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BackgroundThe impact of donor-specific antibodies (DSA) in (highly-) immunized living donor kidney transplant recipients is reported differentially in various patient cohorts.MethodsWe 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.ResultsFor 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.ConclusionIn 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.

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 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. Trial registration The study protocol has been registered in clinicaltrials.gov(NCT04841785). 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 two-year 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.

Background On the basis of findings of observational studies and a meta-analysis, proteinuria reduction has been proposed as a surrogate outcome in IgA nephropathy. How long a reduction in proteinuria needs to be maintained to mitigate the long-term risk of disease progression is unknown. Methods In this retrospective multiethnic cohort of adult patients with IgA nephropathy, we defined proteinuria remission as a $25% reduction in proteinuria from the peak value after biopsy, and an absolute reduction in proteinuria to,1 g/d. The exposure of interest was the total duration of first remission, treated as a time-varying covariate using longitudinal proteinuria measurements. We used time-dependent Cox proportional hazards regression models to quantify the association between the duration of remission and the primary outcome (ESKD or a 50% reduction in eGFR). Results During a median follow-up of 3.9 years, 274 of 1864 patients (14.7%) experienced the primary outcome. The relationship between duration of proteinuria remission and outcome was nonlinear. Each 3 months in sustained remission up to approximately 4 years was associated with an additional 9% reduction in the risk of disease progression (hazard ratio [HR], 0.91; 95% confidence interval [95% CI], 0.89 to 0.93). Thereafter, each additional 3 months in remission was associated with a smaller, nonsignificant risk reduction (HR, 0.99; 95% CI, 0.96 to 1.03). These findings were robust to multivariable adjustment and consistent across clinical and histologic subgroups. Conclusions Our findings support the use of proteinuria as a surrogate outcome in IgA nephropathy, but additionally demonstrate the value of quantifying the duration of proteinuria remission when estimating the risk of hard clinical endpoints. Copyright © 2021 by the American Society of Nephrology.

Background: The VALidation of IGA (VALIGA) study investigated the utility of the Oxford Classification of immunoglobulin A nephropathy (IgAN) in 1147 patients from 13 European countries. Methods. Biopsies were scored by local pathologists followed by central review in Oxford. We had two distinct objectives: to assess how closely pathology findings were associated with the decision to give corticosteroid/immunosuppressive (CS/IS) treatments, and to determine the impact of differences in MEST-C scoring between central and local pathologists on the clinical value of the Oxford Classification. We tested for each lesion the associations between the type of agreement (local and central pathologists scoring absent, local present and central absent, local absent and central present, both scoring present) with the initial clinical assessment, as well as long-term outcomes in those patients who did not receive CS/IS. Results: All glomerular lesions (M, E, C and S) assessed by local pathologists were independently associated with the decision to administer CS/IS therapy, while the severity of tubulointerstitial lesions was not. Reproducibility between local and central pathologists was moderate for S (segmental sclerosis) and T (tubular atrophy/interstitial fibrosis), and poor for M (mesangial hypercellularity), E (endocapillary hypercellularity) and C (crescents). Local pathologists found statistically more of each lesion, except for the S lesion, which was more frequent with central review. Disagreements were more likely to occur when the proportion of glomeruli affected was low. The M lesion, assessed by central pathologists, correlated better with the severity of the disease at presentation and discriminated better with outcomes. In contrast, the E lesion, evaluated by local pathologists, correlated better with the clinical presentation and outcomes when compared with central review. Both C and S lesions, when discordant between local and central pathologists, had a clinical phenotype intermediate to double absent lesions (milder disease) and double present (more severe). Conclusion: We conclude that differences in the scoring of MEST-C criteria between local pathologists and a central reviewer have a significant impact on the prognostic value of the Oxford Classification. Since the decision to offer immunosuppressive therapy in this cohort was intimately associated with the MEST-C score, this study indicates a need for a more detailed guidance for pathologists in the scoring of IgAN biopsies. © 2018 The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

ImportanceAlthough IgA nephropathy (IgAN) is the most common glomerulonephritis in the world, there is no validated tool to predict disease progression. This limits patient-specific risk stratification and treatment decisions, clinical trial recruitment, and biomarker validation. ObjectiveTo derive and externally validate a prediction model for disease progression in IgAN that can be applied at the time of kidney biopsy in multiple ethnic groups worldwide. Design, Setting, and ParticipantsWe derived and externally validated a prediction model using clinical and histologic risk factors that are readily available in clinical practice. Large, multi-ethnic cohorts of adults with biopsy-proven IgAN were included from Europe, North America, China, and Japan. Main Outcomes and MeasuresCox proportional hazards models were used to analyze the risk of a 50% decline in estimated glomerular filtration rate (eGFR) or end-stage kidney disease, and were evaluated using the R-D(2) measure, Akaike information criterion (AIC), C statistic, continuous net reclassification improvement (NRI), integrated discrimination improvement (IDI), and calibration plots. ResultsThe study included 3927 patients; mean age, 35.4 (interquartile range, 28.0-45.4) years; and 2173 (55.3%) were men. The following prediction models were created in a derivation cohort of 2781 patients: a clinical model that included eGFR, blood pressure, and proteinuria at biopsy; and 2 full models that also contained the MEST histologic score, age, medication use, and either racial/ethnic characteristics (white, Japanese, or Chinese) or no racial/ethnic characteristics, to allow application in other ethnic groups. Compared with the clinical model, the full models with and without race/ethnicity had better R-D(2) (26.3% and 25.3%, respectively, vs 20.3%) and AIC (6338 and 6379, respectively, vs 6485), significant increases in C statistic from 0.78 to 0.82 and 0.81, respectively (Delta C, 0.04; 95% CI, 0.03-0.04 and Delta C, 0.03; 95% CI, 0.02-0.03, respectively), and significant improvement in reclassification as assessed by the NRI (0.18; 95% CI, 0.07-0.29 and 0.51; 95% CI, 0.39-0.62, respectively) and IDI (0.07; 95% CI, 0.06-0.08 and 0.06; 95% CI, 0.05-0.06, respectively). External validation was performed in a cohort of 1146 patients. For both full models, the C statistics (0.82; 95% CI, 0.81-0.83 with race/ethnicity; 0.81; 95% CI, 0.80-0.82 without race/ethnicity) and R-D(2) (both 35.3%) were similar or better than in the validation cohort, with excellent calibration. Conclusions and RelevanceIn this study, the 2 full prediction models were shown to be accurate and validated methods for predicting disease progression and patient risk stratification in IgAN in multi-ethnic cohorts, with additional applications to clinical trial design and biomarker research.

Contains fulltext : 193194.pdf (Publisher’s version ) (Closed access) AIMS: Everolimus is a drug from the class of mammalian target of rapamycin inhibitors used for both immunosuppressant and oncological indications. We postulate that there is room for improvement of dosing, as the optimal immunosuppressive dose in calcineurin-free regimens is unknown and since the once daily dosing regimen for oncological indications is often associated with treatment-limiting toxicity. METHODS: We developed a mechanistic population pharmacokinetic model for everolimus in cancer and transplant patients and explored alternative dosing regimens. RESULTS: We found that formulation did not influence bioavailability and that use of >20 mg prednisolone daily increased everolimus clearance. In transplant patients, the approved dose of 0.75-1 mg twice daily (BID) results in subtherapeutic trough levels (

Work described in this thesis was aimed to further understand the role of macrophages in acute cellular rejection of transplanted kidneys, and perform a pre-clinical assessment of the localization and efficacy of liposomal prednisolone. First, we explored the role of anti-inflammatory macrophages in the onset of acute cellular rejection using human biopsy samples. Here, we discovered that the presence of high levels of CD163+ macrophages was associated with a lower risk of rejection, in a population of patients with a high rate of delayed graft function. Subsequently, we identified the ability of liposomal prednisolone to target macrophages in the kidney using in vitro models of human macrophages, and their ability to accumulate in inflamed kidney tissue in vivo rat models of ischemia reperfusion injury in the kidney. Finally, we evaluated the treatment efficacy of liposomal prednisolone in a mouse model of cellular rejection following kidney transplantation. Here, we were able to show an improved efficacy of liposomal prednisolone in treating rejection, when compared to treatment with free prednisolone.

Focal segmental glomerulosclerosis (FSGS) is a heterogeneous renal histopathological entity that affects the glomerulus. It is characterized by podocyte injury, proteinuria and scarring of the glomerular tuft. In this thesis we investigated various mechanisms that are implicated in the development of FSGS. Firstly, we studied biopsy samples of patients with minimal change disease, a related glomerulopathy with minimal glomerular injury and better prognosis. We showed that loss of nephrin could serve as a biomarker for renal function loss and the progression to FSGS in this patient group. We also investigated renal biopsy material of patients with FSGS to determine the role of complement activation and endothelial-podocyte interaction in the pathogenesis of FSGS. We show that complement activation via the classical pathway and endothelial injury, especially via endothelin-1 signaling, are associated with the development of FSGS in humans. This thesis also describes the study of the genomic architecture of the Munich Wistar Frömter rat model for FSGS, which led to the prioritization of TMEM63c and PTGR2 in the development of podocyte injury and proteinuria in this model. The identification of these mechanisms in the development of FSGS, increases our understanding of the pathophysiology of FSGS and can guide future studies into new, highly needed therapeutic strategies.

MOOCs are large-scale (Massive), Open to all, Online Courses. As universities invested substantially in MOOCs, (re)use in campus education manifested.In MOOC integration, it is currently unclear how to design for high-quality teaching and learning. We questioned: 'What do medical MOOCs offer for integration into campus education?' (H2 and H3); ‘What does creating and integrating a MOOC entail?’ (H4 and H5); and 'How can learning in integrated MOOCs be supported?' (H6, H7 and H8). For high-quality teaching we conclude: (1) Medical MOOCs offer numerous opportunities for integration, including high-quality, innovative options; (2) Medical MOOCs do not share one profile for teaching modes or quality principles, and each MOOC should be examined; and (3) the practice of MOOC integration is not a simple process and requires time, several steps and specific knowledge. For high-quality learning we conclude: (1) Monitoring motivation and self-regulated learning is essential for support, and personalized motivation support can be linked to integration designs; (2) Trust in the teacher is important for students, and can be the key to promote motivation; and (3) Learning goal acceptance can bridge the gap between the desire to allow students to set personal goals and the practical preference to assign learning goals.

This thesis demonstrates that kidneys from DCD donors can be fully embraced, and that the perception of DCD kidney transplantation being inferior to DBD kidney transplantation – mainly motivated by concerns regarding high incidences of DGF and EGL – is no longer justified. One explanation for this phenomenon is that outcomes of transplanted DCD kidneys have improved over time, with a similar incidence of EGL following DBD and DCD kidney transplantation in the current era. Another explanation is that both donor types have different biological responses to DGF: whilst DGF severely impacts on DBD graft survival, DGF has no impact on DCD graft survival. This difference relates to donor type-specific regulation of resilience and pro-inflammatory pathways benefitting the DCD graft and its outcomes. As such, the persistent high incidence of DGF in DCD grafts should not be regarded an impediment toward the use of these donor kidneys.This thesis additionally explores a series of physiological and methodological contrasts between preclinical and clinical I/R injury, that all may contribute to the impaired translatability of preclinical studies in clinical practice. Awareness of these pitfalls may help to improve study designs in future research, bringing us one step closer towards bridging the translational gap.

With the rising global health burden of aortic valve diseas and growing awareness of the consequences of severe AS, more patients are expected to be referred for aortic valve replacement. Multimodality imaging remains of paramount importance for proper patient selection, determining optimal timing of intervention and in the evaluation of therapy. For risk stratification and defining optimal timing of intervention, conventional and advanced echocardiography and computed tomography are crucial. Conventional echocardiography can be used to assess extra-aortic valvular cardiac damage in patients with severe AS. On top of conventional echocardiography, advanced echocardiography can provide additional insights. Left ventricular GLS by speckle tracking echocardiography has been suggested as a more sensitive marker of LV systolic dysfunction. LV GLS may be of help to define more optimal timing of intervention in asymptomatic patients with severe AS. Also, LV GLS may be of incremental value on top of conventional echocardiographic parameters for the assessment of cardiac injury. For the evaluation of prothesis function and durability after aortic valve implantation and detection of possible (late) complications, echocardiography is the mainstay imaging modality. Also, both conventional and advanced echocardiography can provide additional information on the effects of therapy on LV function and remodelling.

The aim of this thesis was to gain evidence-based insights to improve anatomical and surgical education by evaluating how various levels of visual-spatial abilities interacts with learning using stereoscopic 3D visualization technology

In chapters 2, 3 and 4, novel biomarkers IGFPB7, TIMP-2 and long noncoding RNAs were studied in order to find new diagnostic possibilities for early recognition and diagnosis of injury in native and transplanted kidneys. In chapter 2, diabetic nephropathy was found to be associated with higher levels of circulating TIMP-2, which did not normalize after simultaneous pancreas-kidney transplantation. In chapter 3, we found that four circulating long noncoding RNAs associated with diabetic nephropathy and did normalize after simultaneous pancreas-kidney transplantation. In chapter 4, acute rejection in kidney transplant recipients resulted in higher circulating LNC-EPHA6 levels. In chapter 5, clinical parameters and single antigen bead assay for measurement of donor specific antibodies were evaluated in the context of antibody-mediated rejection. Female recipients who received a kidney transplant from their spouse were especially at risk for acute antibody-mediated rejection and a single antigen bead assay is more sensitive to detect antibodies in this group than the standard diagnostic strategy. In chapter 6, mesenchymal stromal cell therapy is studied in a randomized controlled trial to evaluate the potential for prevention of acute rejection and fibrosis in transplanted kidneys. MSC therapy resulted in similar fibrosis scores and rejection rates.

This thesis describes the possible applicability of mesenchymal stromal cells (MSCs) in the treatment of liver fibrosis. In CCL4 induced animal models for liver fibrosis, we showed that local administration of MSCs after partial hepatectomy, results in a dose‐dependent on‐site amelioration of fibrosis. Furthermore, we compared the pro-regenerative and anti-fibrotic effects of four different subpopulations of MSCs, categorized on Endoglin (CD105) and VCAM (CD106) membrane expression. Our results showed that VCAM-positive subpopulations of MSCs are superior compared to VCAM-negative subpopulations in relation to their anti-fibrotic and pro-regenerative properties. In another study we showed that TAA induce liver fibrogenesis in zebrafish embryos through mechanisms similar to man and mice. In addition, we found that MSCs ameliorate fibrogenesis in this model.CRIPTO-1 is an (onco)foetal protein and is correlated to poor prognosis in HCC. The observations of our HCC study are suggestive for the existence of a more aggressive subgroup of HCCs recognized by their high CRIPTO-1 expression which also seems to be resistant to Sorafenib treatment. Cell survival and cell proliferation are some of the processes stimulated by CRIPTO-1, which are also known to be important during liver regeneration and fibrogenesis. We identified that multiple species show enhanced CRIPTO-1 during fibrogenesis and that elevated CRIPTO-1 plasma levels in humans with cirrhosis normalize after liver transplantation.

In recent years HLA epitope matching is becoming a hot topic in transplant community to prevent donor-specific antibody formation after transplantation, as such antibodies are associated with inferior graft survival. The number of HLA epitope mismatches between donor and recipient correlates with donor-specific antibody formation, but not every epitope mismatch will trigger an antibody response. Therefore, it is pivotal to define the immunogenic epitopes. In my thesis we describe the development of the software HLA-EMMA to determine HLA amino acid mismatches between donor and recipient to identify immunogenic amino acids. In addition, the generation of recombinant human HLA-DR monoclonal antibodies for antibody-verification of eplets/epitopes is described. These tools will contribute to the definition of immunogenic epitopes, which is required before introducing HLA epitope matching in the clinic.

This thesis explored the diagnosis, management and prognosis of the most common valvular heart diseases: aortic stenosis (AS) and mitral regurgitation (MR) and enlightened their challenging types: the discordant low-gradient severe AS and the secondary MR in non-ischemic cardiomyopathy. This thesis provides new insights into the use of fusion aortic valve area index, by incorporating the measurement of left ventricular outflow tract area on cardiac computed tomography in the continuity equation, for the diagnosis of low-gradient AS. For the treatment of low-gradient AS, TAVR is shown to result in reverse LV remodeling and functional recovery. In comparison to other minimal invasive surgical methods it results in less prosthesis-patient-mismatch although paravalvular aortic regurgitation is a caveat. Regarding the diagnostic assessment of secondary MR due to LV dysfunction this thesis concluded that LV GLS reflects the real LV dysfunction while LVEF overestimates LV function without accounting for the forward LV flow. Mitral valve repair offers LV reverse remodeling and increase in forward flow when used for the treatment of this challenging condition. Regarding the prognostication of low-gradient AS and secondary MR this thesis advocates for the evaluation of the valvular calcium on cardiac computed tomography and the evaluation of LV GLS and forward flow that are associated with survival.

This thesis encompasses the role of various (modifiable) risk factors on the progression of chronic kidney disease, especially in study cohorts with a high baseline cardiovascular risk. We describe the influence of cardiovascular risk factors, for example obesity, diabetes and smoking, lifestyle factors like dietary protein intake, and cholesterol-lowering medication on the rate of kidney function decline. We concluded that patients with diabetes, hypertension, obesity or who smoke, have more rapid kidney function decline, and having more of these risk factors combined incrementally increases the rate of decline. On the other hand, a low-protein diet and use of cholesterol-lowering drugs were associated with slower kidney function decline. Additionally, birth weight in relation to kidney function at middle-age was explored, by three different approaches including Mendelian randomization using genetic data. Furthermore, we assessed the possible role of novel biomarkers in predicting acute kidney injury after cardiac surgery, which is also a well-known risk factor for chronic kidney disease. Finally, we describe the survival benefit of a simultaneous pancreas-kidney transplantation over a kidney transplantation alone, in type 1 diabetes patients with end-stage renal disease, using data of all Dutch type 1 diabetes patients with end-stage renal disease over the past 30 years.

Pancreas transplantation is the only long-lasting curative option patients with type 1 diabetes mellitus. During the last 50 years, it has evolved from an experimental procedure to an accepted treatment. For patients suffering from diabetes mellitus induced end-stage renal disease, a simultaneous pancreas-kidney transplantation is the best option. Due to increased experience, the indications for transplantation have been expanded, causing waiting lists to increase. To match the increasing demand, transplant professionals are forced to accept higher risk donor organs. This thesis investigates those risks and aims to quantify the risk in donor risk indices. Those risk indices were also investigated in this thesis. Furthermore, solitary risk factors for outcome were investigated. There appears to be a significant association between center volume and outcome: high volume center have better results than low volume centers, despite accepting higher risk donor organs. Another risk factor that was investigated was donation after circulatory death (DCD) pancreas transplantation. It showed that DCD pancreas transplantation is a feasible option to expand the donor pool.

Chronic kidney disease (CKD) is a worldwide growing epidemic associated with an increased risk of cardiovascular morbidity and mortality. Heart failure is particularly frequent among patients with CKD. Pressure and volume overload and non-hemodynamic factors associated with CKD induce left ventricular (LV) hypertrophy, reduce capillary density and increase myocardial fibrosis that lead to LV diastolic and systolic dysfunction. These processes have been proposed as important determinants of increased mortality in this population. The aim of this thesis was to evaluate cardiac mechanics using two-dimensional (speckle tracking) echocardiography and coronary computed tomography angiography in patients with CKD to define the prevalence and prognostic implications of cardiovascular diseases. In pre-dialysis and dialysis patients with preserved LV ejection fraction (LVEF), assessment of left ventricular global longitudinal strain (LV GLS) helps to identify patients with higher rates of heart failure hospitalization and all-cause mortality. When LVEF has already declined, patients within the lowest quartile of LV GLS showed worse prognosis compared to the other groups. The burden of cardiovascular diseases in patients with CKD is high and thorough assessment of cardiac mechanics with (advanced) echocardiographic techniques and coronary CTA helps in identifying patients with worse prognosis, who would potentially benefit of early treatment.

Kidney transplantation is the preferred treatment of patients with end stage renal disease, as it provides longer patient survival and better quality of life compared to dialysis. Prediction of DGF, response to steroid resistant rejection and long-term graft outcome remain difficult when using merely clinical parameters. Numerous studies have reported on the predictive value of molecular markers for AR and worse graft outcome. However, the heterogeneity of AR and the variation among transplant centers leads to controversial results and preclude a more general clinical application. In the first part of this thesis, we aimed to investigate the molecular markers of steroid resistance and long-term graft survival on the basis of acute rejection biopsies. In the second part, we focused on genetic variants associated with acute rejection in kidney transplantation. In the final part we described the possible immune regulatory effect of S100 calcium binding proteins.

This thesis explores clinical phenotypes and the pathophysiology of rare monogenic models of migraine with the ultimate goal to identify novel treatment targets for these disorders, as well as for the common types of migraine. The research is divided in two parts: part one describes studies on hemiplegic migraine (HM), a monogenic form of migraine, part two describes studies on Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic manifestations (RVCL-S), a monogenic vascular syndrome hypothesised to be associated with migraine.