COVID-19 vaccination in elderly KTRs after transplantation. This encouraging finding should be investigated in larger cohorts, including transplant recipients of all ages.
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- 2022
27. COVID-19 Vaccination Response in Kidney Transplant Recipients With and Without Mycophenolate Mofetil: Follow-up of a Randomized Controlled Trial
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Zainab Al Fatly, Michiel G.H. Betjes, A. Lianne Messchendorp, Jan-Stephan F. Sanders, Marlies E.J. Reinders, Marcia Mu Lan Kho, Annelies E. de Weerd, Internal Medicine, Groningen Institute for Organ Transplantation (GIOT), and Groningen Kidney Center (GKC)
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SDG 3 - Good Health and Well-being ,Nephrology - Published
- 2022
28. Antibody and T-cell responses 6 months after COVID-19 mRNA-1273 vaccination in patients with chronic kidney disease, on dialysis, or living with a kidney transplant
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Jan Stephan F, Sanders, A, Lianne Messchendorp, Rory D, de Vries, Carla C, Baan, Debbie, van Baarle, Rob, van Binnendijk, Dimitri A, Diavatopoulos, Daryl, Geers, Katharina S, Schmitz, Corine H Geurts, van Kessel, Gerco den, Hartog, Marcia Ml, Kho, Marion Pg, Koopmans, Renate G, van der Molen, Ester Bm, Remmerswaal, Nynke, Rots, Ron T, Gansevoort, Frederike J, Bemelman, Luuk B, Hilbrands, and Marlies Ej, Reinders
- Abstract
The immune response to COVID-19 vaccination is inferior in kidney transplant recipients (KTR), and to a lesser extent in patients on dialysis or with chronic kidney disease (CKD). We assessed the immune response 6 months after mRNA-1273 vaccination in kidney patients and compared this to controls.152 participants with CKD stages G4/5 (eGFR30 mL/min/1.73m2), 145 participants on dialysis, 267 KTR, and 181 controls were included. SARS-CoV-2 Spike S1-specific IgG antibodies were measured by fluorescent bead-based multiplex-immunoassay, neutralizing antibodies to ancestral, Delta and Omicron (BA.1) variants by plaque reduction, and T-cell responses by IFN-γ release assay.At 6 months after vaccination S1-specific antibodies were detected in 100% of controls, 98.7% of CKD G4/5 patients, 95.1% of dialysis patients, and 56.6% of KTR. These figures were comparable to the response rates at 28 days, but antibody levels waned significantly. Neutralization of the ancestral and Delta variant was detected in most participants, whereas neutralization of Omicron was mostly absent. S-specific T-cell responses were detected 6 months in 75.0% of controls, 69.4% of CKD G4/5 patients, 52.6% of dialysis patients, and 12.9% of KTR. T-cell responses at 6 months were significantly lower than responses at 28 days.Although seropositivity rates at 6 months were comparable to that at 28 days after vaccination, significantly decreased antibody levels and T-cell responses were observed. The combination of low antibody levels, reduced T-cell responses, and absent neutralization of the newly-emerging variants indicates the need for additional boosts or alternative vaccination strategies in KTR.
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- 2022
29. Gene variants and treatment outcomes in antineutrophil cytoplasmic antibody-associated vasculitis
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Coen A. Stegeman, Jan-Stephan F. Sanders, Arno C Hessels, and Abraham Rutgers
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0301 basic medicine ,CYCLOPHOSPHAMIDE TREATMENT ,Treatment outcome ,PULSE CYCLOPHOSPHAMIDE ,Bioinformatics ,AUTOIMMUNE-DISEASES ,030226 pharmacology & pharmacy ,PROMOTER POLYMORPHISM ,03 medical and health sciences ,WEGENERS-GRANULOMATOSIS ,0302 clinical medicine ,GLUCOCORTICOID-RECEPTOR GENE ,Genetics ,Medicine ,SYSTEMIC-LUPUS-ERYTHEMATOSUS ,Adverse effect ,Gene ,STAPHYLOCOCCUS-AUREUS ,Anti-neutrophil cytoplasmic antibody ,Pharmacology ,business.industry ,Genetic variants ,medicine.disease ,RHEUMATOID-ARTHRITIS ,030104 developmental biology ,11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1 ,Rheumatoid arthritis ,Molecular Medicine ,business ,Vasculitis ,Pharmacogenetics - Abstract
The introduction of immunosuppressive therapy for ANCA-associated vasculitis (AAV) has greatly improved outcomes, though patients now accumulate damage from vasculitis activity and adverse effects of treatment. Prediction of treatment outcomes using gene variants might help reduce this damage by allowing for personalized treatment. Several studies have studied genetic polymorphisms in relation to treatment outcomes of AAV. This review gives an overview of these studies, discussing both gene polymorphisms associated with inflammatory pathways (potentially influencing disease outcomes such as activity, severity, and relapse risk) and pharmacogenetics (potentially influencing drug metabolism and/or drug response). Subsequently, potential benefits of testing genetic variants for AAV and the steps needed for its implementation in clinical practice are discussed. The conclusion of this review is that measurement of most polymorphisms is currently not indicated in clinical practice.
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- 2020
30. Evidence for enhanced Bruton's tyrosine kinase activity in transitional and naive B cells of patients with granulomatosis with polyangiitis
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Odilia B. J. Corneth, Coen A. Stegeman, Rudi W. Hendriks, Wayel H. Abdulahad, Stephan F.H. Neys, Anouk von Borstel, Jasper Rip, Abraham Rutgers, Jan-Stephan F. Sanders, Peter Heeringa, Pulmonary Medicine, Translational Immunology Groningen (TRIGR), Groningen Kidney Center (GKC), and Groningen Institute for Organ Transplantation (GIOT)
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Male ,0301 basic medicine ,Plasma cell ,ACTIVATION ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,CYCLOPHOSPHAMIDE ,VASCULITIS ,CRITERIA ,Pharmacology (medical) ,Phosphorylation ,Cells, Cultured ,B-Lymphocytes ,Immunity, Cellular ,medicine.diagnostic_test ,biology ,Middle Aged ,Clinical Science ,Flow Cytometry ,Bruton's tyrosine kinase ,medicine.anatomical_structure ,Disease Progression ,Cytokines ,Female ,Tyrosine kinase ,Adult ,B-cell receptor ,Naive B cell ,Enzyme-Linked Immunosorbent Assay ,macromolecular substances ,AMERICAN-COLLEGE ,Peripheral blood mononuclear cell ,CLASSIFICATION ,Flow cytometry ,Young Adult ,03 medical and health sciences ,Rheumatology ,stomatognathic system ,medicine ,Humans ,BTK blocker ,RITUXIMAB ,B cell ,Aged ,Autoantibodies ,030203 arthritis & rheumatology ,B cells ,business.industry ,Granulomatosis with Polyangiitis ,030104 developmental biology ,Cancer research ,biology.protein ,business ,Biomarkers - Abstract
Objectives To determine Bruton’s tyrosine kinase (BTK) protein and phosphorylation levels in B cell subsets of granulomatosis with polyangiitis (GPA) patients and to investigate the effect of BTK blockade on in vitro B cell cytokine production, subset distribution and (auto)antibody production. Methods BTK protein and phosphorylation levels were determined by flow cytometry in peripheral blood B cells of 29 untreated GPA patients [9 active and 20 remission GPA patients (10 ANCA– and 10 ANCA+)], 9 age- and sex-matched healthy controls (HCs) and 9 untreated active RA patients. The effect of BTK blockade on in vitro B cell cytokine production, subset distribution and (auto)antibody production was determined in the same donors in peripheral blood mononuclear cell cultures. Results BTK protein levels were significantly increased in transitional and naïve B cells of active GPA and RA patients compared with remission GPA patients and HCs. Both B cell subsets of active patients were more sensitive to B cell receptor stimulation, as BTK and phospholipase Cγ2 phosphorylation were increased in these patients. In vitro BTK blockade had profound effects on B cell cytokine production, plasma cell formation and (auto)antibody production in both GPA patients and HCs. Interestingly, the effect of BTK blockade was less pronounced in active GPA patients, possibly due to increased activation of B cells. Conclusion We show that BTK protein and phosphorylation levels are most profoundly increased in newly emerging B cells of active GPA patients compared with remission patients. BTK blockade greatly inhibits in vitro B cell effector functions in GPA patients and HCs. These promising data identify BTK as an interesting novel therapeutic target in the treatment of GPA.
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- 2019
31. ABO-incompatible kidney transplantation in perspective of deceased donor transplantation and induction strategies: a propensity-matched analysis
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Jan A.J.G. van den Brand, Maarten H. L. Christiaans, Franka E. van Reekum, Ine M. Dooper, Michiel G. H. Betjes, Madelon van Agteren, Marije C. Baas, Azam S Nurmohamed, Hanneke Bouwsma, Jan-Stephan F. Sanders, Margriet F C de Jong, Annelies E. de Weerd, Aiko P. J. de Vries, Frederike J. Bemelman, Arjan D. van Zuilen, Internal Medicine, Nephrology, AII - Inflammatory diseases, ACS - Diabetes & metabolism, Internal medicine, APH - Aging & Later Life, Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), RS: NUTRIM - R3 - Respiratory & Age-related Health, MUMC+: MA Nefrologie (9), and Interne Geneeskunde
- Subjects
Graft Rejection ,medicine.medical_specialty ,Basiliximab ,patient and graft survival ,ABO Blood-Group System ,ANTIGEN-SPECIFIC IMMUNOADSORPTION ,ABO-incompatible kidney transplantation ,ABO blood group system ,medicine ,Living Donors ,alemtuzumab ,Humans ,HIGHLY SENSITIZED PATIENTS ,RITUXIMAB ,Kidney transplantation ,Retrospective Studies ,deceased donor transplantation ,Transplantation ,OUTCOMES ,business.industry ,RENAL-TRANSPLANTATION ,Hazard ratio ,Graft Survival ,Retrospective cohort study ,medicine.disease ,BARRIER ,Kidney Transplantation ,Surgery ,living donor transplantation ,Blood Group Incompatibility ,SURVIVAL ,Alemtuzumab ,Rituximab ,Renal disorders Radboud Institute for Health Sciences [Radboudumc 11] ,rejection ,business ,medicine.drug - Abstract
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
- Published
- 2021
32. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases
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Carla M. Nester, Adrian Liew, Jürgen Floege, Elizabeth M. Rave, Sharon G. Adler, Kelly A. Burdge, Richard J. Glassock, Sydney C.W. Tang, Vivekanand Jha, Brad H. Rovin, Pierre Ronco, Jai Radhakrishnan, Jan-Stephan F. Sanders, Jonathan Barratt, Yusuke Suzuki, David Jayne, Sanjeev Sethi, Zhihong Liu, Juan M. Mejia-Vilet, Keisha L. Gibson, Heather N. Reich, Fernando C. Fervenza, Tak Mao Chan, Marina Vivarelli, H. Terence Cook, Vladimir Tesar, Jack F.M. Wetzels, Frank Bridoux, Apollo - University of Cambridge Repository, Rovin, Brad H., Adler, Sharon G., Jayne, David R. W., Jha, Vivekanand, Liew, Adrian, Liu, Zhi-Hong, Mejía-Vilet, Juan Manuel, Nester, Carla M., Radhakrishnan, Jai, Rave, Elizabeth M., Reich, Heather N., Ronco, Pierre, Barratt, Jonathan, Sanders, Jan-Stephan F., Sethi, Sanjeev, Suzuki, Yusuke, Tang, Sydney C. W., Tesar, Vladimir, Vivarelli, Marina, Wetzels, Jack F. M., Floege, Jürgen, Bridoux, Frank, Burdge, Kelly A., Chan, Tak Mao, Cook, H. Terence, Fervenza, Fernando C., Gibson, Keisha L., and Glassock, Richard J.
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medicine.medical_specialty ,business.industry ,1103 Clinical Sciences ,Guideline ,Urology & Nephrology ,Clinical Practice ,Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group ,Nephrology ,Medicine ,Humans ,Kidney Diseases ,Renal disorders Radboud Institute for Health Sciences [Radboudumc 11] ,Renal Insufficiency, Chronic ,business ,Intensive care medicine ,Glomerular diseases ,Glomerular Filtration Rate - Abstract
Kidney international 100(4, Supplement) S1-S276 (2021). doi:10.1016/j.kint.2021.05.021 special issue: "KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases", Published by Elsevier, New York, NY
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- 2021
- Full Text
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33. Rationale and design of the OPTIMIZE trial
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Dennis A. Hesselink, A. P. J. de Vries, B. C. van Munster, L. Hilbrands, Johannes G. M. Burgerhof, Shaikh A. Nurmohamed, Michiel G. H. Betjes, S E de Boer, Jan-Stephan F. Sanders, A D van Zuilen, F. J. Bemelman, Stefan P Berger, Dirk Kuypers, Internal Medicine, Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Life Course Epidemiology (LCE), Value, Affordability and Sustainability (VALUE), Molecular Neuroscience and Ageing Research (MOLAR), Nephrology, APH - Aging & Later Life, Epidemiology and Data Science, ACS - Diabetes & metabolism, AII - Inflammatory diseases, and Pediatrics
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Nephrology ,medicine.medical_specialty ,mTOR inhibitor ,Immunosenescence ,medicine.medical_treatment ,Calcineurin Inhibitors ,030232 urology & nephrology ,030230 surgery ,Tacrolimus ,Study Protocol ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,Reduced CNI exposure ,0302 clinical medicine ,Multicenter trial ,Internal medicine ,medicine ,Humans ,Everolimus ,Kidney transplantation ,Aged ,Immunosuppression Therapy ,Elderly kidney transplant recipients ,Patient-reported outcomes ,Frailty ,business.industry ,Immunosuppression ,Mycophenolic Acid ,medicine.disease ,Kidney Transplantation ,Diseases of the genitourinary system. Urology ,Transplantation ,RECIPIENTS ,Regimen ,Immune System ,T-CELLS ,Drug Therapy, Combination ,RC870-923 ,Randomized clinical trial ,Renal disorders Radboud Institute for Health Sciences [Radboudumc 11] ,business ,Immunosuppressive Agents ,(Health-related) quality of life ,medicine.drug - Abstract
Background In 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 recipients aged 65 years and older, compared to standard immunosuppression. Methods This open label, randomized, multicenter clinical trial will include 374 elderly kidney transplant recipients (≥ 65 years) and consists of two strata. Stratum A includes elderly recipients of a kidney from an elderly deceased donor and stratum B includes elderly recipients of a kidney from a living donor or from a deceased donor 2 in stratum A and ≥ 45 ml/min per 1.73 m2 in stratum B, after 2 years, respectively. Conclusions The OPTIMIZE study will help to determine the optimal immunosuppressive regimen after kidney transplantation for elderly patients and the cost-effectiveness of this regimen. It will also provide deeper insight into immunosenescence and both subjective and objective outcomes after kidney transplantation in elderly recipients. Trial registration ClinicalTrials.gov: NCT03797196, registered January 9th, 2019. EudraCT: 2018-003194-10, registered March 19th, 2019.
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- 2021
34. Timing of renal replacement therapy in acute kidney injury
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Gertrude J. Nieuwenhuijs-Moeke, Jan-Stephan F. Sanders, Groningen Kidney Center (GKC), and Groningen Institute for Organ Transplantation (GIOT)
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RISK ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,MEDLINE ,Urology ,Acute kidney injury ,General Medicine ,Acute Kidney Injury ,medicine.disease ,Renal Replacement Therapy ,AKI ,Medicine ,Humans ,Renal replacement therapy ,business - Published
- 2020
35. Complement activation and long-term graft function in ABO-incompatible kidney transplantation
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Marit S van Sandwijk, Sandrine Florquin, Ineke J. M. ten Berge, Astrid Klooster, Arjan Diepstra, Frederike J. Bemelman, Joris J Hoelbeek, Jan-Stephan F. Sanders, Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Kidney Center (GKC), and Groningen Institute for Organ Transplantation (GIOT)
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congenital, hereditary, and neonatal diseases and abnormalities ,business.industry ,030232 urology & nephrology ,Complement ,030204 cardiovascular system & hematology ,Case Control Study ,medicine.disease ,Graft function ,Rejection ,biological factors ,Complement (complexity) ,Complement system ,Kidney transplantation ,03 medical and health sciences ,surgical procedures, operative ,0302 clinical medicine ,ABO-incompatible ,ABO blood group system ,hemic and lymphatic diseases ,Immunology ,parasitic diseases ,Medicine ,business - Abstract
BACKGROUND: ABO-incompatible and ABO-compatible kidney transplantation are equivalent in terms of short-term graft and patient survival. This is thought to be the result of ABO-incompatible graft accommodation, which occurs when anti-blood group antibodies re-occur after transplantation but somehow do not yield their detrimental effect. The underlying mechanism is unclear, but one of the hypotheses is that this is the result of complement inhibition. Since virtually all ABO-incompatible graft biopsies are C4d positive, this complement inhibition must occur somewhere in the complement cascade after the formation of C4d has already taken place, but where exactly is unclear. It is also unclear whether complement inhibition is complete. Incomplete accommodation could explain why recent studies have shown that long-term graft function in ABO-incompatible transplantation is somewhat inferior to ABO-compatible kidney transplantation.AIM: To unravel the relationship between pre-transplant anti-ABO antibodies, complement activation, and long-term graft function.METHODS: We included all 27 ABO-incompatible transplantations that were performed between 2008 and 2013 at the Academic Medical Center Amsterdam and the University Medical Center Groningen. For each ABO-incompatible transplantation, we included four ABO-compatible controls matched by age, sex, and transplantation date.RESULTS: Graft and patient survival were not significantly different. The slope of kidney function during five-year follow-up was also not significantly different, but ABO-incompatible recipients did have a lower kidney function at three months (creatinine clearance 58 vs 69 mL/min, P = 0.02, Modification of Diet in Renal Disease 46 vs 52 mL/min/1.73 m2, P = 0.08), due to a high rate of early rejection (33% vs 15%, P = 0.03), mostly T-cell mediated. Pre-transplant anti-ABO IgG titers were positively correlated with C5b-9 staining, which itself was positively correlated with the occurrence of T-cell mediated rejection. This may be the result of concurrent C5a formation, which could function as a costimulatory signal for T-cell activation.CONCLUSION: Co-stimulation of T-cell activation by ongoing complement activation by anti-ABO antibodies may be responsible for an impaired long-term graft function in ABO-incompatible kidney transplantation.
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- 2019
36. Circulating CD24(hi)CD38(hi) regulatory B cells correlate inversely with the Th(EM)17 cell frequency in granulomatosis with polyangiitis patients
- Author
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Coen A. Stegeman, Abraham Rutgers, Anouk von Borstel, Wayel H. Abdulahad, Peter Heeringa, Lucas L. Lintermans, Jan-Stephan F. Sanders, Translational Immunology Groningen (TRIGR), Groningen Kidney Center (GKC), and Groningen Institute for Organ Transplantation (GIOT)
- Subjects
0301 basic medicine ,Regulatory B cells ,Population ,CD38 ,CXCR3 ,PHENOTYPE ,CD19 ,vasculitis ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,Rheumatology ,Medicine ,Pharmacology (medical) ,RITUXIMAB ,Th17 cells ,education ,B cell ,030203 arthritis & rheumatology ,education.field_of_study ,B cells ,granulomatosis with polyangiitis ,biology ,medicine.diagnostic_test ,business.industry ,medicine.disease ,regulatory B cells ,Molecular biology ,030104 developmental biology ,medicine.anatomical_structure ,biology.protein ,business ,Granulomatosis with polyangiitis - Abstract
Objectives To investigate whether there is a direct relation between expanded proportions of Th17 effector memory (ThEM17) cells and regulatory B cells (Bregs) in peripheral blood of granulomatosis with polyangiitis (GPA) patients. Methods Frequencies of Bregs and ThEM17 cells, as well as ThEM1 cells, were determined by flow cytometry in blood samples from 42 GPA patients in remission and 18 matched healthy controls (HCs). The Breg frequency was defined as CD24hiCD38hiCD19+ cells. ThEM17 cells were defined as CCR6+CXCR3-CCR4+ cells and ThEM1 cells as CCR6-CXCR3+CCR4- cells within the CD3+CD4+CD45RO+CCR7- population. In addition, CD3+CD4+ Th cells from 9 GPA patients were co-cultured in vitro with either total B cells or a Breg-depleted B cell fraction. Cultured cells were stimulated with Staphylococcus Enterotoxin B (SEB) and CpG-oligodeoxynucleotides (CpG-ODN). Th17- (IL-17+) and Th1 cell (IFNγ+) frequencies were determined at baseline and day 5 upon restimulation with phorbol myristate acetate (PMA) and Ca-I. Results A decreased Breg frequency was found in treated GPA patients, whereas an increased ThEM17 cell frequency was observed in treated and untreated GPA patients compared with HCs. Additionally, a decreased ThEM1 cell frequency was seen in untreated GPA patients compared with HCs. In untreated GPA patients circulating Breg frequencies correlated negatively with ThEM17 cells (r = −0.533; P = 0.007) and positively with ThEM1 cells (r = −0.473; P = 0.015). The co-culture experiments revealed a significant increase in the frequency of IL-17+ Th cells in Breg-depleted samples (median: 3%; range: 1–7.5%) compared with Breg-undepleted samples (P = 0.002; undepleted samples median: 2.1%; range: 0.9–6.4%), whereas no difference in the frequency of IFNγ+ Th cells in Breg-depleted cultures was observed (undepleted median: 11.8%; range: 2.8–21% vs Breg-depleted median: 12.2%; range: 2.6–17.6%). Conclusion Bregs modulate ThEM17 responses in GPA patients. Future studies should elaborate on clinical and therapeutical implications of the Breg-Th17 interaction in GPA patients.
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- 2019
37. Psychosocial consequences of living kidney donation
- Author
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Luuk B. Hilbrands, Christina W Hooghof, Henriët van Middendorp, Judith M. Wierdsma, Hiske Wellink, Lieke Wirken, Ruth E Dam, Jan-Stephan F. Sanders, Andrea W M Evers, Elly M. van Duijnhoven, Karlijn A M I van der Pant, Andries J. Hoitsma, Nephrology, MUMC+: MA Nefrologie (9), Interne Geneeskunde, RS: FHML non-thematic output, Groningen Kidney Center (GKC), Groningen Institute for Organ Transplantation (GIOT), and VU University medical center
- Subjects
Gerontology ,Male ,Donation consequences ,Health-related quality of life ,Emotions ,030232 urology & nephrology ,Psychological intervention ,030204 cardiovascular system & hematology ,Kidney ,Nephrectomy ,DECISION REGRET ,0302 clinical medicine ,Living kidney donors ,Quality of life ,Surveys and Questionnaires ,Living Donors ,Prospective Studies ,PREDICTORS ,Fatigue ,Netherlands ,OUTCOMES ,Middle Aged ,EXPERIENCES ,Nephrology ,Donation ,Cohort ,Tissue and Organ Harvesting ,Female ,Psychosocial ,Adult ,LONG-TERM ,03 medical and health sciences ,Young Adult ,All institutes and research themes of the Radboud University Medical Center ,medicine ,Humans ,COHORT ,Interpersonal Relations ,Aged ,Transplantation ,business.industry ,Regret ,medicine.disease ,Kidney Transplantation ,Quality of Life ,Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5] ,Self Report ,Renal disorders Radboud Institute for Health Sciences [Radboudumc 11] ,Course ,FOLLOW-UP ,business ,Kidney disease - Abstract
Background Previous studies have indicated decreased health-related quality of life (HRQoL) shortly after kidney donation, returning to baseline in the longer term. However, a subgroup of donors experiences persistent HRQoL problems. To identify which HRQoL aspects are impacted most by the donation and to identify at-risk donors, more specific insight into psychosocial donation consequences is needed. Methods The current study examined the HRQoL course, donor-perceived consequences of donation for donors, recipients and donor–recipient relationships, and regret up to 12 months post-donation in donors from seven Dutch transplantation centres. Kidney donor candidates (n = 588) completed self-report questionnaires early in the screening procedure, of which 361 (61%) donated their kidney. Results Data for 230 donors (64%) with complete assessments before donation and 6 and 12 months post-donation were analysed. Results indicated that donor physical HRQoL was comparable at all time points, except for an increase in fatigue that lasted up to 12 months post-donation. Mental HRQoL decreased at 6 months post-donation, but returned to baseline at 12 months. Donors reported large improvements in recipient’s functioning and a smaller influence of the recipient’s kidney disease or transplantation on the donor’s life over time. A subgroup experienced negative donation consequences with 14% experiencing regret 12 months post-donation. Predictors of regret were more negative health perceptions and worse social functioning 6 months post-donation. The strongest baseline predictors of higher fatigue levels after donation were more pre-donation fatigue, worse general physical functioning and a younger age. Conclusions Future research should examine predictors of HRQoL after donation to improve screening and to provide potential interventions in at-risk donors.
- Published
- 2019
38. Clinical outcome in anti-neutrophil cytoplasmic antibody-associated vasculitis and gene variants of 11 beta-hydroxysteroid dehydrogenase type 1 and the glucocorticoid receptor
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Janneke Tuin, André P van Beek, Arno C Hessels, Elisabeth F.C. van Rossum, Jan W. Koper, Abraham Rutgers, Coen A. Stegeman, Jan-Stephan F. Sanders, Minke G. Huitema, Groningen Kidney Center (GKC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Translational Immunology Groningen (TRIGR), Groningen Institute for Organ Transplantation (GIOT), and Internal Medicine
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Male ,RELAPSE ,vasculitis ,RECOMMENDATIONS ,0302 clinical medicine ,Glucocorticoid receptor ,Gene Frequency ,11β-hydroxysteroid dehydrogenase type 1 ,11-beta-Hydroxysteroid Dehydrogenase Type 1 ,Genotype ,Pharmacology (medical) ,anti-neutrophil cytoplasm antibody ,genetics ,030212 general & internal medicine ,IN-VIVO ,biology ,microscopic polyangiitis ,Remission Induction ,Middle Aged ,metabolic disease ,Wegener's granulomatosis ,Treatment Outcome ,SURVIVAL ,Female ,epidemiology ,HEALTH ,SENSITIVITY ,Microscopic polyangiitis ,Vasculitis ,Adult ,Prednisolone ,CYCLOPHOSPHAMIDE TREATMENT ,Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis ,HAPLOTYPE ,Polymorphism, Single Nucleotide ,Disease-Free Survival ,03 medical and health sciences ,Receptors, Glucocorticoid ,Rheumatology ,medicine ,Humans ,Glucocorticoids ,Genotyping ,ER22/23EK ,Alleles ,POLYMORPHISMS ,Aged ,Anti-neutrophil cytoplasmic antibody ,030203 arthritis & rheumatology ,business.industry ,Haplotype ,biomarkers ,medicine.disease ,Haplotypes ,Pharmacogenetics ,inflammation ,Immunology ,biology.protein ,business - Abstract
Objectives. We aimed to investigate whether five potential functional haplotypes of the glucocorticoid receptor (GR) gene and a single-nucleotide polymorphism of 11 beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) are associated with clinical outcome in ANCA-associated vasculitis.Methods. Patients diagnosed with ANCA-associated vasculitis (n=241) were genotyped for five polymorphisms of the GR gene and one polymorphism of the HSD11B1 gene. GR gene haplotypes were predicted based on genotyping results. Relapse-free survival, mortality, renal survival, metabolic adverse events and infections were compared between carriers and non-carriers of GR haplotypes and the HSD11B1 genotype.Results. Carriers of haplotype 4 (ER22/23EK + 9 beta+Tthlll1) of GR had a significantly higher 5-year mortality risk [hazard ratio (HR) 4.5 (95% CI 1.6, 12.8)] and had a higher risk of developing end-stage renal disease [HR 7.4 (95% CI 1.9, 28.7)]. Carriers of a minor variant of HSD11B1 more frequently experienced relapse [HR 2.5 (95% CI 1.5, 4.1)] except if they also carried haplotype 1 (Bcll) of GR. Homozygous carriers of haplotype 1 had a higher risk of developing dyslipidaemia [HR 4.1 (95% CI 1.8, 9.6)]. The occurrence of infections did not differ between GR haplotypes and HSD11B1 genotypes.Conclusion. Haplotypes 1 and 4 of GR and a polymorphism of the HSD11B1 gene were associated with clinically relevant inflammatory and metabolic outcomes in ANCA-associated vasculitis.
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- 2019
39. Azathioprine Hypersensitivity Syndrome in a Cohort of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Patients
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Coen A. Stegeman, Annechien J. A. Lambeck, Annick A. J. M. van de Ven, Jan-Stephan F. Sanders, Bart-Jan Kroesen, Abraham Rutgers, Arno C Hessels, Groningen Kidney Center (GKC), Translational Immunology Groningen (TRIGR), and Groningen Institute for Organ Transplantation (GIOT)
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Adult ,Male ,Vasculitis ,medicine.medical_specialty ,Fever ,Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis ,Azathioprine ,Thiopurine methyltransferase ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Interquartile range ,Internal medicine ,medicine ,Humans ,Immunology and Allergy ,030212 general & internal medicine ,Microscopic polyangiitis ,Thiopurines ,Aged ,biology ,ANCA ,Eosinophilic granulomatosis with polyangiitis ,DRUG HYPERSENSITIVITY ,business.industry ,Middle Aged ,medicine.disease ,Hypersensitivity reaction ,030228 respiratory system ,Antirheumatic Agents ,biology.protein ,Prednisolone ,Female ,Granulomatosis with polyangiitis ,Cohort study ,business ,medicine.drug - Abstract
BACKGROUND: Azathioprine hypersensitivity syndrome is a rare complication of azathioprine therapy. Its symptoms resemble infection or relapse of inflammatory disease, hindering correct diagnosis. Current literature is limited to sporadic case reports and reviews.OBJECTIVE: To estimate the incidence of azathioprine hypersensitivity syndrome and describe its characteristics in the context of an observational cohort of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Also, to facilitate early recognition and awareness among clinicians.METHODS: Within a cohort of 290 patients with ANCA-associated vasculitis receiving azathioprine maintenance therapy, frequency of azathioprine hypersensitivity was described and characteristics were compared between hypersensitive and non-hypersensitive patients. Clinical picture, laboratory abnormalities, and concurrent medication of patients with azathioprine hypersensitivity were described.RESULTS: Of 290 patients, 25 (9%) experienced azathioprine hypersensitivity after a median of 14 (interquartile range [IQR] 12-18) days. Frequent symptoms were fever (100%), malaise (60%), arthralgia (36%), and rash (32%). All patients used prednisolone (median 10 mg/day, IQR 9.4-16.3 mg/day) at the time of the hypersensitivity reaction. Most patients had a rise in C-reactive protein (CRP), leukocyte counts, and neutrophil counts, but no eosinophilia. Thiopurine S-methyltransferase (TPMT) activity was significantly lower in hypersensitive patients (median 74.4 [IQR 58.0-80.1] nmol/gHb/L) compared with controls (median 81.4 [71.9-90.5] nmol/gHb/L), P = .01. Hypersensitive patients had a higher risk of relapse (hazard ratio 2.2, 95% confidence interval 1.2-4.2; P=.01).CONCLUSIONS: Azathioprine hypersensitivity syndrome is strikingly common in ANCA-associated vasculitis, might be associated with reduced TPMT activity, is accompanied by an increase in neutrophil counts, and may occur even during concomitant prednisolone therapy. Proper recognition may prevent unnecessary hospital procedures and damage to the patient. (C) 2018 American Academy of Allergy, Asthma & Immunology
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- 2019
40. Urinary and serum soluble CD25 complements urinary soluble CD163 to detect active renal anti-neutrophil cytoplasmic autoantibody-associated vasculitis
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Sarah M Moran, Gerjan J. Dekkema, Coen A. Stegeman, Theo Bijma, Jan-Stephan F. Sanders, Mark A. Little, Louise Ryan, Wayel H. Abdulahad, Peter Heeringa, Translational Immunology Groningen (TRIGR), Groningen Kidney Center (GKC), and Groningen Institute for Organ Transplantation (GIOT)
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CD4-Positive T-Lymphocytes ,Male ,030232 urology & nephrology ,030204 cardiovascular system & hematology ,DISEASE-ACTIVITY ,Gastroenterology ,Cohort Studies ,T-CELL-ACTIVATION ,chemistry.chemical_compound ,0302 clinical medicine ,MARKERS ,IL-2 receptor ,Kidney ,Proteinuria ,soluble CD163 ,Middle Aged ,3. Good health ,medicine.anatomical_structure ,Nephrology ,Female ,Kidney Diseases ,medicine.symptom ,Vasculitis ,Adult ,medicine.medical_specialty ,Urinary system ,Antigens, Differentiation, Myelomonocytic ,Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis ,Enzyme-Linked Immunosorbent Assay ,Receptors, Cell Surface ,ANCA vasculitis ,Sensitivity and Specificity ,Antibodies, Antineutrophil Cytoplasmic ,03 medical and health sciences ,INTERLEUKIN-2-RECEPTOR ,WEGENERS-GRANULOMATOSIS ,Antigens, CD ,Internal medicine ,renal dysfunction ,medicine ,Humans ,NEPHRITIS ,Aged ,Autoantibodies ,Transplantation ,Creatinine ,Cluster of differentiation ,business.industry ,Autoantibody ,Interleukin-2 Receptor alpha Subunit ,medicine.disease ,soluble CD25 ,MAINTENANCE ,chemistry ,ROC Curve ,ANTIBODIES ,business ,Biomarkers ,glomerulonephritis - Abstract
Background. Early detection of renal involvement in anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is of major clinical importance to allow prompt initiation of treatment and limit renal damage. Urinary soluble cluster of differentiation 163 (usCD163) has recently been identified as a potential biomarker for active renal vasculitis. However, a significant number of patients with active renal vasculitis test negative using usCD163. We therefore studied whether soluble CD25 (sCD25), a T cell activation marker, could improve the detection of renal flares in AAV.Methods. sCD25 and sCD163 levels in serum and urine were measured by enzyme-linked immunosorbent assay in 72 patients with active renal AAV, 20 with active extrarenal disease, 62 patients in remission and 18 healthy controls. Urinary and blood CD4(+) T and CD4(+) T effector memory (TEM) cell counts were measured in 22 patients with active renal vasculitis. Receiver operating characteristics (ROC) curves were generated and recursive partitioning was used to calculate whether usCD25 and serumsoluble CD25 (ssCD25) add utility to usCD163.Results. usCD25, ssCD25 and usCD163 levels were significantly higher during active renal disease and significantly decreased after induction of remission. A combination of usCD25, usCD163 and ssCD25 outperformed all individual markers (sensitivity 84.7%, specificity 95.1%). Patients positive for sCD25 but negative for usCD163 (n = 10) had significantly higher C-reactive protein levels and significantly lower serum creatinine and proteinuria levels compared with the usCD163positive patients. usCD25 correlated positively with urinary CD4(+) T and CD4(+) TEM cell numbers, whereas ssCD25 correlated negatively with circulating CD4(+) T and CD4+ TEMcells.Conclusion. Measurement of usCD25 and ssCD25 complements usCD163 in the detection of active renal vasculitis.
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- 2019
41. A paired kidney analysis on the impact of pre-transplant anti-HLA antibodies on graft survival
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Annechien J. A. Lambeck, Maarten H. L. Christiaans, Frans H.J. Claas, Wendy Swelsen, Paul J M van der Boog, Mariëlle A C J Gelens, Marc A. Seelen, Eric Spierings, Caroline Roozendaal, Laura Bungener, Luuk B. Hilbrands, Laura A. Michielsen, Bouke G. Hepkema, Lotte Wieten, N M Lardy, Marije C. Baas, Arjan D. van Zuilen, Sebastiaan Heidt, Karlijn A M I van der Pant, Wil A. Allebes, Arnold van der Meer, Frederike J. Bemelman, Bram W. Wisse, Michiel L. Bots, Ineke J. M. ten Berge, Franka E. van Reekum, Henderikus G. Otten, Cornelis E. Hack, Jan-Stephan F. Sanders, Frans J. van Ittersum, Marcel G.J. Tilanus, Andries J. Hoitsma, Christien Voorter, Dave L. Roelen, Adriaan C.A.D. Drop, Neelke C. van der Weerd, Johan W. de Fijter, Shaikh A. Nurmohamed, Irma Joosten, Loes Plaisier, Marianne C. Verhaar, Elena G. Kamburova, Elizabeth M. van Duijnhoven, Michiel G. H. Betjes, Internal Medicine, Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Interne Geneeskunde, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, MUMC+: DA TI Staf (9), MUMC+: DA TI Laboratorium (9), MUMC+: MA Nefrologie (9), RS: NUTRIM - R3 - Respiratory & Age-related Health, Nephrology, AII - Inflammatory diseases, APH - Aging & Later Life, ACS - Atherosclerosis & ischemic syndromes, ACS - Diabetes & metabolism, and Cardiology
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Nephrology ,Graft Rejection ,Male ,030232 urology & nephrology ,graft survival ,030204 cardiovascular system & hematology ,Gastroenterology ,acute rejection ,Kidney transplantation ,immunology ,0302 clinical medicine ,HLA Antigens ,Isoantibodies ,Medicine ,DONOR-SPECIFIC ANTIBODIES ,Netherlands ,Kidney ,biology ,INDUCTION ,Middle Aged ,HLA antibodies ,BEAD ASSAY ,Tissue Donors ,medicine.anatomical_structure ,surgical procedures, operative ,DP-SPECIFIC ANTIBODIES ,Acute rejection ,Female ,Antibody ,Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5] ,Adult ,Risk ,medicine.medical_specialty ,CLINICAL-RELEVANCE ,kidney transplantation ,Other Research Radboud Institute for Molecular Life Sciences [Radboudumc 0] ,Human leukocyte antigen ,03 medical and health sciences ,Young Adult ,Antigen ,MEDIATED REJECTION ,RISK-FACTOR ,Internal medicine ,Journal Article ,Humans ,Risk factor ,Transplantation ,LOSS EVEN ,business.industry ,Histocompatibility Antigens Class I ,HUMAN-LEUKOCYTE ANTIGEN ,medicine.disease ,RECIPIENTS ,biology.protein ,Renal disorders Radboud Institute for Health Sciences [Radboudumc 11] ,business - 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
42. Renal functional reserve capacity before and after living kidney donation
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Stephan J. L. Bakker, A. Lianne Messchendorp, Stefan P Berger, Niek R. Hessels, Gerjan Navis, Jan-Stephan F. Sanders, Nicolien Kasper, Martin H. de Borst, Marco van Londen, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), and Value, Affordability and Sustainability (VALUE)
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Male ,renal hemodynamics ,Time Factors ,Physiology ,medicine.medical_treatment ,030232 urology & nephrology ,DONORS ,Hemodynamics ,030204 cardiovascular system & hematology ,Kidney ,GLOMERULAR-FILTRATION-RATE ,HYPERFILTRATION ,DOPAMINE ,0302 clinical medicine ,Functional residual capacity ,Risk Factors ,renal functional reserve ,reserve capacity ,Living Donors ,Prospective Studies ,Infusions, Intravenous ,living kidney donation ,glomerular filtration rate ,NEPHRECTOMY ,INFUSION ,Kidney donation ,Middle Aged ,Nephrectomy ,Treatment Outcome ,HEMODYNAMICS ,Female ,Adult ,medicine.medical_specialty ,Urology ,Renal function ,TERM ,Risk Assessment ,Donor Selection ,MECHANISMS ,03 medical and health sciences ,Predictive Value of Tests ,medicine ,Humans ,Renal hemodynamics ,Renal response ,urogenital system ,business.industry ,Kidney Transplantation ,Reserve capacity ,business - Abstract
Compensatory gomerular filtration rate (GFR) increase after kidney donation results in a GFR above 50% of the predonation value. The renal functional reserve (RFR) assessed by the renal response to dopamine infusion (RFRdopa) is considered to reflect functional reserve capacity and is thought to be a tool for living donor screening. However, it is unknown if the RFRdopapredicts long-term kidney function. Between 1984 and 2017, we prospectively measured GFR (125I-iothalamate) and RFR by dopamine infusion in 937 living kidney donors. We performed linear regression analysis of predonation RFRdopaand postdonation GFR. In donors with 5-yr follow-up after donation we assessed the association with long-term GFR. Mean donor age was 52 yr (SD 11); 52% were female. Mean predonation GFR was 114 ml/min (SD 22), GFRdopawas 124 ml/min (SD 24), resulting in an RFR of 9 ml/min (SD 10). Three months postdonation, GFR was 72 ml/min (SD 15) and GFRdopawas 75 ml/min (SD 15), indicating that donors still had RFRdopa[3 ml/min (SD 6), P < 0.001]. Predonation RFRdopawas not associated with predonation GFR [standardized (st.) β −0.009, P = 0.77] but was positively associated with GFR 3 mo after donation (st. β 0.12, P < 0.001). In the subgroup of donors with 5-yr follow-up data ( n = 383), RFRdopawas not associated with GFR at 5 yr postdonation (st. β 0.05, P = 0.35). In conclusion, RFRdopais a predictor of short-term GFR after living kidney donation but not of long-term kidney function. Therefore, measurement of the RFRdopais not a useful tool for donor screening. Studies investigating long-term renal adaptation are warranted to study the effects of living kidney donation and improve donor screening.
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- 2018
43. Gut Microbiome Dysbiosis is Associated with Increased Mortality following Solid Organ Transplantation
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Jingyuan Fu, Tim J Knobbe, Alexander Kurilshikov, Rianne M Douwes, António W Gomes-Neto, Michele F Eisenga, Collij, Bernadien H. Jansen, Arnau Vich Vila, Johannes R. Björk, Adrian Post, Jan-Stephan F. Sanders, Stephan J. L. Bakker, Hermie J. M. Harmsen, Cuperus F, Daan Kremer, Meijer Vd, Alexandra Zhernakova, Hans Blokzijl, M. Heiner-Fokkema, Ranko Gacesa, Marjolein A Y Klaassen, Rinse K. Weersma, Robert J. Porte, E Festen, Cisca Wijmenga, Swarte Jc, Li Y, Hu S, and Stefan P Berger
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business.industry ,Immunology ,Medicine ,business ,medicine.disease ,Solid organ transplantation ,Dysbiosis ,Gut microbiome - Abstract
Organ transplantation is a life-saving treatment for patients with end-stage disease, but survival post-transplantation varies considerably. There is now increasing evidence that the gut microbiome is linked to the survival of hematopoietic cell transplant patients, yet little is known about the role of the gut microbiome in solid organ transplantation. We analyzed 1,370 fecal samples from liver and renal transplant recipients using shotgun metagenomic sequencing to assess microbial taxonomy, metabolic pathways, antibiotic resistance genes and virulence factors. To quantify taxonomic and metabolic dysbiosis, we analyzed 1,183 age-, sex- and BMI-matched subjects from the same population. A subset of patients were also followed longitudinally from pre- to post-transplantation. Our data show that transplant recipients suffer from gut dysbiosis—including lower microbial diversity, increased abundance of unhealthy microbial species, decreased abundance of important metabolic pathways, and increased prevalence and diversity of antibiotic resistant genes and virulence factors—that persist up to 20 years post-transplantation. Finally, we demonstrate that the use of immunosuppressive drugs is significantly associated with the observed dysbiosis and that the extent of dysbiosis is associated with increased post-transplant mortality.
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- 2021
44. The RECOVAC IR study
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RECOVAC Collaborators, M.M.L. (Marcia) Kho, M.E.J. (Marlies) Reinders, C.C. (Carla) Baan, Debbie van Baarle, F. J. Bemelman, Dimitri A. Diavatopoulos, Ron T. Gansevoort, Fiona R.M. van der Klis, M.P.G. (Marion) Koopmans, A. Lianne Messchendorp, RG van der Molen, Ester B.M. Remmerswaal, Nynke Rots, Priya Vart, R.D. (Rory) de Vries, Luuk B. Hilbrands, Jan Stephan F. Sanders, RECOVAC Collaborators, M.M.L. (Marcia) Kho, M.E.J. (Marlies) Reinders, C.C. (Carla) Baan, Debbie van Baarle, F. J. Bemelman, Dimitri A. Diavatopoulos, Ron T. Gansevoort, Fiona R.M. van der Klis, M.P.G. (Marion) Koopmans, A. Lianne Messchendorp, RG van der Molen, Ester B.M. Remmerswaal, Nynke Rots, Priya Vart, R.D. (Rory) de Vries, Luuk B. Hilbrands, and Jan Stephan F. Sanders
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- 2021
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45. Ischemia and reperfusion injury in kidney transplantation: Relevant mechanisms in injury and repair
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Stefan P Berger, Michel Struys, Henri G. D. Leuvenink, Rutger J. Ploeg, Gertrude J. Nieuwenhuijs-Moeke, Søren Erik Pischke, Robert A. Pol, and Jan-Stephan F. Sanders
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Necrosis ,030232 urology & nephrology ,Ischemia ,lcsh:Medicine ,kidney transplantation ,innate immune system ,Review ,Bioinformatics ,ANTIBODY-MEDIATED REJECTION ,DENDRITIC CELLS ,endothelial dysfunction ,necrosis ,DELAYED GRAFT FUNCTION ,delayed graft ,03 medical and health sciences ,0302 clinical medicine ,delayed graft function ,adaptive immune system ,Medicine and Health Sciences ,medicine ,HYPOXIA-INDUCIBLE FACTOR-1-ALPHA ,REGULATORY T-CELLS ,Endothelial dysfunction ,IN-VIVO ,Kidney transplantation ,030304 developmental biology ,ischemia reperfusion injury ,function ,MESENCHYMAL TRANSITION ,RECEPTOR 4 ,0303 health sciences ,IMMUNE-RESPONSES ,business.industry ,urogenital system ,lcsh:R ,apoptosis ,hypoxic inducible factor ,General Medicine ,medicine.disease ,Acquired immune system ,Pathophysiology ,Transplantation ,ANTIBODY-MEDIATED ,REJECTION ,INNATE IMMUNITY ,medicine.symptom ,business ,Reperfusion injury - Abstract
Ischemia and reperfusion injury (IRI) is a complex pathophysiological phenomenon, inevitable in kidney transplantation and one of the most important mechanisms for non- or delayed function immediately after transplantation. Long term, it is associated with acute rejection and chronic graft dysfunction due to interstitial fibrosis and tubular atrophy. Recently, more insight has been gained in the underlying molecular pathways and signalling cascades involved, which opens the door to new therapeutic opportunities aiming to reduce IRI and improve graft survival. This review systemically discusses the specific molecular pathways involved in the pathophysiology of IRI and highlights new therapeutic strategies targeting these pathways.
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- 2020
46. Prolonged Organ Extraction Time Negatively Impacts Kidney Transplantation Outcome
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Hanno Maassen, Henri G. D. Leuvenink, Harry van Goor, Jan-Stephan F. Sanders, Robert A. Pol, Cyril Moers, H. Sijbrand Hofker, University of Groningen, Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), and Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE)
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RISK ,Transplantation ,kidney ,Tissue and Organ Procurement ,Kidney Transplantation/methods ,Graft Survival ,Delayed Graft Function ,ISCHEMIA-REPERFUSION INJURY ,Kidney Transplantation ,DECEASED DONORS ,Tissue Donors ,Risk Factors ,COLD ISCHEMIA ,extraction ,nephrectomy ,Humans ,transplantation outcome ,time ,STORAGE - Abstract
Main Problem: Following cold aortic flush in a deceased organ donation procedure, kidneys never reach the intended 0–4°C and stay ischemic at around 20°C in the donor’s body until actual surgical retrieval. Therefore, organ extraction time could have a detrimental influence on kidney transplant outcome.Materials and Methods: We analyzed the association between extraction time and kidney transplant outcome in multicenter data of 5,426 transplant procedures from the Dutch Organ Transplantation Registry (NOTR) and 15,849 transplant procedures from the United Network for Organ Sharing (UNOS).Results: Extraction time was grouped per 10-min increment. In the NOTR database, extraction time was independently associated with graft loss [HR 1.027 (1.004–1.050); p = 0.022] and with DGF [OR 1.043 (1.021–1.066); p < 0.005]. An extraction time >80 min was associated with a 27.4% higher hazard rate of graft failure [HR 1.274 (1.080–1.502); p = 0.004] and such kidneys had 43.8% higher odds of developing DGF [OR 1.438, (1.236–1.673); p < 0.005]. In the UNOS database, increasing extraction times in DCD donors were associated with DGF [OR 1.036 (1.016–1.055); p < 0.005]. An extraction time >30 min was associated with 14.5% higher odds of developing DGF [OR 1.145 (1.063–1.233); p < 0.005].Discussion: Prolonged kidney extraction time negatively influenced graft survival in Dutch donors and increased DGF risk in all deceased donor recipients.
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- 2022
47. Mycophenolic acid and 6-mercaptopurine both inhibit B-cell proliferation in granulomatosis with polyangiitis patients, whereas only mycophenolic acid inhibits B-cell IL-6 production
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Coen A. Stegeman, Abraham Rutgers, Anouk von Borstel, Wayel H. Abdulahad, Peter Heeringa, Gerjan J. Dekkema, Jan-Stephan F. Sanders, Johanna Veldman, Translational Immunology Groningen (TRIGR), Groningen Kidney Center (GKC), and Groningen Institute for Organ Transplantation (GIOT)
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Male ,B Cells ,AZATHIOPRINE ,Physiology ,medicine.medical_treatment ,Azathioprine ,Pharmacology ,White Blood Cells ,0302 clinical medicine ,Animal Cells ,Immune Physiology ,CYCLOPHOSPHAMIDE ,Medicine and Health Sciences ,VASCULITIS ,Lymphocytes ,Innate Immune System ,B-Lymphocytes ,Multidisciplinary ,biology ,Chemistry ,Mercaptopurine ,Drugs ,Middle Aged ,Flow Cytometry ,Immunosuppressives ,medicine.anatomical_structure ,Cytokine ,Medicine ,Cytokines ,Female ,Cellular Types ,Granulomatosis with polyangiitis ,Immunosuppressive Agents ,medicine.drug ,Research Article ,Adult ,Cyclophosphamide ,Science ,Immune Cells ,Immunology ,B-Lymphocyte Subsets ,Mycophenolic acid ,Autoimmune Diseases ,03 medical and health sciences ,medicine ,Humans ,RITUXIMAB ,Wegener Granulomatosis ,Interleukin 6 ,Antibody-Producing Cells ,B cell ,Aged ,Cell Proliferation ,030203 arthritis & rheumatology ,Blood Cells ,Interleukin-6 ,Granulomatosis with Polyangiitis ,Biology and Life Sciences ,Cell Biology ,Molecular Development ,Mycophenolic Acid ,medicine.disease ,Memory B cells ,Immune System ,biology.protein ,Clinical Immunology ,AUTOANTIBODIES ,Clinical Medicine ,Ex vivo ,030215 immunology ,Developmental Biology - Abstract
Granulomatosis with polyangiitis (GPA) is an autoimmune disease affecting mainly small blood vessels. B-cells are important in the GPA pathogenesis as precursors of autoantibody-producing cells but likely also contribute (auto)antibody-independently. This has been underlined by the effectiveness of B-cell-depletion (with Rituximab) in inducing and maintaining disease remission. Mycophenolate-mofetil (MMF) and azathioprine (AZA) are immunosuppressive therapies frequently used in GPA-patients. Interestingly, MMF-treated GPA-patients are more prone to relapses than AZA-treated patients, while little is known about the influence of these drugs on B-cells. We investigated whether MMF or AZA treatment (or their active compounds) alters the circulating B-cell subset distribution and has differential effects on in vitro B-cell proliferation and cytokine production in GPA-patients that might underlie the different relapse rate. Circulating B-cell subset frequencies were determined in samples from AZA-treated (n = 13), MMF-treated (n = 12), untreated GPA-patients (n = 19) and matched HCs (n = 41). To determine the ex vivo effects of the active compounds of MMF and AZA, MPA and 6-MP respectively, on B-cell proliferation and cytokine production, PBMCs of untreated GPA-patients (n = 29) and matched HCs (n = 30) were cultured for 3-days in the presence of CpG-oligodeoxynucleotides (CpG) with MPA or 6-MP. After restimulation (with phorbol myristate acetate, calcium-ionophore), cytokine-positive B-cell frequencies were measured. Finally, to assess the effect of MMF or AZA treatment on in vitro B-cell proliferation and cytokine production, PBMCs of MMF-treated (n = 18), and AZA-treated patients (n = 28) and HCs (n = 41) were cultured with CpG. The memory B-cell frequency was increased in AZA- compared to MMF-treated patients, while no other subset was different. The active compounds of MMF and AZA showed in vitro that MPA decreased B-cell proliferation in GPA-patients and HCs. B-cell proliferation in MMF- and AZA-treated patients was not different. Finally, the IL-6+ B-cell frequency was decreased by MPA compared to 6-MP. No differences in IL-10+, IL-6+ or TNFα+ B-cell proportions or proliferation were found in MMF- and AZA-treated patients. Our results indicate that MMF could be superior to AZA in inhibiting B-cell cytokine production in GPA-patients. Future studies should assess the effects of these immunosuppressive drugs on other immune cells to elucidate mechanisms underlying the potential differences in relapse rates.
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- 2020
48. Antibodies against ARHGDIB are associated with long-term kidney graft loss
- Author
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Karlijn A M I van der Pant, Michiel G. H. Betjes, Elena G. Kamburova, Irma Joosten, Jan-Stephan F. Sanders, Laura Bungener, Henny G. Otten, Bram W. Wisse, Adriaan C.A.D. Drop, Elly M. van Duijnhoven, Franka E. van Reekum, Maartje L Gruijters, Mariëlle A C J Gelens, Maarten H. L. Christiaans, Wendy Swelsen, Marc A. Seelen, Sebastiaan Heidt, Johan W. de Fijter, Cornelis E. Hack, Shaikh A. Nurmohamed, Michiel L. Bots, Loes Plaisier, Frederike J. Bemelman, Annechien J. A. Lambeck, Luuk B. Hilbrands, Bouke G. Hepkema, Arjan D. van Zuilen, Frans J. van Ittersum, Andries J. Hoitsma, Neelke C. van der Weerd, Marianne C. Verhaar, Frans H.J. Claas, Eric Spierings, N M Lardy, Paul J M van der Boog, Marije C. Baas, Arnold van der Meer, Tineke Kardol-Hoefnagel, Ineke J. M. ten Berge, Dave L. Roelen, Marcel G.J. Tilanus, Wil A. Allebes, Lotte Wieten, Rowena C A Melchers, Caroline Roozendaal, Christina E.M. Voorter, Nephrology, ACS - Atherosclerosis & ischemic syndromes, ACS - Diabetes & metabolism, AII - Inflammatory diseases, Cardiology, APH - Aging & Later Life, Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Interne Geneeskunde, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, MUMC+: DA TI Staf (9), MUMC+: DA TI Laboratorium (9), MUMC+: MA Nefrologie (9), RS: NUTRIM - R3 - Respiratory & Age-related Health, Oral and Maxillofacial Surgery, Erasmus MC other, and Internal Medicine
- Subjects
Graft Rejection ,Male ,ARHGDIB ,030230 surgery ,Gastroenterology ,Postoperative Complications ,0302 clinical medicine ,rho Guanine Nucleotide Dissociation Inhibitor beta ,HLA Antigens ,Isoantibodies ,Risk Factors ,Living Donors ,Immunology and Allergy ,Pharmacology (medical) ,Kidney transplantation ,education.field_of_study ,Kidney ,biology ,Graft Survival ,Hazard ratio ,PRETRANSPLANT SENSITIZATION ,Clinical Science ,Middle Aged ,Prognosis ,non-HLA antibodies ,TARGET ,medicine.anatomical_structure ,REJECTION ,II TYPE-1 RECEPTOR ,Original Article ,Female ,Antibody ,non‐HLA antibodies ,Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5] ,Adult ,medicine.medical_specialty ,Population ,kidney transplantation ,Other Research Radboud Institute for Molecular Life Sciences [Radboudumc 0] ,ANTIGENS ,03 medical and health sciences ,RISK-FACTOR ,Internal medicine ,medicine ,Journal Article ,Humans ,Clinical significance ,education ,Autoantibodies ,Retrospective Studies ,Transplantation ,IDENTIFICATION ,business.industry ,Autoantibody ,medicine.disease ,PHOSPHOLIPASE-A2 RECEPTOR ,biology.protein ,Kidney Failure, Chronic ,Renal disorders Radboud Institute for Health Sciences [Radboudumc 11] ,ORIGINAL ARTICLES ,business ,Follow-Up Studies - Abstract
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., From a multicenter evaluation of kidney transplants, the authors report that the pretransplant presence of autoantibodies against ARHGDIB are associated with long‐term graft loss in recipients transplanted with a deceased donor kidney, independent from donor‐specific HLA antibodies.
- Published
- 2019
49. Renal scintigraphy for post-transplant monitoring after kidney transplantation
- Author
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Stefan P Berger, Stan Benjamens, Jan-Stephan F. Sanders, Robert A. Pol, Riemer H. J. A. Slart, Andor W. J. M. Glaudemans, Groningen Institute for Organ Transplantation (GIOT), Translational Immunology Groningen (TRIGR), Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Groningen Kidney Center (GKC), and Cardiovascular Centre (CVC)
- Subjects
medicine.medical_specialty ,Procedural approach ,030232 urology & nephrology ,MEDLINE ,Cochrane Library ,ACUTE REJECTION ,Renal scintigraphy ,RENOGRAPHY ,030218 nuclear medicine & medical imaging ,Diagnostic modalities ,RESISTANCE INDEX ,DELAYED GRAFT FUNCTION ,03 medical and health sciences ,Postoperative Complications ,0302 clinical medicine ,medicine ,Humans ,UROLOGICAL COMPLICATIONS ,Radionuclide Imaging ,Intensive care medicine ,Acute tubular necrosis ,Kidney transplantation ,ULTRASOUND ,Transplantation ,business.industry ,ARTERY STENOSIS ,TC-99M DTPA ,medicine.disease ,Kidney Transplantation ,n/a OA procedure ,Post transplant ,ACUTE TUBULAR-NECROSIS ,ALLOGRAFT DYSFUNCTION ,business - Abstract
Background: Clinicians use several diagnostic modalities to recognize post-transplant complications, such as acute tubular necrosis, acute rejection, urologic and vascular complications. Currently, there is no consensus about the best procedural approach to evaluate post-transplant renal dysfunction. Renal needle-biopsy is often required, however, this is invasive and may lead to sample errors and complications, and most clinicians prefer using one of the noninvasive diagnostic modalities.Methods: A systematic literature search was performed using PubMed, EMBASE, the Cochrane Library, MEDLINE (OvidSP), Web of Science, and Google Scholar to identify relevant articles. This review provides a literature overview of the technical aspects, new developments and clinical value of renal scintigraphy (RS), after kidney transplantation. Additionally, the advantages and limitations of RS in comparison to other diagnostic modalities are addressed. The study protocol is registered with PROSPERO, protocol number CRD42017078391.Results: A total of 32 studies were included. Studies were categorized in the following groups: tracer pharmacokinetics; acute rejection and acute tubular necrosis; vascular complications; urological complications; postoperative fluid collections; early transplant outcomes; one-year transplant outcomes.Conclusions: Several studies have described the use of RS for the diagnosis of acute rejection, however, differentiating between rejection and acute tubular necrosis remains difficult. For the diagnosis of vascular complications, RS has been described as an alternative for invasive procedures. For urologic complications, studies support the use of RS in combination with routine ultrasonography (US) surveillance. For the diagnosis of postoperative fluid collections, RS provides information to differentiate lymphoceles and urinomas. Altogether, RS should be considered in case of non-acute complications, and if US provides insufficient results. (C) 2017 Elsevier Inc. All rights reserved.
- Published
- 2018
50. Cellular immune regulation in the pathogenesis of ANCA-associated vasculitides
- Author
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Jan-Stephan F. Sanders, Coen A. Stegeman, Wayel H. Abdulahad, Anouk von Borstel, Abraham Rutgers, and Peter Heeringa
- Subjects
0301 basic medicine ,Lymphocyte ,viruses ,T regulatory cells ,Immunology ,Vasculitides ,Inflammation ,Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis ,Disease pathogenesis ,ANCA-Associated Vasculitides ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Immunology and Allergy ,Humans ,Immunity, Cellular ,business.industry ,ANCA ,Autoantibody ,Immune regulation ,B regulatory cells ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,medicine.symptom ,business ,030215 immunology - Abstract
Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) are systemic autoimmune diseases characterized by necrotizing inflammation of small- to medium-sized blood vessels, affecting primarily the lungs and kidneys. Both animal and human studies show that the balance between inflammatory- and regulatory T- and B cells determines the AAV disease pathogenesis. Recent evidence shows malfunctioning of the regulatory lymphocyte compartment in AAV. In this review we summarize the immune regulatory properties of both T- and B cells in patients with AAV and discuss how aberrations herein might contribute to the disease pathogenesis.
- Published
- 2018
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