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... Show moreKidney 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. Show less
Dreyer, G.J.; Drabbels, J.J.M.; Fijter, J.W. de; Kooten, C. van; Reinders, M.E.J.; Heidt, S. 2023
IntroductionMesenchymal stromal cell (MSC) therapy is a promising treatment that allows for drug minimization in clinical kidney transplantation. While it is thought that MSCs rapidly go into... Show moreIntroductionMesenchymal stromal cell (MSC) therapy is a promising treatment that allows for drug minimization in clinical kidney transplantation. While it is thought that MSCs rapidly go into apoptosis after infusion, clinical evidence for this is scarce since methods to detect cell death of infused cells in vivo are lacking. Cell-free DNA (cfDNA) has recently gained attention as a biomarker for cell death.MethodsIn this study, we longitudinally measured cfDNA in plasma samples of the recipient, kidney donor, and allogeneic third-party MSC in the context of the Neptune study. cfDNA levels were measured at several time points before and after allogeneic MSC infusion in the 10 recipients who participated in the Neptune study. cfDNA ratios between the recipient, kidney graft, and MSC were determined.ResultsWe observed a peak in MSC-derived cfDNA 4 h after the first and second infusions, after which MSC-derived cfDNA became undetectable. Generally, kidney graft-derived cfDNA remained in the baseline-level range.DiscussionOur results support preclinical data that MSC are short-lived after infusion, also in a clinical in vivo setting, and are relevant for further research into the mechanism of action of MSC therapy. Show less
Hendriks, S.H.; Heidt, S.; Schulz, A.R.; Fijter, J.W. de; Reinders, M.E.J.; Koning, F.; Kooten, C. van 2023
Tacrolimus is the backbone of immunosuppressive agents to prevent transplant rejection. Paradoxically, tacrolimus is nephrotoxic, causing irreversible tubulointerstitial damage. Therefore, infusion... Show moreTacrolimus is the backbone of immunosuppressive agents to prevent transplant rejection. Paradoxically, tacrolimus is nephrotoxic, causing irreversible tubulointerstitial damage. Therefore, infusion of mesenchymal stromal cells (MSC) 6 and 7 weeks post-transplantation was assessed to facilitate withdrawal of tacrolimus in the randomized phase II TRITON trial. Here, we performed detailed analysis of the peripheral blood immune composition using mass cytometry to assess potential effects of MSC therapy on the immune system. We developed two metal-conjugated antibody panels containing 40 antibodies each. PBMC samples from 21 MSC-treated patients and 13 controls, obtained pre-transplant and at 24 and 52 weeks post-transplantation, were analyzed. In the MSC group at 24 weeks, 17 CD4(+) T cell clusters were increased of which 14 Th2-like clusters and three Th1/Th2-like clusters, as well as CD4+FoxP3+ Tregs. Additionally, five B cell clusters were increased, representing either class switched memory B cells or proliferating B cells. At 52 weeks, CCR7(+)CD38(+) mature B cells were decreased. Finally, eight Tc1 (effector) memory cytotoxic T cell clusters were increased. Our work provides a comprehensive account of the peripheral blood immune cell composition in kidney transplant recipients after MSC therapy and tacrolimus withdrawal. These results may help improving therapeutic strategies using MSCs with the aim to reduce the use of calcineurin inhibitors. Show less
Recently, the randomized phase-II Triton study demonstrated that mesenchymal stromal cell (MSC) therapy facilitated early tacrolimus withdrawal in living donor kidney transplant recipients. The... Show moreRecently, the randomized phase-II Triton study demonstrated that mesenchymal stromal cell (MSC) therapy facilitated early tacrolimus withdrawal in living donor kidney transplant recipients. The current sub-study analyzed formation of de novo donor-specific HLA antibodies (dnDSA) in the context of the degree of HLA eplet mismatches. At the time of protocol biopsy at 6 months, 7/29 patients (24%) in the MSC group and 1/27 patient (3.7%) in the control group had developed dnDSA. In the MSC group, all dnDSA were antiHLA-DQ; two patients had anti-DQ alone and five patients combined with anti-class I, HLA-DR or-DP. Despite excess dnDSA formation in the MSC-arm of the study, the evolution of eGFR (CKD-EPI) and proteinuria were comparable 2 years posttransplant. All dnDSA were complement-binding and three patients had antibody-mediated rejection in the protocol biopsy, but overall rejection episodes were not increased. Everolimus had to be discontinued in nine patients because of toxicity, and tacrolimus was reintroduced in six patients because of dnDSA formation. The HLA-DQ eplet mismatch load independently associated with dnDSA (adjusted hazard ratio = 1.07 per eplet mismatch, p = 0.008). A threshold of >= 11 HLA-DQ eplet mismatches predicted subsequent dnDSA in all 11 patients in the MSC group, but specificity was low (44%). Further research is warranted to explore HLA molecular mismatch load as a biomarker to guide personalized maintenance immunosuppression in kidney transplantation. Show less
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... Show moreBackground 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 mu g mRNA-1273, 2 x 100 mu g mRNA-1273, or Ad26.COV2-S vaccination. In addition, 103 KTRs receiving 100 mu g 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 x 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 -0middot4% (-16 to 15; p=0middot96) for 2 x mRNA-1273 and -6% (-21 to 10; p=0middot49) 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=0middot15). 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; p<0middot0001). No acute rejection occurred. There were no serious adverse events related to vaccination.Interpretation 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.Copyright (c) 2022 Elsevier Ltd. All rights reserved. Show less
BackgroundAutologous bone marrow–derived mesenchymal stromal cell (MSC) therapy and withdrawal of calcineurin inhibitors (CNIs) has been shown to improve systemic blood pressure control and left ve...Show moreBackgroundAutologous bone marrow–derived mesenchymal stromal cell (MSC) therapy and withdrawal of calcineurin inhibitors (CNIs) has been shown to improve systemic blood pressure control and left ventricular hypertrophy regression in kidney transplant recipients. In the current subanalysis, we aimed to evaluate the impact of this novel immunosuppressive regimen on the longitudinal changes of left atrial (LA) structure and function after kidney transplantation.MethodsKidney transplant recipients randomized to MSC therapy—infused at weeks 6 and 7 after transplantation, with complete discontinuation at week 8 of tacrolimus (MSC group)—or standard tacrolimus dose (control group) were evaluated with transthoracic echocardiography at weeks 4 and 24 after kidney transplantation. The changes in echocardiographic parameters were compared between the randomization arms using an analysis of covariance model adjusted for baseline variable.ResultsFifty-four participants (MSC therapy = 27; tacrolimus therapy = 27) were included. There was no significant interaction between the allocated treatment and the changes of indexed maximal LA volume (LAVImax) over the study period. Conversely, between 4 and 24 weeks post-transplantation, an increase in indexed minimal LA volume (LAVImin) was observed in control subjects, while it remained unchanged in the MSC group, leading to a significant difference between groups (P = .021). Additionally, patients treated with MSC therapy showed a benefit in LA function, assessed by a significant interaction between changes in LA emptying fraction and LA reservoir strain and the randomization arm (P = .012 and P = .027, respectively).ConclusionsThe combination of MSC therapy and CNIs withdrawal prevents progressive LA dilation and dysfunction in the first 6 months after kidney transplantation. LAVImin and LA reservoir strain may be more sensitive markers of LA reverse remodeling, compared with LAVImax. Show less
For medical students, the transition from the preclinical to the clinical phase of their curriculum (clerkships) can result in increased levels of stress and anxiety. This is partly caused by low... Show moreFor medical students, the transition from the preclinical to the clinical phase of their curriculum (clerkships) can result in increased levels of stress and anxiety. This is partly caused by low self-perception of preparedness. By using 360 & DEG; video-based virtual reality it is possible to provide learners virtual access to clinical situations ahead of time. This technique can provide active and contextual user experiences and offers opportunities to demonstrate both behavioral skills and subject knowledge. We developed two 360 & DEG; video-based virtual reality applications for medical students transitioning to the clerkships. In this study, we describe the development and evaluated the user experiences. Two virtual reality applications were developed for use in a small group learning session. One of the applications is an interactive virtual tour of a hospital ward, in which learners explore the Internal Medicine ward and learn about the roles of different health care professionals and their mutual interactions. In each room, the learners listen to a voice-over and look at hotspots to gather additional information. The other application has been developed to train students in observing (un)professional behavior of healthcare providers in their daily activities. An evaluation was performed by an anonymous explorative questionnaire with open and closed questions (Likert scales) regarding the user experience and cybersickness symptoms. In our study, 171 students used the applications and completed the questionnaire. For 63% of the respondents, this was their first experience with a virtual reality headset. Qualitative analysis showed that students evaluated the learning method as realistic, informative and enjoyable. Most students evaluated virtual reality as a good (59%) or excellent (26%) tool for learning. Forty-five percent of the students experienced physical discomfort, such as nausea, dizziness, headache and disorientation. In most cases, these complaints were mild, although a small number experienced severe nausea (n = 6) or severe headache (n = 2). Students suggested several areas of improvement including increase of display resolution and decrease of ambient noise causing distraction. 360 & DEG; video-based virtual reality can successfully be implemented in the medical curriculum to create a realistic learning experience to prepare students for the clerkships. Show less
Background: The impact of donor-specific antibodies (DSA) in (highly-) immunized living donor kidney transplant recipients is reported differentially in various patient cohorts. Methods: We have... Show moreBackground: The impact of donor-specific antibodies (DSA) in (highly-) immunized living donor kidney transplant recipients is reported differentially in various patient cohorts. Methods: We have performed a retrospective analysis of all consecutive HLA-incompatible living donor kidney transplant recipients in our center between 2010-2019. Recipients who underwent plasmafiltration for a positive CDC-crossmatch were excluded. For each DSA+ recipient (DSA+), one immunized recipient without DSA (pPRA+) and two non-immunized recipients (pPRA-) were included. Patient and graft survival were analyzed and a subgroup analysis of DSA+ recipients was performed. Results: For 63 DSA+ recipients, 63 PRA+ and 126 PRA- recipients were included. 26 (41%) had class I, 24 (38%) class II and 13 (21%) combined HLA class I and II DSA. Death-censored graft survival was inferior in DSA+ recipients compared to pPRA+ (HR 2.38 [95% CI 1.00-5.70]) as well as to pPRA- (HR 3.91 [1.86-8.22]). In multivariate analysis, DSA remained of negative influence on death-censored graft survival. Flowcytometric crossmatch, MFI value, HLA class and origin of DSA were not of significant impact. Conclusion: In our cohort of (highly-) immunized recipients, pretransplant DSA led to inferior death-censored graft survival. There were no "safe" DSA characteristics since only DSA per se impacted death-censored graft survival. Show less
AimAlemtuzumab is a monoclonal antibody used as induction immunosuppressive therapy in kidney transplantation. It targets CD52 on lymphocytes, inducing profound immune cell depletion upon... Show moreAimAlemtuzumab is a monoclonal antibody used as induction immunosuppressive therapy in kidney transplantation. It targets CD52 on lymphocytes, inducing profound immune cell depletion upon administration. Owing to its off-label status in kidney transplantation, its pharmacokinetic characteristics are largely unknown in this setting, and its current fixed dosing algorithm originates from other populations. We developed a population pharmacokinetic model for alemtuzumab in kidney transplant recipients and investigated the potential of personalized alemtuzumab therapy. MethodsIn total, 362 pharmacokinetic observations drawn 0-165 days after transplantation were available from 61 adult kidney transplant recipients who received two consecutive doses of 15 mg alemtuzumab subcutaneously. A population pharmacokinetic model was developed using nonlinear mixed-effects modelling and applied to simulate various dosing regimens. ResultsThe alemtuzumab concentration-time data were best described by a two-compartmental model with first-order absorption and parallel first-order and time-varying concentration-dependent elimination, with between-subject variability on the first-order elimination (39.6%) and central distribution volume (39.6%). Alemtuzumab pharmacokinetics varied with body size, rendering lighter individuals exposed to lympholytic alemtuzumab concentrations (>0.1 mg/L) for prolonged durations as compared to their heavier peers. This between-subject variability could be reduced through lean bodyweight-adjusted dosing, showing a twofold to threefold reduction in the slope of the median alemtuzumab exposure over the bodyweight range. ConclusionAlemtuzumab displays substantial pharmacokinetic variability in kidney transplant recipients, which may warrant a personalized treatment strategy. Lean bodyweight-adjusted dosing poses an option for individualized dosing, but further evaluation of its potential clinical benefit is warranted. Show less
Background: Clinical workplace learning takes place in a dynamic and complex learning environment that is designated as a site for patient care and education. Challenges in clinical training can be... Show moreBackground: Clinical workplace learning takes place in a dynamic and complex learning environment that is designated as a site for patient care and education. Challenges in clinical training can be overcome by implementing blended learning, as it offers flexible learning programs suitable for student-centered learning, web-based collaboration, and peer learning. Objective: The aim of this study is to evaluate the Small Private Online Course (SPOC) by interns' first impressions and satisfaction measures (N=20) on using the SPOC. This study describes the design process of a SPOC from a theoretical and practical perspective and how it has been integrated into a clinical internship in internal medicine. Methods: The design of the SPOC was based on general theoretical principles that learning should be constructive, contextual, collaborative, and self-regulated, and the self-determination theory to stimulate intrinsic motivation. Interns' impressions and level of satisfaction were evaluated with a web-based questionnaire and group interview. Results: Interns thought the web-based learning environment to be a useful and accessible alternative to improve knowledge and skills. Peer learning and web-based collaboration through peer interaction was perceived as less effective, as student feedback was felt inferior to teacher feedback. The interns would prefer more flexibility within the course, which could improve self-regulated learning and autonomy. Conclusions: The evaluation shows that the SPOC is a useful and accessible addition to the clinical learning environment, providing an alternative opportunity to improve knowledge and skills. Further research is needed to improve web-based collaboration and interaction in our course. Show less
Over the past decade, high HLA epitope mismatch scores have been associated with inferior transplant outcomes using several tools, of which HLAMatchmaker is most well-known. This software uses... Show moreOver the past decade, high HLA epitope mismatch scores have been associated with inferior transplant outcomes using several tools, of which HLAMatchmaker is most well-known. This software uses theoretically defined polymorphic amino acid configurations, called eplets, for HLA compatibility analysis. Although consideration of eplet mismatch loads has potential for immunological risk stratification of transplant patients, the use of eplet matching in organ allocation algorithms is hindered by lacking knowledge of the immunogenicity of individual eplets, and the possibility that single mismatched amino acids, rather than complete eplets, are responsible for HLA antibody induction.There are several approaches to define eplet immunogenicity, such as antibody verification of individual eplets, and data-driven approaches using large datasets that correlate specific eplet mismatches to donor specific antibody formation or inferior transplant outcomes. Data-driven approaches can also be used to define whether single amino acid mismatches may be more informative than eplet mismatches for predicting HLA antibody induction.When using epitope knowledge for the assignment of unacceptable antigens, it important to realize that alleles sharing an eplet to which antibodies have formed are not automatically all unacceptable since multiple contact sites determine the binding strength and thus biological function and pathogenicity of an antibody, which may differ between reactive alleles.While the future looks bright for using HLA epitopes in clinical decision making, major steps need to be taken to make this a clinical reality.(c) 2021 The Author(s). Published by Elsevier Inc. on behalf of American Society for Histocompatibility and Immunogenetics. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/). Show less
Background: COVID-19 is associated with increased morbidity and mortality in patients with chronic kidney disease (CKD) stages G4-G5, on dialysis or after kidney transplantation (kidney replacement... Show moreBackground: COVID-19 is associated with increased morbidity and mortality in patients with chronic kidney disease (CKD) stages G4-G5, on dialysis or after kidney transplantation (kidney replacement therapy, KRT). SARS-CoV-2 vaccine trials do not elucidate if SARS-CoV-2 vaccination is effective in these patients. Vaccination against other viruses is known to be less effective in kidney patients. Our objective is to assess the efficacy and safety of various types of SARS-CoV-2 vaccinations in patients with CKD stages G4-G5 or on KRT. Methods: In this national prospective observational cohort study we will follow patients with CKD stages G4-G5 or on KRT (n = 12,000) after SARS-CoV-2 vaccination according to the Dutch vaccination program. Blood will be drawn for antibody response measurements at day 28 and month 6 after completion of vaccination. Patient characteristics and outcomes will be extracted from registration data and questionnaires during 2 years of follow-up. Results will be compared with a control group of non-vaccinated patients. The level of antibody response to vaccination will be assessed in subgroups to predict protection against COVID-19 breakthrough infection. Results: The primary endpoint is efficacy of SARS-CoV-2 vaccination determined as the incidence of COVID-19 after vaccination. Secondary endpoints are the antibody based immune response at 28 days after vaccination, the durability of this response at 6 months after vaccination, mortality and (serious) adverse events. Conclusion: This study will fulfil the lack of knowledge on efficacy and safety of SARS-CoV-2 vaccination in patients with CKD stages G4-G5 or on KRT. Current knowledge about this subject. COVID-19 has devastating impact on patients with CKD stages G4-G5, on dialysis or after kidney transplantation.. Effective SARS-CoV-2 vaccination is very important in these vulnerable patient groups.. Recent studies on vaccination in these patient groups are small short-term studies with surrogate endpoints. Contribution of this study. Assessment of incidence and course of COVID-19 after various types of SARS-CoV-2 vaccination during a twoyear follow-up period in not only patients on dialysis or kidney transplant recipients, but also in patients with CKD stages G4-G5.. Quantitative analysis of antibody response after SARS-CoV-2 vaccination and its relationship with incidence and course of COVID-19 in patients with CKD stages G4-G5, on dialysis or after kidney transplantation compared with a control group.. Monitoring of (serious) adverse events and development of anti-HLA antibodies. Impact on practice or policy. Publication of the study design contributes to harmonization of SARS-CoV-2 vaccine study methodology in kidney patients at high-risk for severe COVID-19.. Data on efficacy of SARS-CoV-2 vaccination in patients with CKD will provide guidance for future vaccination policy. Show less
Matching strategies based on HLA eplets instead of HLA antigens in solid organ transplantation may not only increase the donor pool for highly sensitized patients, but also decrease the incidence... Show moreMatching strategies based on HLA eplets instead of HLA antigens in solid organ transplantation may not only increase the donor pool for highly sensitized patients, but also decrease the incidence of de novo donor-specific antibody formation. However, since not all eplets are equally capable of inducing an immune response, antibody verification is needed to confirm their ability to be bound by antibodies, such that only clinically relevant eplets are considered. The HLA Epitope Registry has documented all theoretically defined HLA eplets along with their antibody verification status and has been the foundation for many clinical studies investigating eplet mismatch in transplantation. The verification methods for eplets in the Registry range from polyclonal sera from multi- and uni-parous women to murine and human monoclonal antibodies (mAbs), and antibodies purified by adsorption and elution from sera of HLA immunized individuals. The classification of antibody verification based on different methods for validation is problematic, since not all approaches represent the same level of evidence. In this study, we introduce a classification system to evaluate the level of evidence for the antibody-verified status of all eplets in the HLA Epitope Registry. We demonstrate that for a considerable number of eplets, the antibody-verified status is solely based on polyclonal serum reactivity of multiparous women or on reactivity of murine mAbs. Furthermore, we noted that a substantial proportion of patient sera analyses and human mAb data presented in the HLA Epitope Registry Database has never been published in a peer-reviewed journal. Therefore, we tested several unpublished human HLA-specific mAbs by luminex single antigen beads assay to analyze their HLA reactivity for eplet antibody verification. Although the majority of analyzed mAbs indeed verified their assigned eplets, this was not the case for a number of eplets. This comprehensive overview of evidence for antibody verification of eplets in the HLA Epitope Registry is instrumental for future investigations towards eplet immunogenicity and clinical studies considering antibody-verified eplet mismatch in transplantation and warrants further standardization of antibody verification using high quality data. Show less
BACKGROUND: After renal transplantation, there is a need of immunosuppressive regimens that effectively prevent allograft rejection while minimizing cardiovascular complications. This substudy of... Show moreBACKGROUND: After renal transplantation, there is a need of immunosuppressive regimens that effectively prevent allograft rejection while minimizing cardiovascular complications. This substudy of the TRITON trial evaluated the cardiovascular effects of autologous bone marrow-derived mesenchymal stromal cells (MSCs) in renal transplant recipients.METHODS AND RESULTS: Renal transplant recipients were randomized to MSC therapy, infused at weeks 6 and 7 after transplantation, with withdrawal at week 8 of tacrolimus or standard tacrolimus dose. Fifty-four patients (MSC group=27; control group=27) underwent transthoracic echocardiography at weeks 4 and 24 after transplantation and were included in this substudy. Changes in clinical and echocardiographic variables were compared. The MSC group showed a benefit in blood pressure control, assessed by a significant interaction between changes in diastolic blood pressure and the treatment group (P=0.005), and a higher proportion of patients achieving the predefined blood pressure target of <140/90 mm Hg compared with the control group (59.3% versus 29.6%, P=0.03). A significant reduction in left ventricular mass index was observed in the MSC group, whereas there were no changes in the control group (P=0.002). The proportion of patients with left ventricular hypertrophy decreased at 24 weeks in the MSC group (33.3% versus 70.4%, P=0.006), whereas no changes were noted in the control group (63.0% versus 48.1%, P=0.29). Additionally, MSC therapy prevented progressive left ventricular diastolic dysfunction, as demonstrated by changes in mitral deceleration time and tricuspid regurgitant jet velocity.CONCLUSIONS: MSC strategy is associated with improved blood pressure control, regression of left ventricular hypertrophy, and prevention of progressive diastolic dysfunction at 24 weeks after transplantation. Registration URL: ; Unique identifier: NCT03398681. Show less
Reinders, M.E.J.; Groeneweg, K.E.; Hendriks, S.H.; Bank, J.R.; Dreyer, G.J.; Vries, A.P.J. de; ... ; Fijter, J.W. de 2021
After renal transplantation, there is a need for immunosuppressive regimens which effectively prevent allograft rejection, while preserving renal function and minimizing side effects. From this... Show moreAfter renal transplantation, there is a need for immunosuppressive regimens which effectively prevent allograft rejection, while preserving renal function and minimizing side effects. From this perspective, mesenchymal stromal cell (MSC) therapy is of interest. In this randomized prospective, single-center, open-label trial, we compared MSCs infused 6 and 7 weeks after renal transplantation and early tacrolimus withdrawal with a control tacrolimus group. Primary end point was quantitative evaluation of interstitial fibrosis in protocol biopsies at 4 and 24 weeks posttransplant. Secondary end points included acute rejection, graft loss, death, renal function, adverse events, and immunological responses. Seventy patients were randomly assigned of which 57 patients were included in the final analysis (29 MSC; 28 controls). Quantitative progression of fibrosis failed to show benefit in the MSC group and GFR remained stable in both groups. One acute rejection was documented (MSC group), while subclinical rejection in week 24 protocol biopsies occurred in seven patients (four MSC; three controls). In the MSC group, regulatory T cell numbers were significantly higher compared to controls (p = .014, week 24). In conclusion, early tacrolimus withdrawal with MSC therapy was safe and feasible without increased rejection and with preserved renal function. MSC therapy is a potentially useful approach after renal transplantation. Show less
Groeneweg, K.E.; Toorn, F.A. van der; Roelen, D.L.; Kooten, C. van; Heidt, S.; Claas, F.H.J.; ... ; Soonawala, D. 2021
Background: The COVID-19 pandemic has markedly affected renal transplant care. During this time of social distancing, limited in-person visits, and uncertainty, patients and donors are relying more... Show moreBackground: The COVID-19 pandemic has markedly affected renal transplant care. During this time of social distancing, limited in-person visits, and uncertainty, patients and donors are relying more than ever on telemedicine and web-based information. Several factors can influence patients' understanding of web-based information, such as delivery modes (instruction, interaction, and assessment) and social-epistemological dimensions (choices in interactive knowledge building).Objective: The aim of this study was to systemically evaluate the content, delivery modes, and social-epistemological dimensions of web-based information on COVID-19 and renal transplantation at time of the pandemic.Methods: Multiple keyword combinations were used to retrieve websites on COVID-19 and renal transplantation using the search engines Google.com and Google.nl. From 14 different websites, 30 webpages were examined to determine their organizational sources, topics, delivery modes, and social-epistemological dimensions.Results: The variety of topics and delivery modes was limited. A total of 13 different delivery modes were encountered, of which 8 (62%) were instructional and 5 (38%) were interactional; no assessment delivery modes were observed. No website offered all available delivery modes. The majority of delivery modes (8/13, 62%) focused on individual and passive learning, whereas group learning and active construction of knowledge were rarely encountered.Conclusions: By taking interactive knowledge transfer into account, the educational quality of eHealth for transplant care could increase, especially in times of crisis when rapid knowledge transfer is needed. Show less
