Chronic kidney disease (CKD) has a major impact on the mortality and quality of life of patients. Mounting evidence indicates an important role of chronic inflammation in the development of CKD.... Show moreChronic kidney disease (CKD) has a major impact on the mortality and quality of life of patients. Mounting evidence indicates an important role of chronic inflammation in the development of CKD. This thesis evaluated the feasibility of stimulating the function of two anti-inflammatory proteins, thrombomodulin and soluble fms-like tyrosine kinase-1 (sFLT1), as novel therapeutic strategies for CKD. In the first part, the clinicopathologic significance of aberrant thrombomodulin expression was evaluated in various renal diseases. Here, a dysregulation of glomerular thrombomodulin expression was associated with increased local macrophage infiltration and endothelial dysfunction in the kidneys of patients with diabetic nephropathy and preeclampsia. In the second part, we demonstrated that treatment with the VEGF inhibitor sFLT1 ameliorates tissue damage and improves organ function in mouse models of chronic inflammatory skin and renal disease. In both models, treatment with sFLT1 dampened the infiltration of immune cells within the affected tissues. Finally, we demonstrated that sFLT1 directly binds to the cell surface of macrophages in vitro, offering a novel anti-inflammatory mechanism of sFLT1. Together these works indicate potent anti-inflammatory effects of thrombomodulin and sFLT1, thereby providing a basis for the further development of TM- and sFLT1-based therapies to prevent disease progression of CKD in patients. Show less
Purpose Obesity may promote kidney damage through hemodynamic and hormonal effects. We investigated the association between body mass index (BMI), total body fat (TBF) and chronic kidney disease ... Show morePurpose Obesity may promote kidney damage through hemodynamic and hormonal effects. We investigated the association between body mass index (BMI), total body fat (TBF) and chronic kidney disease (CKD) and whether hypertension, diabetes, leptin and adiponectin mediated these associations. Methods In this cross-sectional analysis of the Netherlands Epidemiology of Obesity study, 6671 participants (45–65 y) were included. We defined CKD as eGFR <60 ml/min/1.73 m2 and/or moderately increased albuminuria. The percentage of mediation was calculated using general structural equation modeling, adjusted for potential confounding factors age, sex, smoking, ethnicity, physical activity and Dutch healthy diet index. Results At baseline mean (SD) age was 56 (6), BMI 26.3 (4.4), 44% men, and 4% had CKD. Higher BMI and TBF were associated with 1.08 (95%CI 1.05; 1.11) and 1.05-fold (95%CI 1.02; 1.08) increased odds of CKD, respectively. As adiponectin was not associated with any of the outcomes, it was not studied further as a mediating factor. The association between BMI and CKD was 8.5% (95%CI 0.5; 16.5) mediated by diabetes and 22.3% (95%CI 7.5; 37.2) by hypertension. In addition, the association between TBF and CKD was 9.6% (95%CI −0.4; 19.6) mediated by diabetes and 22.4% (95%CI 4.2; 40.6) by hypertension. We could not confirm mediation by leptin in the association between BMI and CKD (35.6% [95%CI −18.8; 90.3]), nor between TBF and CKD (59.7% [95%CI −7.1; 126.6]). Conclusion Our results suggest that the relations between BMI, TBF and CKD are in part mediated by diabetes and hypertension. Show less
Proteinuria is an independent risk factor for the progression of kidney injury, cardiovascular morbidity, and overall mortality. In this thesis, the pathways leading to proteinuria are explored by... Show moreProteinuria is an independent risk factor for the progression of kidney injury, cardiovascular morbidity, and overall mortality. In this thesis, the pathways leading to proteinuria are explored by revisiting elements previously considered essential, investigating known pathways, and identifying new players in the field of proteinuria. First, a zebrafish embryo model for developing new therapeutic options for the rare but devastating disease of nephropathic cystinosis is presented. The studies presented in thesis also investigate loss of heparan sulphate glycosaminoglycans in a zebrafish embryo model and in multiple osteochondroma patients. These studies show that loss of heparan sulphate glycosaminoglycans does not always lead to proteinuria. Next, dynamin is described as a promising potential therapeutic target for treating proteinuria. The final study introduces transmembrane protein 14A as an essential factor in maintaining glomerular filtration barrier function. Overall, these studies contribute to elucidating the pathways to proteinuria in the hope to keep advancing the field towards targeted treatment of proteinuria for the benefit of our patients. Show less
Chronic kidney disease has restricted treatment options and leads to a lower quality of life, even before the end stage of renal disease is reached. The ability to generate new transplantable... Show moreChronic kidney disease has restricted treatment options and leads to a lower quality of life, even before the end stage of renal disease is reached. The ability to generate new transplantable kidney tissue could help millions of people worldwide and is therefore of great interest. This thesis explores options within regenerative medicine to develop new transplantable kidney tissue from a bio-engineering point of view. Show less
Flow-based arterial spin labeling is a set of techniques used for non-contrast enhanced perfusion imaging. This work describes technical development done for application in body.
With advancement of techniques in endourology, treatments for renal stones have increased possibilities. This thesis analyses existing surgical treatments, pain treatments and renal anatomy.
Immunisation against Human Leucocyte Antigens (HLA) can be caused by pregnancy, blood transfusion, or organ transplants. The HLA antibody status of a given patient significantly influences their... Show moreImmunisation against Human Leucocyte Antigens (HLA) can be caused by pregnancy, blood transfusion, or organ transplants. The HLA antibody status of a given patient significantly influences their access and waiting time to transplant. For some highly sensitised patients (HSP) there is hardly any suitable donor available in the deceased donor pool of their allocation organisation and therefore they wait a very long time before being offered a kidney for transplant. Especially patients with rare HLA phenotypes in relation to the actual donor pool are waiting extremely long. As HLA phenotypes are different in the various European populations, we hypothesized that extension of the donor pool outside the respective allocation system will increase the chance of receiving a compatible transplant for this subgroup of highly sensitised patients. One of the objectives of the EUROSTAM project, (a Europe-wide Strategy to enhance Transplantation of highly sensitised patients on the basis of Acceptable HLA Mismatches) was to develop a tool to compare the chance of transplanting HSP in different European populations with donor organs from within and outside their own donor pool.Information on the HLA type and ABO blood group of the actual donor population, as well as the acceptable mismatches of long waiting HSP were obtained from the EUROSTAM partner organizations i.e. Eurotransplant (ET), UK National Health Service Blood and Transplant (NHSBT), Barcelona, Prague and Athens.Results from simulations using the newly developed tool shows that 195 (27%) of the 724 long waiting highly sensitised patients registered at each partner organisation have increased chances of transplant in a different European donor pool. This makes a strong case for sharing kidneys between European countries for selected difficult to transplant patients. Show less
Harteveld, A.A.; Boer, A. de; Franklin, S.L.; Leiner, T.; Stralen, M. van; Bos, C. 2020
Objective To compare the most commonly used labeling approaches, flow-sensitive alternating inversion recovery (FAIR) and pseudocontinuous arterial spin labeling (pCASL), for renal perfusion... Show moreObjective To compare the most commonly used labeling approaches, flow-sensitive alternating inversion recovery (FAIR) and pseudocontinuous arterial spin labeling (pCASL), for renal perfusion measurement using arterial spin labeling (ASL) MRI. Methods Multi-delay FAIR and pCASL were performed in 16 middle-aged healthy volunteers on two different occasions at 3T. Relative perfusion-weighted signal (PWS), temporal SNR (tSNR), renal blood flow (RBF), and arterial transit time (ATT) were calculated for the cortex and medulla in both kidneys. Bland-Altman plots, intra-class correlation coefficient, and within-subject coefficient of variation were used to assess reliability and agreement between measurements. Results For the first visit, RBF was 362 +/- 57 and 140 +/- 47 mL/min/100 g, and ATT was 0.47 +/- 0.13 and 0.70 +/- 0.10 s in cortex and medulla, respectively, using FAIR; RBF was 201 +/- 72 and 84 +/- 27 mL/min/100 g, and ATT was 0.71 +/- 0.25 and 0.86 +/- 0.12 s in cortex and medulla, respectively, using pCASL. For both labeling approaches, RBF and ATT values were not significantly different between visits. Overall, FAIR showed higher PWS and tSNR. Moreover, repeatability of perfusion parameters was better using FAIR. Discussion This study showed that compared to (balanced) pCASL, FAIR perfusion values were significantly higher and more comparable between visits. Show less
Harmonization of acquisition and analysis protocols is an important step in the validation of BOLD MRI as a renal biomarker. This harmonization initiative provides technical recommendations based... Show moreHarmonization of acquisition and analysis protocols is an important step in the validation of BOLD MRI as a renal biomarker. This harmonization initiative provides technical recommendations based on a consensus report with the aim to move towards standardized protocols that facilitate clinical translation and comparison of data across sites. We used a recently published systematic review paper, which included a detailed summary of renal BOLD MRI technical parameters and areas of investigation in its supplementary material, as the starting point in developing the survey questionnaires for seeking consensus. Survey data were collected via the Delphi consensus process from 24 researchers on renal BOLD MRI exam preparation, data acquisition, data analysis, and interpretation. Consensus was defined as >= 75% unanimity in response. Among 31 survey questions, 14 achieved consensus resolution, 12 showed clear respondent preference (65-74% agreement), and 5 showed equal (50/50%) split in opinion among respondents. Recommendations for subject preparation, data acquisition, processing and reporting are given based on the survey results and review of the literature. These technical recommendations are aimed towards increased inter-site harmonization, a first step towards standardization of renal BOLD MRI protocols across sites. We expect this to be an iterative process updated dynamically based on progress in the field. Show less
Dekkers, I.A.; Boer, A. de; Sharma, K.; Cox, E.F.; Lamb, H.J.; Buckley, D.L.; ... ; Francis, S. 2019
Aims: Chronic-active antibody mediated rejection (c-aABMR) is a major cause of kidney graft loss. Currently, little is known about the relation between histopathologic parameters and renal... Show moreAims: Chronic-active antibody mediated rejection (c-aABMR) is a major cause of kidney graft loss. Currently, little is known about the relation between histopathologic parameters and renal allograft survival.Methods and results: Between 2008 and 2014, 41 patients with a progressive decrease in renal function were diagnosed with c-aABMR according to Banff 2015 and followed up for at least 3 years. Clinical and renal biopsy characteristics were analyzed for association with graft survival.During follow-up 26 cases lost their graft because of c-aABMR at a median follow up of 40 months after diagnosis.Cases with v-lesions in their biopsy had a significant higher loss of eGFR prior to diagnosis. The total inflammation score (r = -0.45 p = .007) and the severity of interstitial fibrosis (r = -0.38 p = .023) were related to the eGFR at time of biopsy.Univariate regression analysis showed that eGFR at time of biopsy, total inflammation, interstitial fibrosis and the sum chronicity score were significantly related to the risk for graft failure during follow-up. In a multivariate analysis only the severity of interstitial fibrosis remained associated with decreased graft survival (HR 1.9 per score point, 95% CI 1.2-2.8, p = .004).Conclusion: Severity of renal interstitial fibrosis and not inflammation predicts graft survival in cases of c-aABMR. Show less
The glycocalyx is a thin layer consisting of sugar moieties on the endothelium of the whole vasculature. This layer has been shown to play a role in diabetic kidney disease and beyond. In this... Show moreThe glycocalyx is a thin layer consisting of sugar moieties on the endothelium of the whole vasculature. This layer has been shown to play a role in diabetic kidney disease and beyond. In this thesis we studied structural and compositional changes of the endothelial glycocalyx upon diabetes in mice and in vitro. In glomerular capillaries, the endothelial glycocalyx contributes to the filtration barrier in the glomeruli. In diabetes the glycocalyx is damaged but can be restored via several pharmacological compounds that subsequently results in a shift from inflammatory towards anti-inflammatory macrophage function (chapter 2-3). In our model this appeared not to a result of changes in nitric oxide availability, affirming the potential overruling role for glomerular macrophages in glycocalyx degradation in diabetic nephropathy (chapter 4). Enzymatic cleavage of heparan sulfates reduced the total amount of luminal glycosaminoglycan content, but increased inflammatory heparan sulfate epitopes in vitro and in zebrafish (chapter 5). In chapter 6 we demonstrate that endothelial-specific loss of hyaluronan, another glycocalyx constituent, results in loss of endothelial barrier function. Overall, this thesis provides evidence that inhibition of glycocalyx degrading enzymes is a potent treatment option in diabetic nephropathy and other vascular diseases. Show less
In this thesis we investigated various mechanisms by which the immune system plays a role in the development of diabetic nephropathy. In chapter 2 we describe that APOC1-tg mice develop... Show moreIn this thesis we investigated various mechanisms by which the immune system plays a role in the development of diabetic nephropathy. In chapter 2 we describe that APOC1-tg mice develop glomerulosclerosis at 15 months of age, with increased number of glomerular macrophages. Our results suggest that apoCI may exacerbate the development of DN by increasing the inflammatory response in activated glomerular macrophages. In chapter 3 we demonstrate that sFLT-1 significantly improves kidney function, resolves diabetes-related kidney damage, and reduces endothelial cell activation and inflammation, suggesting that sFLT-1 can reduce the severity of DN by reducing glomerular inflammation and supporting cellular repair mechanisms.In chapter 4 we show that reducing endoglin levels diminished VEGF-A-induced endothelial activation by increasing pAkt and reducing pATF-2. These data suggest that targeting endoglin may have therapeutic value in patients who are at risk for developing DN.In chapter 5 we demonstrate that renal complement activation is associated with more severe classes of DN, reduced kidney function, and the presence of histological lesions.In chapter 6 we describe that transfecting APOC1-tg mice with sFlt-1 does not accelerate development of glomerulosclerosis, but lowered the number of glomerular macrophages. These data suggest that sFLT-1 treatment has an anti-inflammatory effect. Show less
Thomsen, L.H.; Fog-Tonnesen, M.; Fink, L.N.; Norlin, J.; Vinuesa, A.G. de; Hansen, T.K.; ... ; Rosendahl, A. 2017
In this thesis several aspects of SLE were investigated. First, we studied interobserver agreement concerning class III/IV lupus nephritis lesions in a renal biopsy and found that agreement was... Show moreIn this thesis several aspects of SLE were investigated. First, we studied interobserver agreement concerning class III/IV lupus nephritis lesions in a renal biopsy and found that agreement was poor. This seemed, in part, due to inconsistent or ambiguous definitions as provided in the 2004 ISN/RPS classification. This led us to re-evaluate the current classification with an international group of highly experienced nephrologists. Second, we compared and summarized the lupus nephritis management guidelines that were published in 2012. Third, we studied microchimerism in peripheral blood of women with SLE and control subjects. We found that women with SLE have more microchimerism in their peripheral blood than control subjects. Then, we studied microchimerism in the peripheral blood of women with SLE and control subjects during and after pregnancy. We found that only just after delivery did the SLE patients have more chimeric cells in the granulocyte fraction than control subjects. These results suggest that after pregnancy chimeric cells become undetectable in peripheral blood, but possibly remain at other sites, only to re-emerge after un unknown trigger. Finally, we compared sporadic and familial lupus nephritis to find that, although there were clinical differences, no differences in histology or genetic background were apparent. Show less
