Publications by authors named "Marianne C Verhaar"

228 Publications

End-stage kidney disease in patients with clinically manifest vascular disease; incidence and risk factors: results from the UCC-SMART cohort study.

J Nephrol 2021 Mar 13. Epub 2021 Mar 13.

Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Patients with cardiovascular disease (CVD) are at increased risk of end-stage kidney disease (ESKD). Insights into the incidence and role of modifiable risk factors for end-stage kidney disease may provide means for prevention in patients with cardiovascular disease.

Methods: We included 8402 patients with stable cardiovascular disease. Incidence rates (IRs) for end-stage kidney disease were determined stratified according to vascular disease location. Cox proportional hazard models were used to assess the risk of end-stage kidney disease for the different determinants.

Results: Sixty-five events were observed with a median follow-up of 8.6 years. The overall incidence rate of end-stage kidney disease was 0.9/1000 person-years. Patients with polyvascular disease had the highest incidence rate (1.8/1000 person-years). Smoking (Hazard ratio (HR) 1.87; 95% CI 1.10-3.19), type 2 diabetes (HR 1.81; 95% CI 1.05-3.14), higher systolic blood pressure (HR 1.37; 95% CI 1.24-1.52/10 mmHg), lower estimated glomerular filtration rate (eGFR) (HR 2.86; 95% CI 2.44-3.23/10 mL/min/1.73 m) and higher urine albumin/creatinine ratio (uACR) (HR 1.19; 95% CI 1.15-1.23/10 mg/mmol) were independently associated with elevated risk of end-stage kidney disease. Body mass index (BMI), waist circumference, non-HDL-cholesterol and exercise were not independently associated with risk of end-stage kidney disease.

Conclusions: Incidence of end-stage kidney disease in patients with cardiovascular disease varies according to vascular disease location. Several modifiable risk factors for end-stage kidney disease were identified in patients with cardiovascular disease. These findings highlight the potential of risk factor management in patients with manifest cardiovascular disease.
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http://dx.doi.org/10.1007/s40620-021-00996-1DOI Listing
March 2021

Functional assays to assess the therapeutic potential of extracellular vesicles.

J Extracell Vesicles 2020 Nov 29;10(1):e12033. Epub 2020 Nov 29.

Department of Nephrology and Hypertension UMC Utrecht Utrecht The Netherlands.

An important aspect in the development of extracellular vesicle (EV) therapeutics is identifying and quantifying the key features defining their identity, purity, sterility, potency and stability to ensure batch-to-batch reproducibility of their therapeutic efficacy. Apart from EV-inherent features, therapeutic efficacy depends on a variety of additional parameters, like dosing, frequency of application, and administration route, some of which can be addressed only in clinical trials. Before initiating clinical trials, EV-inherent features should be tested in well-standardized quantitative assays or in appropriate animal models . Ideally, such assays would predict if a particular EV preparation has the potential to achieve its intended therapeutic effects, and could be further developed into formal potency assays as published by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use guidelines. Furthermore, such assays should facilitate the comparison of EV preparations produced in different batches, on different manufacturing platforms or deriving from different cell sources. For now, a wide spectrum of and assays has been used to interrogate the therapeutic functions of EVs. However, many cannot accurately predict therapeutic potential. Indeed, several unique challenges make it difficult to set up reliable assays to assess the therapeutic potential of EVs, and to develop such assays into formal potency tests. Here, we discuss challenges and opportunities around and testing of EV therapeutic potential, including the need for harmonization, establishment of formal potency assays and novel developments for functional testing.
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http://dx.doi.org/10.1002/jev2.12033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890556PMC
November 2020

Culture and analysis of kidney tubuloids and perfused tubuloid cells-on-a-chip.

Nat Protoc 2021 Mar 5. Epub 2021 Mar 5.

Hubrecht Institute-Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht, the Netherlands.

Advanced in vitro kidney models are of great importance to the study of renal physiology and disease. Kidney tubuloids can be established from primary cells derived from adult kidney tissue or urine. Tubuloids are three-dimensional multicellular structures that recapitulate tubular function and have been used to study infectious, malignant, metabolic, and genetic diseases. For tubuloids to more closely represent the in vivo kidney, they can be integrated into an organ-on-a-chip system that has a more physiological tubular architecture and allows flow and interaction with vasculature or epithelial and mesenchymal cells from other organs. Here, we describe a detailed protocol for establishing tubuloid cultures from tissue and urine (1-3 weeks), as well as for generating and characterizing tubuloid cell-derived three-dimensional tubular structures in a perfused microfluidic multi-chip platform (7 d). The combination of the two systems yields a powerful in vitro tool that better recapitulates the complexity of the kidney tubule with donor-specific properties.
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http://dx.doi.org/10.1038/s41596-020-00479-wDOI Listing
March 2021

Editorial for Special Issue on Drug and Disease Testing Model Systems.

Tissue Eng Part C Methods 2021 Feb;27(2):47-48

Department of Nephrology and Hypertension, Regenerative Medicine Utrecht, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

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http://dx.doi.org/10.1089/ten.tec.2021.29023.ychDOI Listing
February 2021

Modeling Distal Convoluted Tubule (Patho)Physiology: An Overview of Past Developments and an Outlook Toward the Future.

Tissue Eng Part C Methods 2021 Mar;27(3):200-212

Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

The kidneys are essential for maintaining electrolyte homeostasis. Blood electrolyte composition is controlled by active reabsorption and secretion processes in dedicated segments of the kidney tubule. Specifically, the distal convoluted tubule (DCT) and connecting tubule are important for regulating the final excretion of sodium, magnesium, and calcium. Studies unravelling the specific function of these segments have greatly improved our understanding of DCT (patho)physiology. Over the years, experimental models used to study the DCT have changed and the field has advanced from early dissection studies with rats and rabbits to the use of various transgenic mouse models. Developments in dissection techniques and cell culture methods have resulted in immortalized mouse DCT cell lines and made it possible to specifically obtain DCT fragments for studies. However, we still do not fully understand the complex (patho)physiology of this segment and there is need for advanced human DCT models. Recently, kidney organoids and tubuloids have emerged as new complex cell models that provide excellent opportunities for physiological studies, disease modeling, drug discovery, and even personalized medicine in the future. This review presents an overview of cell models used to study the DCT and provides an outlook on kidney organoids and tubuloids as model for DCT (patho)physiology. Impact statement This study provides a detailed overview of past and future developments on cell models used to study kidney (patho)physiology and specifically the distal convoluted tubule (DCT) segment. Hereby, we highlight the need for an advanced human cell model of this segment and summarize recent advances in the field of kidney organoids and tubuloids with a focus on DCT properties. The findings reported in this review are significant for future developments toward an advanced human model of the DCT that will help to increase our understanding of DCT (patho)physiology.
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http://dx.doi.org/10.1089/ten.TEC.2020.0345DOI Listing
March 2021

A plasma creatinine- and urea-based equation to estimate glomerular filtration rate in rats.

Am J Physiol Renal Physiol 2021 03 1;320(3):F518-F524. Epub 2021 Feb 1.

Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.

Monitoring renal function is a vital part of kidney research involving rats. The laborious measurement of glomerular filtration rate (GFR) with administration of exogenous filtration markers does not easily allow serial measurements. Using an in-house database of inulin clearances, we developed and validated a plasma creatinine- and plasma urea-based equation to estimate GFR in a large cohort of male rats [development cohort = 325,  = 0.816, percentage of predictions that fell within 30% of the true value (P30) = 76%] that had high accuracy in the validation cohort ( = 116 rats,  = 0.935, P30 = 79%). The equation was less accurate in rats with nonsteady-state creatinine, in which the equation should therefore not be used. In conclusion, applying this equation facilitates easy and repeatable estimates of GFR in rats. This is the first equation, that we know of, which estimates glomerular filtration rate in rats based on a single measurement of body weight, plasma creatinine, and plasma urea.
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http://dx.doi.org/10.1152/ajprenal.00656.2020DOI Listing
March 2021

Progression of coronary artery calcification in conventional hemodialysis, nocturnal hemodialysis, and kidney transplantation.

PLoS One 2020 30;15(12):e0244639. Epub 2020 Dec 30.

Department of Nephrology and Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.

Introduction: Cardiovascular disease is the leading cause of death in end-stage renal disease (ESRD) and is strongly associated with vascular calcification. An important driver of vascular calcification is high phosphate levels, but these become lower when patients initiate nocturnal hemodialysis or receive a kidney transplant. However, it is unknown whether nocturnal hemodialysis or kidney transplantation mitigate vascular calcification. Therefore, we compared progression of coronary artery calcification (CAC) between patients treated with conventional hemodialysis, nocturnal hemodialysis, and kidney transplant recipients.

Methods: We measured CAC annually up to 3 years in 114 patients with ESRD that were transplantation candidates: 32 that continued conventional hemodialysis, 34 that initiated nocturnal hemodialysis (≥4x 8 hours/week), and 48 that received a kidney transplant. We compared CAC progression between groups as the difference in square root transformed volume scores per year (ΔCAC SQRV) using linear mixed models. Reference category was conventional hemodialysis.

Results: The mean age of the study population was 53 ±13 years, 75 (66%) were male, and median dialysis duration was 28 (IQR 12-56) months. Median CAC score at enrollment was 171 (IQR 10-647), which did not differ significantly between treatment groups (P = 0.83). Compared to conventional hemodialysis, CAC progression was non-significantly different in nocturnal hemodialysis -0.10 (95% CI -0.77 to 0.57) and kidney transplantation -0.33 (95% CI -0.96 to 0.29) in adjusted models.

Conclusions: Nocturnal hemodialysis and kidney transplantation are not associated with significantly less CAC progression compared to conventional hemodialysis during up to 3 years follow-up. Further studies are needed to confirm these findings, to determine which type of calcification is measured with CAC in end-stage renal disease, and whether that reflects cardiovascular risk.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244639PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773242PMC
March 2021

Evaluation of a system for sorbent-assisted peritoneal dialysis in a uremic pig model.

Physiol Rep 2020 12;8(23):e14593

Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.

A system for sorbent-assisted peritoneal dialysis (SAPD) has been developed that continuously recirculates dialysate via a tidal mode using a single-lumen peritoneal catheter with the regeneration of spent dialysate by means of sorbents. SAPD treatment may improve plasma clearance by the maintenance of a high plasma-to-dialysate concentration gradient and by increasing the mass transfer area coefficient (MTAC) of solutes. The system is designed for daily 8-hr treatment (12 kg, nighttime system). A wearable system (2.3 kg, daytime system) may further enhance the clearance of phosphate and organic waste solutes during the day. Uremic pigs (n = 3) were treated with the day- (n = 3) and nighttime system (n = 15) for 4-8 hr per treatment. Plasma clearance (Cl), MTAC, and total mass transport (MT) of urea, creatinine, phosphate, and potassium were compared with a static dwell (n = 28). Cl, MTAC, and MT of urea, creatinine, phosphate, and potassium were low in the pig as compared to humans due to the pig's low peritoneal transport status and could be enhanced only to a limited extent by SAPD treatment compared with a static dwell (nighttime system: Cl urea: ×1.5 (p = .029), Cl creatinine: ×1.7 (p = .054), Cl phosphate: ×1.5 (p = .158), Cl potassium: ×1.6 (p = .011); daytime system: Cl creatinine: ×2.7 (p = .040), Cl phosphate: ×2.2 (p = .039)). Sorbent-assisted peritoneal dialysis treatment in a uremic pig model is safe and enhances small solute clearance as compared to a static dwell. Future studies in humans or animal species with higher peritoneal transport should elucidate whether our SAPD system enhances clearance to a clinically relevant extent as compared to conventional PD.
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http://dx.doi.org/10.14814/phy2.14593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718839PMC
December 2020

Implementation of Pericytes in Vascular Regeneration Strategies.

Tissue Eng Part B Rev 2021 Jan 20. Epub 2021 Jan 20.

Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.

For the survival and integration of complex large-sized tissue-engineered (TE) organ constructs that exceed the maximal nutrients and oxygen diffusion distance required for cell survival, graft (pre)vascularization to ensure medium or blood supply is crucial. To achieve this, the morphology and functionality of the microcapillary bed should be mimicked by incorporating vascular cell populations, including endothelium and mural cells. Pericytes play a crucial role in microvascular function, blood vessel stability, angiogenesis, and blood pressure regulation. In addition, tissue-specific pericytes are important in maintaining specific functions in different organs, including vitamin A storage in the liver, renin production in the kidneys and maintenance of the blood-brain-barrier. Together with their multipotential differentiation capacity, this makes pericytes the preferred cell type for application in TE grafts. The use of a tissue-specific pericyte cell population that matches the TE organ may benefit organ function. In this review, we provide an overview of the literature for graft (pre)-vascularization strategies and highlight the possible advantages of using tissue-specific pericytes for specific TE organ grafts. Impact statement The use of a tissue-specific pericyte cell population that matches the tissue-engineered (TE) organ may benefit organ function. In this review, we provide an overview of the literature for graft (pre)vascularization strategies and highlight the possible advantages of using tissue-specific pericytes for specific TE organ grafts.
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http://dx.doi.org/10.1089/ten.TEB.2020.0229DOI Listing
January 2021

Plasma Methylglyoxal Levels Are Associated With Amputations and Mortality in Severe Limb Ischemia Patients With and Without Diabetes.

Diabetes Care 2021 Jan 3;44(1):157-163. Epub 2020 Nov 3.

Department of Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM) School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands.

Objective: Diabetes is a risk factor for severe limb ischemia (SLI), a condition associated with high mortality, morbidity, and limb loss. The reactive glucose-derived dicarbonyl methylglyoxal (MGO) is a major precursor for advanced glycation end products (AGEs) and a potential driver of cardiovascular disease. We investigated whether plasma MGO levels are associated with poor outcomes in SLI.

Research Design And Methods: We measured plasma levels of MGO, free AGEs, and d-lactate, the detoxification end product of MGO, with ultraperformance liquid chromatography-tandem mass spectrometry at baseline in 160 patients (64.8 ± 13.3 years, 67.5% male, 37.5% with diabetes) with no-option SLI and recorded major adverse outcomes ( = 86, comprising = 53 deaths and = 49 amputations [first event counted]) over the 5-year follow-up. Data were analyzed with linear or Cox regression, after Ln-transformation of the independent variables, adjusted for sex, age, trial arm, diabetes, estimated glomerular filtration rate, systolic blood pressure, cholesterol levels, and BMI. Associations are reported per 1 SD plasma marker.

Results: Higher plasma MGO levels were associated with more adverse outcomes (relative risk 1.44; 95% CI 1.11-1.86) and amputations separately (1.55; 1.13-2.21). We observed a similar but weaker trend for mortality (1.28; 0.93-1.77). The MGO-derived AGE N-(carboxyethyl)lysine was also associated with more adverse outcomes (1.46; 1.00-2.15) and amputations (1.71; 1.04-2.79). d-Lactate was not associated with adverse incident outcomes. Higher plasma MGO levels were also associated with more inflammation and white blood cells and fewer progenitor cells.

Conclusions: Plasma MGO levels are associated with adverse outcomes in SLI. Future studies should investigate whether MGO-targeting therapies improve outcomes in SLI.
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http://dx.doi.org/10.2337/dc20-0581DOI Listing
January 2021

Bleeding risk of haemodialysis and peritoneal dialysis patients.

Nephrol Dial Transplant 2021 01;36(1):170-175

Department of Nephrology and Hypertension, University Medical Centre Utrecht, Utrecht, The Netherlands.

Background: Dialysis patients have an increased bleeding risk as compared with the general population. However, there is limited information whether bleeding risks are different for patients treated with haemodialysis (HD) or peritoneal dialysis (PD). From a clinical point of view, this information could influence therapy choice. Therefore the aim of this study was to investigate the association between dialysis modality and bleeding risk.

Methods: Incident dialysis patients from the Netherlands Cooperative Study on the Adequacy of Dialysis were prospectively followed for major bleeding events over 3 years. Hazard ratios with 95% confidence intervals (CIs) were calculated for HD compared with PD using a time-dependent Cox regression analysis, with updates on dialysis modality.

Results: In total, 1745 patients started dialysis, of whom 1211 (69.4%) received HD and 534 (30.6%) PD. The bleeding rate was 60.8/1000 person-years for HD patients and 34.6/1000 person-years for PD patients. The time-dependent Cox regression analysis showed that after adjustment for age, sex, primary kidney disease, prior bleeding, cardiovascular disease, antiplatelet drug use, vitamin K antagonist use, erythropoietin use, arterial hypertension, residual glomerular filtratin rate, haemoglobin and albumin levels, bleeding risk for HD patients compared with PD increased 1.5-fold (95% CI 1.0-2.2).

Conclusions: In this large prospective cohort of incident dialysis patients, HD patients had an increased bleeding risk compared with PD patients. In particular, HD patients with a history of prior bleeding had an increased bleeding risk.
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http://dx.doi.org/10.1093/ndt/gfaa216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771974PMC
January 2021

Dosage reduction of low weight heparin in patients with renal dysfunction: Effects on anti-Xa levels and clinical outcomes.

PLoS One 2020 1;15(10):e0239222. Epub 2020 Oct 1.

Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, the Netherlands.

Background: To prevent bio-accumulation of low molecular weight heparins (LMWHs) in patients with decreased kidney function, dosage reduction and anti-Xa monitoring has been suggested. The aim of this study was to investigate the effect of pre-emptive dosage reduction of LMWH on anti-Xa levels. Furthermore, we investigated the association between anti-Xa levels and bleeding, thrombotic events and mortality.

Methods: In this single center study, we followed 499 patients with decreased renal function in whom anti-Xa levels were measured. We observed how many patients had anti-Xa levels that fell within the reference range, with a standard protocol of a pre-emptive dosage reduction of LMWH (25% reduction in patients with an estimated glomerular filtration rate (eGFR) between 30 and 60 ml/min/1.73m2 and a reduction of 50% in patients with an eGFR below the 30 ml/min/1.73m2). Furthermore, Cox proportional hazard analyses were used to estimate hazard ratios to investigate the association between anti-Xa levels and major bleeding, thrombotic events and mortality within three months of follow-up.

Results: In a cohort of 499 patients (445 dalteparin and 54 nadroparin users), a pre-emptive dosage reduction of LMWH led to adequate levels of anti-Xa in only 19% of the patients (12% for the dalteparin users and 50% for nadroparin users). We did not find an association between anti-Xa levels and bleeding, thrombosis or mortality.

Conclusion: Pre-emptive dosage reduction of LMWH leads to low anti-Xa levels in a large proportion, but this was not associated with bleeding, thrombosis or mortality.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239222PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529211PMC
November 2020

Validation of multiparametric MRI by histopathology after nephrectomy: a case study.

MAGMA 2020 Sep 20. Epub 2020 Sep 20.

Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Objectives: Renal multiparametric MRI (mpMRI) is a promising tool to monitor renal allograft health to enable timely treatment of chronic allograft nephropathy. This study aims to validate mpMRI by whole-kidney histology following transplantectomy.

Materials And Methods: A patient with kidney transplant failure underwent mpMRI prior to transplantectomy. The mpMRI included blood oxygenation level-dependent (BOLD) MRI, T and T mapping, diffusion-weighted imaging (DWI), 2D phase contrast (2DPC) and arterial spin labeling (ASL). Parenchymal mpMRI measures were compared to normative values obtained in 19 healthy controls. Differences were expressed in standard deviations (SD) of normative values. The mpMRI measures were compared qualitatively to histology.

Results: The mpMRI showed a heterogeneous parenchyma consistent with extensive interstitial hemorrhage on histology. A global increase in T (+ 3.0 SD) and restricted diffusivity (- 3.6 SD) were consistent with inflammation and fibrosis. Decreased T (- 1.8 SD) indicated fibrosis or hemorrhage. ASL showed diminished cortical perfusion (- 2.9 SD) with patent proximal arteries. 2DPC revealed a 69% decrease in renal perfusion. Histological evaluation showed a dense inflammatory infiltrate and fibrotic changes, consistent with mpMRI results. Most interlobular arteries were obliterated while proximal arteries were patent, consistent with ASL findings.

Discussion: mpMRI findings correlated well with histology both globally as well as locally.
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http://dx.doi.org/10.1007/s10334-020-00887-9DOI Listing
September 2020

Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Extracellular Matrix Remodeling during Left Ventricular Diastolic Dysfunction and Heart Failure with Preserved Ejection Fraction: A Systematic Review and Meta-Analysis.

Int J Mol Sci 2020 Sep 14;21(18). Epub 2020 Sep 14.

Department Nephrology and Hypertension, University Medical Center Utrecht, P.O. Box 8599, 3508 GA Utrecht, The Netherlands.

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are pivotal regulators of extracellular matrix (ECM) composition and could, due to their dynamic activity, function as prognostic tools for fibrosis and cardiac function in left ventricular diastolic dysfunction (LVDD) and heart failure with preserved ejection fraction (HFpEF). We conducted a systematic review on experimental animal models of LVDD and HFpEF published in MEDLINE or Embase. Twenty-three studies were included with a total of 36 comparisons that reported established LVDD, quantification of cardiac fibrosis and cardiac MMP or TIMP expression or activity. LVDD/HFpEF models were divided based on underlying pathology: hemodynamic overload (17 comparisons), metabolic alteration (16 comparisons) or ageing (3 comparisons). Meta-analysis showed that echocardiographic parameters were not consistently altered in LVDD/HFpEF with invasive hemodynamic measurements better representing LVDD. Increased myocardial fibrotic area indicated comparable characteristics between hemodynamic and metabolic models. Regarding MMPs and TIMPs; MMP2 and MMP9 activity and protein and TIMP1 protein levels were mainly enhanced in hemodynamic models. In most cases only mRNA was assessed and there were no correlations between cardiac tissue and plasma levels. Female gender, a known risk factor for LVDD and HFpEF, was underrepresented. Novel studies should detail relevant model characteristics and focus on MMP and TIMP protein expression and activity to identify predictive circulating markers in cardiac ECM remodeling.
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http://dx.doi.org/10.3390/ijms21186742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555240PMC
September 2020

Health-Related Quality of Life in Home Dialysis Patients Compared to In-Center Hemodialysis Patients: A Systematic Review and Meta-analysis.

Kidney Med 2020 Mar-Apr;2(2):139-154. Epub 2020 Feb 11.

Department of Nephrology, Amsterdam University Medical Centers, Location AMC, Amsterdam, the Netherlands.

Rationale & Objective: Dialysis patients judge health-related quality of life (HRQoL) as an essential outcome. Remarkably, little is known about HRQoL differences between home dialysis and in-center hemodialysis (HD) patients worldwide.

Study Design: Systematic review and meta-analysis.

Setting & Study Populations: Search strategies were performed on the Cochrane Library, Pubmed, and EMBASE databases between 2007 and 2019. Home dialysis was defined as both peritoneal dialysis and home HD.

Selection Criteria For Studies: Randomized controlled trials and observational studies that compared HRQoL in home dialysis patients versus in-center HD patients.

Data Extraction: The data extracted by 2 authors included HRQoL scores of different questionnaires, dialysis modality, and subcontinent.

Analytical Approach: Data were pooled using a random-effects model and results were expressed as standardized mean difference (SMD) with 95% CIs. Heterogeneity was explored using subgroup analyses.

Results: Forty-six articles reporting on 41 study populations were identified. Most studies were cross-sectional in design (90%), conducted on peritoneal dialysis patients (95%), and used the 12-item or 36-item Short-Form Health Survey questionnaires (83%). More than half the studies showed moderate or high risk of bias. Pooled analysis of 4,158 home dialysis patients and 7,854 in-center HD patients showed marginally better physical HRQoL scores in home dialysis patients compared with in-center HD patients (SMD, 0.14; 95% CI, 0.04 to 0.24), although heterogeneity was high (>80%). In a subgroup analysis, Western European home dialysis patients had higher physical HRQoL scores (SMD, 0.39; 95% CI, 0.17 to 0.61), while home dialysis patients from Latin America had lower physical scores (SMD, -0.20; 95% CI, -0.28 to -0.12). Mental HRQoL showed no difference in all analyses.

Limitations: No randomized controlled trials were found and high heterogeneity among studies existed.

Conclusions: Although pooled data showed marginally better physical HRQoL for home dialysis patients, the quality of design of the included studies was poor. Large prospective studies with adequate adjustments for confounders are necessary to establish whether home dialysis results in better HRQoL.

Trial Registration: PROSPERO 95985.
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http://dx.doi.org/10.1016/j.xkme.2019.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380444PMC
February 2020

H3K27ac acetylome signatures reveal the epigenomic reorganization in remodeled non-failing human hearts.

Clin Epigenetics 2020 07 14;12(1):106. Epub 2020 Jul 14.

Department of Nephrology and Hypertension, DIGD, UMC Utrecht, University of Utrecht, Utrecht, Netherlands.

Background: H3K27ac histone acetylome changes contribute to the phenotypic response in heart diseases, particularly in end-stage heart failure. However, such epigenetic alterations have not been systematically investigated in remodeled non-failing human hearts. Therefore, valuable insight into cardiac dysfunction in early remodeling is lacking. This study aimed to reveal the acetylation changes of chromatin regions in response to myocardial remodeling and their correlations to transcriptional changes of neighboring genes.

Results: We detected chromatin regions with differential acetylation activity (DARs; P < 0.05) between remodeled non-failing patient hearts and healthy donor hearts. The acetylation level of the chromatin region correlated with its RNA polymerase II occupancy level and the mRNA expression level of its adjacent gene per sample. Annotated genes from DARs were enriched in disease-related pathways, including fibrosis and cell metabolism regulation. DARs that change in the same direction have a tendency to cluster together, suggesting the well-reorganized chromatin architecture that facilitates the interactions of regulatory domains in response to myocardial remodeling. We further show the differences between the acetylation level and the mRNA expression level of cell-type-specific markers for cardiomyocytes and 11 non-myocyte cell types. Notably, we identified transcriptome factor (TF) binding motifs that were enriched in DARs and defined TFs that were predicted to bind to these motifs. We further showed 64 genes coding for these TFs that were differentially expressed in remodeled myocardium when compared with controls.

Conclusions: Our study reveals extensive novel insight on myocardial remodeling at the DNA regulatory level. Differences between the acetylation level and the transcriptional level of cell-type-specific markers suggest additional mechanism(s) between acetylome and transcriptome. By integrating these two layers of epigenetic profiles, we further provide promising TF-encoding genes that could serve as master regulators of myocardial remodeling. Combined, our findings highlight the important role of chromatin regulatory signatures in understanding disease etiology.
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http://dx.doi.org/10.1186/s13148-020-00895-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362435PMC
July 2020

Sodium thiosulfate improves renal function and oxygenation in L-NNA-induced hypertension in rats.

Kidney Int 2020 08 23;98(2):366-377. Epub 2020 Mar 23.

Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address:

Sodium thiosulfate, a reversible oxidation product of hydrogen sulfide, has vasodilating and anti-oxidative properties, making it an attractive agent to alleviate damaging effects of hypertension. In experimental settings, inhibition of nitric oxide synthase causes hypertension, renal dysfunction and damage. We hypothesized that thiosulfate would attenuate renal injury and improve renal function, hemodynamics and the efficiency of oxygen utilization for sodium reabsorption in hypertensive renal disease. Additionally, thiosulfate co-administration would further improve these variables when compared to inhibiting the renin-angiotensin system alone. Nitric oxide synthase was inhibited in Sprague Dawley rats by administering N-ω-nitro-L-arginine (L-NNA) in the food for three weeks. After one week, rats were split into two groups; without and with thiosulfate in the drinking water. In a parallel study, rats given N-ω-nitro-L-arginine and the angiotensin converting enzyme inhibitor lisinopril at a relatively low dose in their food were divided into two groups; without and with thiosulfate in the drinking water. Treatment with thiosulfate alleviated hypertension (mean 190 vs. 229 mmHg), lowered plasma urea (mean 11.3 vs. 20.0 mmol/L) and improved the terminal glomerular filtration rate (mean 503 vs. 260 μl/min/100 gbw), effective renal plasma flow (mean 919 vs. 514 μl/min/100 gbw) and oxygen utilization for sodium reabsorption (mean 14.3 vs. 8.6 μmol/μmol). Combining thiosulfate with lisinopril further lowered renal vascular resistance (mean 43 vs. 63 mmHg/ml/min/100 gbw) and prevented glomerulosclerosis. Thus, our results suggest that thiosulfate has therapeutic potential in hypertensive renal disease and might be of value when added to standard antihypertensive therapies.
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http://dx.doi.org/10.1016/j.kint.2020.02.020DOI Listing
August 2020

Drugs Commonly Applied to Kidney Patients May Compromise Renal Tubular Uremic Toxins Excretion.

Toxins (Basel) 2020 06 12;12(6). Epub 2020 Jun 12.

Department of Nephrology and Hypertension, University Medical Center Utrecht, 3582 CX Utrecht, The Netherlands.

In chronic kidney disease (CKD), the secretion of uremic toxins is compromised leading to their accumulation in blood, which contributes to uremic complications, in particular cardiovascular disease. Organic anion transporters (OATs) are involved in the tubular secretion of protein-bound uremic toxins (PBUTs). However, OATs also handle a wide range of drugs, including those used for treatment of cardiovascular complications and their interaction with PBUTs is unknown. The aim of this study was to investigate the interaction between commonly prescribed drugs in CKD and endogenous PBUTs with respect to OAT1-mediated uptake. We exposed a unique conditionally immortalized proximal tubule cell line (ciPTEC) equipped with OAT1 to a panel of selected drugs, including angiotensin-converting enzyme inhibitors (ACEIs: captopril, enalaprilate, lisinopril), angiotensin receptor blockers (ARBs: losartan and valsartan), furosemide and statins (pravastatin and simvastatin), and evaluated the drug-interactions using an OAT1-mediated fluorescein assay. We show that selected ARBs and furosemide significantly reduced fluorescein uptake, with the highest potency for ARBs. This was exaggerated in presence of some PBUTs. Selected ACEIs and statins had either no or a slight effect at supratherapeutic concentrations on OAT1-mediated fluorescein uptake. In conclusion, we demonstrate that PBUTs may compete with co-administrated drugs commonly used in CKD management for renal OAT1 mediated secretion, thus potentially compromising the residual renal function.
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http://dx.doi.org/10.3390/toxins12060391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354492PMC
June 2020

Extracellular Matrix Analysis of Human Renal Arteries in Both Quiescent and Active Vascular State.

Int J Mol Sci 2020 May 30;21(11). Epub 2020 May 30.

Department of Nephrology and Hypertension, Division of Internal Medicine and Dermatology, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands.

In vascular tissue engineering strategies, the addition of vascular-specific extracellular matrix (ECM) components may better mimic the in vivo microenvironment and potentially enhance cell-matrix interactions and subsequent tissue growth. For this purpose, the exact composition of the human vascular ECM first needs to be fully characterized. Most research has focused on characterizing ECM components in mature vascular tissue; however, the developing fetal ECM matches the active environment required in vascular tissue engineering more closely. Consequently, we characterized the ECM protein composition of active (fetal) and quiescent (mature) renal arteries using a proteome analysis of decellularized tissue. The obtained human fetal renal artery ECM proteome dataset contains higher levels of 15 ECM proteins versus the mature renal artery ECM proteome, whereas 16 ECM proteins showed higher levels in the mature tissue compared to fetal. Elastic ECM proteins EMILIN1 and FBN1 are significantly enriched in fetal renal arteries and are mainly produced by cells of mesenchymal origin. We functionally tested the role of EMILIN1 and FBN1 by anchoring the ECM secreted by vascular smooth muscle cells (SMCs) to glass coverslips. This ECM layer was depleted from either EMILIN1 or FBN1 by using siRNA targeting of the SMCs. Cultured endothelial cells (ECs) on this modified ECM layer showed alterations on the transcriptome level of multiple pathways, especially the Rho GTPase controlled pathways. However, no significant alterations in adhesion, migration or proliferation were observed when ECs were cultured on EMILIN1- or FNB1-deficient ECM. To conclude, the proteome analysis identified unique ECM proteins involved in the embryonic development of renal arteries. Alterations in transcriptome levels of ECs cultured on EMILIN1- or FBN1-deficient ECM showed that these candidate proteins could affect the endothelial (regenerative) response.
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http://dx.doi.org/10.3390/ijms21113905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313045PMC
May 2020

Kidney Organoids and Tubuloids.

Cells 2020 05 26;9(6). Epub 2020 May 26.

Hubrecht Institute-Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, the Netherlands.

In the past five years, pluripotent stem cell (PSC)-derived kidney organoids and adult stem or progenitor cell (ASC)-based kidney tubuloids have emerged as advanced in vitro models of kidney development, physiology, and disease. PSC-derived organoids mimic nephrogenesis. After differentiation towards the kidney precursor tissues ureteric bud and metanephric mesenchyme, their reciprocal interaction causes self-organization and patterning in vitro to generate nephron structures that resemble the fetal kidney. ASC tubuloids on the other hand recapitulate renewal and repair in the adult kidney tubule and give rise to long-term expandable and genetically stable cultures that consist of adult proximal tubule, loop of Henle, distal tubule, and collecting duct epithelium. Both organoid types hold great potential for: (1) studies of kidney physiology, (2) disease modeling, (3) high-throughput screening for drug efficacy and toxicity, and (4) regenerative medicine. Currently, organoids and tubuloids are successfully used to model hereditary, infectious, toxic, metabolic, and malignant kidney diseases and to screen for effective therapies. Furthermore, a tumor tubuloid biobank was established, which allows studies of pathogenic mutations and novel drug targets in a large group of patients. In this review, we discuss the nature of kidney organoids and tubuloids and their current and future applications in science and medicine.
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http://dx.doi.org/10.3390/cells9061326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349753PMC
May 2020

Early Estimation of Renal Function After Transplantation to Enable Appropriate Dosing of Critical Drugs: Retrospective Analysis of 103 Patients in a Single Center.

Clin Pharmacokinet 2020 10;59(10):1303-1311

Department of Nephrology and Hypertension, UMC Utrecht, Utrecht University, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands.

Background: Immediately after renal transplantation (RTX), estimation of renal function (eGFR) is important for drug dosing and the detection of potential complications. Conventional formulas cannot be used since the serum creatinine concentration is not at steady-state. In this study, we evaluated different dynamic renal function formulas (DRFFs) to estimate eGFR immediately after RTX.

Methods: We retrospectively included 154 RTX patients, of whom 45 had delayed graft function (DGF) and required dialysis, and 6 had unstable graft function without the need for dialysis; 103 patients had early, and thereafter stable, graft function (EGF). DRFFs were evaluated to calculate eGFR 1 day after transplantation (T1) using a new dynamic creatinine clearance calculation (D3C), two previously published formulas (Jelliffe, and the kinetic eGFR [KeGFR]), and a naive predictor (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] at T1). The estimated DRFF-based renal functions at T1 were compared with the CKD-EPI after stabilization of renal function 3 days after transplantation (eGFR-T3), which was considered the underlying renal function immediately after RTX.

Results: The D3C showed low bias (mean prediction error [MPE] - 4.5 ml/min/1.73 m) and performed well on other outcome measures (R = 0.82, root mean squared error [RMSE] = 11.8 ml/min/1.73 m, percentage of predictions within 30% of the reference value [p] = 76%). In addition, the D3C outperformed the KeGFR (MPE 20.5 ml/min/1.73 m, R = 0.79, RMSE = 26.9 ml/min/1.73 m, p = 29%), Jelliffe (MPE - 13.3 ml/min/1.73 m, R = 0.76, RMSE = 19.1 ml/min/1.73 m, p = 53%), and the naive predictor (bias - 24.8 ml/min/1.73 m, R = 0.60, RMSE = 30.2 ml/min/1.73 m, p = 21%).

Conclusions: The newly developed D3C enables reliable assessment of renal function immediately after RTX, provides crucial information for drug dosing, and might also advance the detection of functional decline, potentially improving treatment and renal outcome.
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http://dx.doi.org/10.1007/s40262-020-00893-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550320PMC
October 2020

Innovations in approaches to remove uraemic toxins.

Nat Rev Nephrol 2020 10;16(10):552-553

Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.

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http://dx.doi.org/10.1038/s41581-020-0299-0DOI Listing
October 2020

Both male and female obese ZSF1 rats develop cardiac dysfunction in obesity-induced heart failure with preserved ejection fraction.

PLoS One 2020 6;15(5):e0232399. Epub 2020 May 6.

Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.

Heart failure with a preserved ejection fraction (HFpEF) is associated with multiple comorbidities, such as old age, hypertension, type 2 diabetes and obesity and is more prevalent in females. Although the male obese ZSF1 rat has been proposed as a suitable model to study the development of diastolic dysfunction and early HFpEF, studies in female animals have not been performed yet. Therefore, we aimed to characterize the cardiac phenotype in female obese ZSF1 rats and their lean counterparts. Additionally, we aimed to investigate whether differences exist in disease progression in obese male and female ZSF1 rats. Therefore, male and female ZSF1 rats, lean as well as obese (N = 6-9/subgroup), were used. Every two weeks, from 12 to 26 weeks of age, systolic blood pressure and echocardiographic measurements were performed, and venous blood was sampled. Female obese ZSF1 rats, as compared to female lean ZSF1 rats, developed diastolic dysfunction with cardiac hypertrophy and fibrosis in the presence of severe dyslipidemia, increased plasma growth differentiation factor 15 and mild hypertension, and preservation of systolic function. Although obese female ZSF1 rats did not develop hyperglycemia, their diastolic dysfunction was as severe as in the obese males. Taken together, the results from the present study suggest that the female obese ZSF1 rat is a relevant animal model for HFpEF with multiple comorbidities, suitable for investigating novel therapeutic interventions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232399PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202634PMC
July 2020

A new microfluidic model that allows monitoring of complex vascular structures and cell interactions in a 3D biological matrix.

Lab Chip 2020 05;20(10):1827-1844

Department of Nephrology and Hypertension, University Medical Center Utrecht, PO Box 85500, 3584 CX Utrecht, The Netherlands.

Microfluidic organ-on-a-chip designs are used to mimic human tissues, including the vasculature. Here we present a novel microfluidic device that allows the interaction of endothelial cells (ECs) with pericytes and the extracellular matrix (ECM) in full bio-matrix encased 3D vessel structures (neovessels) that can be subjected to continuous, unidirectional flow and perfusion with circulating immune cells. We designed a polydimethylsiloxane (PDMS) device with a reservoir for a 3D fibrinogen gel with pericytes. Open channels were created for ECs to form a monolayer. Controlled, continuous, and unidirectional flow was introduced via a pump system while the design facilitated 3D confocal imaging. In this vessel-on-a-chip system, ECs interact with pericytes to create a human cell derived blood vessel which maintains a perfusable lumen for up to 7 days. Dextran diffusion verified endothelial barrier function while demonstrating the beneficial role of supporting pericytes. Increased permeability after thrombin stimulation showed the capacity of the neovessels to show natural vascular response. Perfusion of neovessels with circulating THP-1 cells demonstrated this system as a valuable platform for assessing interaction between the endothelium and immune cells in response to TNFα. In conclusion: we created a novel vascular microfluidic device that facilitates the fabrication of an array of parallel soft-channel structures in ECM gel that develop into biologically functional neovessels without hard-scaffold support. This model provides a unique tool to conduct live in vitro imaging of the human vasculature during perfusion with circulating cells to mimic (disease) environments in a highly systematic but freely configurable manner.
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http://dx.doi.org/10.1039/d0lc00059kDOI Listing
May 2020

Multiparametric Renal MRI: An Intrasubject Test-Retest Repeatability Study.

J Magn Reson Imaging 2021 03 16;53(3):859-873. Epub 2020 Apr 16.

Department of Radiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Background: Renal multiparametric magnetic resonance imaging (MRI) is a promising tool for diagnosis, prognosis, and treatment monitoring in kidney disease.

Purpose: To determine intrasubject test-retest repeatability of renal MRI measurements.

Study Type: Prospective.

Population: Nineteen healthy subjects aged over 40 years.

Field Strength/sequences: T and T mapping, R * mapping or blood oxygenation level-dependent (BOLD) MRI, diffusion tensor imaging (DTI), and intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI), 2D phase contrast, arterial spin labelling (ASL), dynamic contrast enhanced (DCE) MRI, and quantitative Dixon for fat quantification at 3T.

Assessment: Subjects were scanned twice with ~1 week between visits. Total scan time was ~1 hour. Postprocessing included motion correction, semiautomated segmentation of cortex and medulla, and fitting of the appropriate signal model.

Statistical Test: To assess the repeatability, a Bland-Altman analysis was performed and coefficients of variation (CoVs), repeatability coefficients, and intraclass correlation coefficients were calculated.

Results: CoVs for relaxometry (T , T , R */BOLD) were below 6.1%, with the lowest CoVs for T maps and highest for R */BOLD. CoVs for all diffusion analyses were below 7.2%, except for perfusion fraction (F ), with CoVs ranging from 18-24%. The CoV for renal sinus fat volume and percentage were both around 9%. Perfusion measurements were most repeatable with ASL (cortical perfusion only) and 2D phase contrast with CoVs of 10% and 13%, respectively. DCE perfusion had a CoV of 16%, while single kidney glomerular filtration rate (GFR) had a CoV of 13%. Repeatability coefficients (RCs) ranged from 7.7-87% (lowest/highest values for medullary mean diffusivity and cortical F , respectively) and intraclass correlation coefficients (ICCs) ranged from -0.01 to 0.98 (lowest/highest values for cortical F and renal sinus fat volume, respectively).

Data Conclusion: CoVs of most MRI measures of renal function and structure (with the exception of F and perfusion as measured by DCE) were below 13%, which is comparable to standard clinical tests in nephrology.

Level Of Evidence: 2 TECHNICAL EFFICACY: Stage 1.
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http://dx.doi.org/10.1002/jmri.27167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891585PMC
March 2021

Protein-Bound Uremic Toxins in Hemodialysis Patients Relate to Residual Kidney Function, Are Not Influenced by Convective Transport, and Do Not Relate to Outcome.

Toxins (Basel) 2020 04 7;12(4). Epub 2020 Apr 7.

Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.

Protein-bound uremic toxins (PBUTs) are predominantly excreted by renal tubular secretion and hardly removed by traditional hemodialysis (HD). Accumulation of PBUTs is proposed to contribute to the increased morbidity and mortality of patients with end-stage kidney disease (ESKD). Preserved PBUT excretion in patients with residual kidney function (RKF) and/or increased PBUT clearance with improved dialysis techniques might improve the prognosis of patients with ESKD. The aims of this study are to explore determinants of PBUTs in HD patients, and investigate whether hemodiafiltration (HDF) lowers PBUT plasma concentrations, and whether PBUTs are related to the outcome. Predialysis total plasma concentrations of kynurenine, kynurenic acid, indoxyl sulfate, indole-3-acetic acid, p-cresyl sulfate, p-cresyl glucuronide, and hippuric acid were measured by UHPLC-MS at baseline and after 6 months of follow-up in the first 80 patients participating in the CONvective TRAnsport Study (CONTRAST), a randomized controlled trial that compared the effects of online HDF versus low-flux HD on all-cause mortality and new cardiovascular events. RKF was inversely related to kynurenic acid ( < 0.001), indoxyl sulfate ( = 0.001), indole-3-acetic acid ( = 0.024), p-cresyl glucuronide ( = 0.004) and hippuric acid ( < 0.001) plasma concentrations. Only indoxyl sulfate decreased by 8.0% (-15.3 to 34.6) in patients treated with HDF and increased by 11.9% (-15.4 to 31.9) in HD patients after 6 months of follow-up (HDF vs. HD: = 0.045). No independent associations were found between PBUT plasma concentrations and either risk of all-cause mortality or new cardiovascular events. In summary, in the current population, RKF is an important determinant of PBUT plasma concentrations in HD patients. The addition of convective transport did not consistently decrease PBUT plasma concentrations and no relation was found between PBUTs and cardiovascular endpoints.
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http://dx.doi.org/10.3390/toxins12040234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232478PMC
April 2020

External validation of the Vascular Quality Initiative prediction model for survival in no-option chronic limb-threatening ischemia patients.

J Vasc Surg 2020 11 2;72(5):1659-1666.e1. Epub 2020 Apr 2.

Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address:

Objective: Chronic limb-threatening ischemia (CLTI) is associated with high morbidity and mortality rates. More than 50% of all CLTI patients die within 5 years after presentation. Patient-specific survival prediction is critical for informing treatment strategies, even for those without a clear option for revascularization. We validated a survival prediction model, developed in a revascularized Vascular Quality Initiative (VQI) cohort, in a Western European no-option CLTI cohort.

Methods: The VQI survival prediction model was applied to the validation cohort (N = 150) to compare estimated mortality and observed mortality at 2 years after baseline. Performance of the VQI model was tested by evaluating discrimination using the receiver operating characteristic area under the curve and calibration using the Hosmer-Lemeshow goodness-of-fit test.

Results: The 2-year survival rate was 79% in the validation cohort compared with 83% in the VQI cohort. Baseline characteristics were significantly different for 13 of 17 variables. The C statistic was 0.86 (95% confidence interval, 0.78-0.95), which indicates good discrimination. The Hosmer-Lemeshow goodness-of-fit test had a P value of .30, which indicates good fit.

Conclusions: This is the first external validation of the VQI survival prediction model. The good model performance suggests that this model can be used in different CLTI populations, including no-option CLTI, and underlines its contributory role in this challenging population.
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http://dx.doi.org/10.1016/j.jvs.2020.02.018DOI Listing
November 2020

A systematic review and external validation of stroke prediction models demonstrates poor performance in dialysis patients.

J Clin Epidemiol 2020 07 30;123:69-79. Epub 2020 Mar 30.

Department of Clinical Epidemiology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.

Objectives: The objective of this study was to systematically review and externally assess the predictive performance of models for ischemic stroke in incident dialysis patients.

Study Design And Setting: Two reviewers systematically searched and selected ischemic stroke models. Risk of bias was assessed with the PROBAST. Predictive performance was evaluated within The Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD), a large prospective multicenter cohort of incident dialysis patients. For discrimination, c-statistics were calculated; calibration was assessed by plotting predicted and observed probabilities for stroke, and calibration-in-the-large.

Results: Seventy-seven prediction models for stroke were identified, of which 15 were validated. Risk of bias was high, with all of these models scoring high risk in one or more domains. In NECOSAD, of the 1,955 patients, 127 (6.5%) suffered an ischemic stroke during the follow-up of 2.5 years. Compared with the original studies, most models performed worse with all models showing poor calibration and discriminative abilities (c-statistics ranging from 0.49 to 0.66). The Framingham showed reasonable calibration; however, with a c-statistic of 0.57 (95% CI 0.50-0.63), the discrimination was poor.

Conclusion: This external validation demonstrates the weak predictive performance of ischemic stroke models in incident dialysis patients. Instead of using these models in this fragile population, either existing models should be updated, or novel models should be developed and validated.
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http://dx.doi.org/10.1016/j.jclinepi.2020.03.015DOI Listing
July 2020

Perturbations in myocardial perfusion and oxygen balance in swine with multiple risk factors: a novel model of ischemia and no obstructive coronary artery disease.

Basic Res Cardiol 2020 02 25;115(2):21. Epub 2020 Feb 25.

Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.

Comorbidities of ischemic heart disease, including diabetes mellitus (DM), hypercholesterolemia (HC) and chronic kidney disease (CKD), are associated with coronary microvascular dysfunction (CMD). Increasing evidence suggests that CMD may contribute to myocardial 'Ischemia and No Obstructive Coronary Artery disease' (INOCA). In the present study, we tested the hypothesis that CMD results in perturbations in myocardial perfusion and oxygen delivery using a novel swine model with multiple comorbidities. DM (streptozotocin), HC (high-fat diet) and CKD (renal embolization) were induced in 10 female swine (DM + HC + CKD), while 12 healthy female swine on a normal diet served as controls (Normal). After 5 months, at a time when coronary atherosclerosis was still negligible, myocardial perfusion, metabolism, and function were studied at rest and during treadmill exercise. DM + HC + CKD animals showed hyperglycemia, hypercholesterolemia, and impaired kidney function. During exercise, DM + HC + CKD swine demonstrated perturbations in myocardial blood flow and oxygen delivery, necessitating a higher myocardial oxygen extraction-achieved despite reduced capillary density-resulting in lower coronary venous oxygen levels. Moreover, myocardial efficiency was lower, requiring higher oxygen consumption for a given level of myocardial work. These perturbations in myocardial oxygen balance were associated with lower myocardial lactate consumption, stroke volume, and LVdP/dt, suggestive of myocardial ischemia and dysfunction. Further analyses showed a reduction in adenosine-recruitable coronary flow reserve, but this was exclusively the result of an increase in basal coronary blood flow, while maximal coronary flow per gram of myocardium was maintained; the latter was consistent with the unchanged arteriolar wall/lumen ratio, arteriolar density and peri-arteriolar collagen content. However, isolated small arteries displayed selective blunting of endothelium-dependent vasodilation in response to bradykinin in DM + HC + CKD swine, suggesting that changes in coronary microvascular function rather than in structure contributed to the perturbations in myocardial oxygen delivery. In conclusion, common comorbidities in swine result in CMD, in the absence of appreciable atherosclerosis, which is severe enough to produce perturbations in myocardial oxygen balance, particularly during exercise, resembling key features of INOCA.
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http://dx.doi.org/10.1007/s00395-020-0778-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042191PMC
February 2020

Phenylglyoxaldehyde-Functionalized Polymeric Sorbents for Urea Removal from Aqueous Solutions.

ACS Appl Polym Mater 2020 Feb 18;2(2):515-527. Epub 2019 Dec 18.

Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.

For realization of a wearable artificial kidney based on regeneration of a small volume of dialysate, efficient urea removal from dialysate is a major challenge. Here a potentially suitable polymeric sorbent based on phenylglyoxaldehyde (PGA), able to covalently bind urea under physiological conditions, is described. Sorbent beads containing PGA groups were obtained by suspension polymerization of either styrene or vinylphenylethan-1-one (VPE), followed by modification of the aromatic groups of poly(styrene) and poly(VPE) into PGA. It was found that PGA-functionalized sorbent beads had maximum urea binding capacities of 1.4-2.2 mmol/g and removed ∼0.6 mmol urea/g in 8 h at 37 °C under static conditions from urea-enriched phosphate-buffered saline, conditions representative of dialysate regeneration. This means that the daily urea production of a dialysis patient can be removed with a few hundred grams of this sorbent which, is an important step forward in the development of a wearable artificial kidney.
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http://dx.doi.org/10.1021/acsapm.9b00948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027168PMC
February 2020