Publications by authors named "Stephan J L Bakker"

628 Publications

Nonalcoholic fatty liver disease, circulating ketone bodies and all-cause mortality in a general population-based cohort.

Eur J Clin Invest 2021 Jun 13:e13627. Epub 2021 Jun 13.

Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent, paralleling the obesity epidemic. Ketone bodies are produced in the liver, but it is currently uncertain whether circulating ketone bodies are increased in the context of NAFLD. We investigated the association between NAFLD and circulating ketone bodies and determined the extent to which NAFLD and circulating ketone bodies are associated with all-cause mortality.

Methods: Plasma ketone bodies were measured by nuclear magnetic resonance spectroscopy in participants of the general population-based PREVEND study. A fatty liver index (FLI) ≥60 was regarded as a proxy of NAFLD. Associations of an elevated FLI and ketone bodies with all-cause mortality were investigated using Cox regression analyses.

Results: The study included 6,297 participants aged 54 ± 12 years, of whom 1,970 (31%) had elevated FLI. Participants with elevated FLI had higher total ketone bodies (194 [153-259] vs 170 [133-243] µmol/L; P < .001) than participants without elevated FLI. During 7.9 [7.8-8.9] years of follow-up, 387 (6%) participants died. An elevated FLI was independently associated with an increased risk of mortality (HR: 1.34 [1.06-1.70]; P = .02). Higher total ketone bodies were also associated with an increased mortality risk (HR per doubling: 1.29 [1.12-1.49]; P < .001). Mediation analysis suggested that the association of elevated FLI with all-cause mortality was in part mediated by ketone bodies (proportion mediated: 10%, P < .001).

Conclusion: Circulating ketone bodies were increased in participants with suspected NAFLD. Both suspected NAFLD and higher circulating ketone bodies are associated with an increased risk of all-cause mortality.
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http://dx.doi.org/10.1111/eci.13627DOI Listing
June 2021

Barriers to and Facilitators of Sustained Employment: A Qualitative Study of Experiences in Dutch Patients With CKD.

Am J Kidney Dis 2021 Jun 9. Epub 2021 Jun 9.

Department of Health Sciences, Applied Health Research, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Rationale & Objective: Although patients with chronic kidney disease (CKD) are at risk for work disability and work loss, not all experience work disruption. We aimed to describe the experienced barriers to and facilitators of sustained employment among Dutch patients with CKD.

Study Design: Qualitative study using semi-structured interviews.

Setting & Participants: CKD Stage G3b-G5 patients (n = 27) from 4 nephrology outpatient clinics in the Netherlands.

Analytical Approach: Content analyses with constant comparison of interview data based on the International Classification of Functioning, Disability and Health (ICF) framework.

Results: Participants were 6 patients with CKD Stage G3b-G4, 8 patients receiving maintenance dialysis, and 13 patients with functioning kidney transplants. We identified: 1) health-related barriers (symptoms, physical toll of dialysis/transplantation, limited work capacity) and facilitators (few physical symptoms, successful posttransplantation recovery, absence of comorbidities, good physical condition); 2) personal barriers (psychological impact, limited work experience) and facilitators (positive disposition, job satisfaction, work attitude, person-job fit); and 3) environmental barriers related to nephrology care (waiting time, use of a hemodialysis catheter) and to work context (reorganization, temporary contract, working hours, physical demands). Environmental facilitators related to nephrology care (personalized dialysis, pre-emptive transplantation), to work context (large employer, social climate, mental job, flexible working hours, adjustment of work tasks, reduced hours, remote working, support at work, peritoneal dialysis exchange facility), and to support at home. Occupational health services and social security could be either barriers or facilitators.

Limitations: The study sample of Dutch patients may limit the transferability of these findings to other countries.

Conclusions: The wide range of barriers and facilitators in all ICF components suggests great diversity among patients and their circumstances. These findings underline the importance of personalized nephrology and occupational healthcare as well as the importance of individually tailored workplace accommodations to promote sustained employment for patients with CKD.
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http://dx.doi.org/10.1053/j.ajkd.2021.04.008DOI Listing
June 2021

Circulating Trimethylamine N-Oxide Is Associated with Increased Risk of Cardiovascular Mortality in Type-2 Diabetes: Results from a Dutch Diabetes Cohort (ZODIAC-59).

J Clin Med 2021 May 24;10(11). Epub 2021 May 24.

Department of Internal Medicine, Division of Endocrinology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands.

Trimethylamine N-oxide (TMAO), a novel cardiovascular (CV) disease and mortality risk marker, is a gut microbiota-derived metabolite as well. Recently, plasma concentrations of branched-chain amino acids (BCAA) have been reported to be affected by microbiota. The association of plasma TMAO with CV mortality in Type 2 Diabetes (T2D) and its determinants are still incompletely described. We evaluated the association between plasma BCAA and TMAO, and the association of TMAO with CV mortality in T2D individuals. We used data of 595 participants (mean age 69.5 years) from the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) cohort were analyzed. Plasma TMAO and BCAA were measured with nuclear magnetic resonance spectroscopy. CV mortality risk was estimated using multivariable-adjusted Cox regression models. Cross-sectionally, TMAO was independently associated with BCAA standardized (Std) β = 0.18 (95% Confidence Interval (CI) 0.09; 0.27), <0.001. During a median follow-up of 10 years, 113 CV deaths were recorded. In Cox regression analyses, adjusted for multiple clinical and laboratory variables including BCAA, TMAO was independently associated with CV mortality: adjusted hazard ratio (HR) 1.93 (95% CI 1.11; 3.34), = 0.02 (for the highest vs. the lowest tertile of the TMAO distribution). The same was true for analyses with TMAO as continuous variable: HR 1.32 (95% CI 1.07; 1.63), = 0.01 (per 1 SD increase). In contrast, BCAAs were not associated with increased CV mortality. In conclusion, higher plasma TMAO but not BCAA concentrations are associated with an increased risk of CV mortality in individuals with T2D, independent of clinical and biochemical risk markers.
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http://dx.doi.org/10.3390/jcm10112269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197378PMC
May 2021

Boron contents of German Mineral and Medicinal Waters and Their Bioavailability in Drosophila melanogaster and Humans.

Mol Nutr Food Res 2021 Jun 1:e2100345. Epub 2021 Jun 1.

Institute of Human Nutrition and Food Science, University of Kiel, Germany.

Scope: Boron is a trace element that naturally occurs in soil, making mineral and medicinal water important contributors to overall intake. Thus, in a systematic screening, the mean boron concentrations of 381 German mineral and medicinal waters were determined.

Methods And Results: Boron concentrations in mineral and medicinal waters were analysed by inductively coupled mass spectrometry (ICP-MS). Highest boron values found in waters from the southwest of Germany. The boron content of the waters was positively correlated with the concentration of most other analysed bulk elements, including calcium, potassium, magnesium and sodium. Mineral waters with either low (7.9 μg/L), medium (113.9 μg/L) or high (2193.3 μg/L) boron content were chosen for boron exposure experiments in fruit flies (Drosophila melanogaster) and humans. In flies, boron-rich mineral water significantly increased boron accumulation, with the accumulation predominantly occurring in the exoskeleton. In humans, serum boron and 24-h urinary boron excretion significantly increased only in response to the intake of boron-rich mineral water.

Conclusion: Overall, the current data demonstrate that mineral and medicinal waters vary substantially in the content of boron and that boron-rich mineral water can be used to elevate the boron status, both in flies and humans. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/mnfr.202100345DOI Listing
June 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 Jun 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Self-reported alcohol consumption, carbohydrate deficient transferrin and risk of cardiovascular disease: The PREVEND prospective cohort study.

Clin Chim Acta 2021 May 26;520:1-7. Epub 2021 May 26.

Department of Internal Medicine, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands.

Background: Self-reported alcohol consumption is an established risk factor for cardiovascular disease (CVD). Carbohydrate deficient transferrin (CDT) is an established objective marker of excessive alcohol consumption, but data on its prospective association with CVD are lacking. We aimed to evaluate the associations of self-reported alcohol consumption and CDT (expressed as %CDT, a more reliable marker than absolute CDT levels) with CVD risk.

Materials And Methods: In the PREVEND prospective study of 5,206 participants (mean age, 53 years; 47.7% males), alcohol consumption by self-reports, absolute CDT measured using the Siemens nephelometric assay and %CDT calculated as the percentage of total transferrin concentrations, were assessed at baseline. Alcohol consumption was classified into 5 categories: abstention (reference), light, light-moderate, moderate and heavy alcohol consumption.Hazard ratios (HRs) (95% confidence intervals [CI]) for first CVD events were estimated.

Results: Mean (SD) of %CDT was 1.59 (0.54) %. During a median follow-up of 8.3 years, 326 first CVD events were recorded. Compared with abstainers, the multivariable-adjusted HRs (95% CIs) of CVD for light, light-moderate, moderate and heavy alcohol consumption were 0.66 (0.46-0.95), 0.83 (0.62-1.11), 0.83 (0.61-1.14) and 0.80 (0.48-1.36), respectively. Light alcohol consumption was associated with reduced coronary heart disease risk 0.62 (0.40-0.96), whereas light-moderate alcohol consumption was associated with reduced stroke risk 0.45 (0.24-0.83). The association of %CDT with CVD risk was not significant.

Conclusions: Our findings confirm the established association between self-reported light to moderate alcohol consumption and reduced CVD risk. However, %CDT within the normal reference range may not be a risk indicator for CVD.
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http://dx.doi.org/10.1016/j.cca.2021.05.024DOI Listing
May 2021

Statin use and incident cardiovascular events in renal transplant recipients.

Eur J Clin Invest 2021 May 27:e13594. Epub 2021 May 27.

Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.

Background: Statins achieve potent LDL lowering in the general population leading to a significant cardiovascular (CV) risk reduction. In renal transplant recipients (RTR) statins are included in treatment guidelines, however, conclusive evidence of improved cardiovascular outcomes has not been uniformly provided and concerns have been raised about simultaneous use of statins and the immunosuppressant cyclosporine. This study aimed to elucidate the effect of statins on a compound CV endpoint, comprised of ischaemic CV events and CV mortality in RTR, with subgroup analysis focussing on cyclosporine users.

Method: 622 included RTR (follow-up 5.4 years) were matched based on propensity scores and dichotomized by statin use. Survival analysis was conducted.

Results: Cox regression showed that statin use was not significantly associated with the compound CV endpoint in a fully adjusted model (HR = 0.81, 95% CI = 0.53-1.24, P = .33). Subgroup analyses in RTR using cyclosporine revealed a strong positive association of statin use with the CV compound outcome in a fully adjusted model (HR = 6.60, 95% CI 1.75-24.9, P = .005). Furthermore, statin use was positively correlated with cyclosporine trough levels (correlation coefficient 0.11, P = .04).

Conclusion: In conclusion, statin use does not significantly decrease incident CV events in an overall RTR cohort, but is independently associated with CV-specific mortality and events in cyclosporine using RTR, possibly due to a bilateral pharmacological interaction.
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http://dx.doi.org/10.1111/eci.13594DOI Listing
May 2021

Frailty and Kidney Transplantation: A Systematic Review and Meta-analysis.

Transplant Direct 2021 Jun 18;7(6):e701. Epub 2021 May 18.

Division of Transplantation Surgery, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Frailty is a multidimensional condition and is the result of the body's age-associated decline in physical, cognitive, physiological, and immune reserves. The aim of this systematic review is to assess the quality of evidence of the included studies, determine the prevalence of frailty among kidney transplant candidates, and evaluate the relationship between frailty and associated patient characteristics and outcomes after kidney transplantation.

Methods: A systematic search was performed for relevant literature on frailty and kidney transplantation. This was followed by a meta-analysis for patient characteristics and outcomes reported by a minimum of 2 studies including mean age, gender, mean body mass index, type of kidney transplantation, dialysis, previous kidney transplantation, comorbidities, hypertension, race, preemptive kidney transplantation, delayed graft function, and length of stay.

Results: A total of 18 studies were included in the systematic review and 14 of those studies were suitable for meta-analysis. The overall pooled prevalence of frailty before transplantation was estimated at 17.1% (95% confidence interval [CI], 15.4-18.7). Frailty was significantly associated with higher age (mean difference, 3.6; 95% CI, 1.4-5.9), lower rate of preemptive transplantation (relative risk, 0.60; 95% CI, 0.4-0.9), longer duration of delayed graft function (relative risk, 1.80; 95% CI, 1.1-3.0), and length of stay longer than 2 wk (odds ratio, 1.64; 95% CI, 1.2-2.3).

Conclusions: One in 6 kidney transplant recipients is frail before transplantation. The presence of frailty is associated with lower rates of preemptive transplantation, older recipient age, higher rates of delayed graft function, and longer length of stay. Future research is required to explore the association of frailty with other adverse outcomes after kidney transplantation and the effects of intervention programs to improve the different frailty domains.
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http://dx.doi.org/10.1097/TXD.0000000000001156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133203PMC
June 2021

Interleukin 6 and Development of Heart Failure With Preserved Ejection Fraction in the General Population.

J Am Heart Assoc 2021 Jun 17;10(11):e018549. Epub 2021 May 17.

Division of Nephrology Department of Internal Medicine University of GroningenUniversity Medical Center Groningen Groningen the Netherlands.

Background The cause of heart failure with preserved ejection fraction (HFpEF) is poorly understood, and specific therapies are lacking. Previous studies suggested that inflammation plays a role in the development of HFpEF. Herein, we aimed to investigate in community-dwelling individuals whether a higher plasma interleukin 6 (IL-6) level is associated with an increased risk of developing new-onset heart failure (HF) over time, and specifically HFpEF. Methods and Results We performed a case-cohort study based on the PREVEND (Prevention of Renal and Vascular End-Stage Disease) study, a prospective general population-based cohort study. We included 961 participants, comprising 200 participants who developed HF and a random group of 761 controls. HF with reduced ejection fraction or HFpEF was defined on the basis of the left ventricular ejection fraction of ≤40% or >40%, respectively. In Cox proportional hazard regression analyses, IL-6 levels were statistically significantly associated with the development of HF (hazard ratio [HR], 1.28; 95% CI, 1.02-1.61; =0.03) after adjustment for key risk factors. Specifically, IL-6 levels were significantly associated with the development of HFpEF (HR, 1.59; 95% CI, 1.16-2.19; =0.004), whereas the association with HF with reduced ejection fraction was nonsignificant (HR, 1.05; 95% CI, 0.75-1.47; =0.77). In sensitivity analyses, defining HFpEF as left ventricular ejection fraction ≥50%, IL-6 levels were also significantly associated with the development of HFpEF (HR, 1.47; 95% CI, 1.04-2.06; =0.03) after adjustment for key risk factors. Conclusions IL-6 is associated with new-onset HFpEF in community-dwelling individuals, independent of potential confounders. Our findings warrant further research to investigate whether IL-6 might be a novel treatment target to prevent HFpEF.
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http://dx.doi.org/10.1161/JAHA.120.018549DOI Listing
June 2021

Circulating trimethylamine-N-oxide is associated with all-cause mortality in subjects with nonalcoholic fatty liver disease.

Liver Int 2021 May 16. Epub 2021 May 16.

Department of Internal Medicine, Division of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background And Aims: Trimethylamine-N-oxide (TMAO), a gut microbiota-liver metabolite, has been associated with cardiometabolic disease. However, whether TMAO is associated with nonalcoholic fatty liver disease (NAFLD) and NAFLD-related health outcomes remains unclear. We aimed to investigate the association of TMAO with NAFLD and to assess the extent to which the association of TMAO with all-cause mortality is dependent on the presence of NAFLD in the general population.

Methods: We included 5292 participants enrolled in the Prevention of Renal and Vascular End-stage Disease (PREVEND) cohort study. Cox proportional-hazards regression analyses were performed to study the association of TMAO with all-cause mortality in subjects with and without a fatty liver index (FLI) ≥60, which was used as a proxy of NAFLD.

Results: During a median follow-up of 8.2 years, 307 subjects died, of whom 133 were classified with NAFLD. TMAO was positively and independently associated with baseline FLI (Std β 0.08, 95% CI 0.05, 0.11, P < .001). Higher TMAO was associated with increased risk of all-cause mortality in subjects with NAFLD, in crude analysis (hazard ratio [HR] per 1 SD, 2.55, 95% CI 1.60, 4.05, P < .001) and after full adjustment ( HR 1.90, 95% CI 1.18, 3.04, P = .008). Such an association was not present in subjects without NAFLD (crude HR 1.14, 95% CI 0.81, 1.71, P = .39; HR 0.95, 95% CI 0.65, 1.39, P = .78).

Conclusion: This prospective study revealed that plasma concentrations of TMAO were associated with all-cause mortality in subjects with NAFLD, independently of traditional risk factors.
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http://dx.doi.org/10.1111/liv.14963DOI Listing
May 2021

Interplay between gut microbiota, bone health and vascular calcification in chronic kidney disease.

Eur J Clin Invest 2021 May 4:e13588. Epub 2021 May 4.

Department of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Deregulations in gut microbiota may play a role in vascular and bone disease in chronic kidney disease (CKD). As glomerular filtration rate declines, the colon becomes more important as a site of excretion of urea and uric acid, and an increased bacterial proteolytic fermentation alters the gut microbial balance. A diet with limited amounts of fibre, as well as certain medications (eg phosphate binders, iron supplementation, antibiotics) further contribute to changes in gut microbiota composition among CKD patients. At the same time, both vascular calcification and bone disease are common in patients with advanced kidney disease. This narrative review describes emerging evidence on gut dysbiosis, vascular calcification, bone demineralization and their interrelationship termed the 'gut-bone-vascular axis' in progressive CKD. The role of diet, gut microbial metabolites (ie indoxyl sulphate, p-cresyl sulphate, trimethylamine N-oxide (TMAO) and short-chain fatty acids (SCFA)), vitamin K deficiency, inflammatory cytokines and their impact on both bone health and vascular calcification are discussed. This framework may open up novel preventive and therapeutic approaches targeting the microbiome in an attempt to improve cardiovascular and bone health in CKD.
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http://dx.doi.org/10.1111/eci.13588DOI Listing
May 2021

Iron deficiency, with and without anemia, across strata of kidney function in kidney transplant recipients.

Nephrol Dial Transplant 2021 May 3. Epub 2021 May 3.

Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, The Netherlands.

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http://dx.doi.org/10.1093/ndt/gfab173DOI Listing
May 2021

Proteoglycan binding as proatherogenic function metric of apoB-containing lipoproteins and chronic kidney graft failure.

J Lipid Res 2021 Apr 30;62:100083. Epub 2021 Apr 30.

Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Clinical Chemistry, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden. Electronic address:

Lipoprotein-proteoglycan binding is an early key event in atherosclerotic lesion formation and thus conceivably could play a major role in vasculopathy-driven chronic graft failure and cardiovascular mortality in renal transplant recipients. The present study investigated whether lipoprotein-proteoglycan binding susceptibility (LPBS) of apoB-containing lipoproteins and levels of the classical atherosclerosis biomarker LDL-C were associated with cardiovascular mortality (n = 130) and graft failure (n = 73) in 589 renal transplant recipients who were followed up from at least 1 year after transplantation for 9.5 years. At baseline, LPBS was significantly higher in patients who subsequently developed graft failure than in those with a surviving graft (1.68 ± 0.93 vs. 1.46 ± 0.49 nmol/mmol, P = 0.001). Cox regression analysis showed an association between LPBS and chronic graft failure in an age- and sex-adjusted model (hazard ratio: 1.45; 95% CI, 1.14-1.85; P = 0.002), but no association was observed with cardiovascular mortality. LDL-C levels were not associated with graft failure or cardiovascular mortality. This study shows that measurement of cholesterol retention outperformed the traditionally used quantitative parameter of LDL-C levels in predicting graft failure, suggesting a higher relevance of proatherogenic function than the quantity of apoB-containing lipoproteins in chronic kidney graft failure.
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http://dx.doi.org/10.1016/j.jlr.2021.100083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173310PMC
April 2021

Plasma Vitamin C and Risk of Late Graft Failure in Kidney Transplant Recipients: Results of the TransplantLines Biobank and Cohort Study.

Antioxidants (Basel) 2021 Apr 21;10(5). Epub 2021 Apr 21.

Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.

Recent studies have shown that depletion of vitamin C is frequent in outpatient kidney transplant recipients (KTR) and that vitamin C is inversely associated with risk of death. Whether plasma vitamin C is associated with death-censored kidney graft failure remains unknown. We investigated KTR who participated in the TransplantLines Insulin Resistance and Inflammation Biobank and Cohort Study. The primary outcome was graft failure (restart of dialysis or re-transplantation). Overall and stratified ( < 0.1) multivariable-adjusted Cox regression analyses are presented here. Among 598 KTR (age 51 ± 12 years-old; 55% males), baseline median (IQR) plasma vitamin C was 44.0 (31.0-55.3) µmol/L. Through a median follow-up of 9.5 (IQR, 6.3‒10.2) years, 75 KTR developed graft failure (34, 26, and 15 events over increasing tertiles of vitamin C, log-rank < 0.001). Plasma vitamin C was inversely associated with risk of graft failure (HR per 1-SD increment, 0.69; 95% CI 0.54-0.89; = 0.004), particularly among KTR with triglycerides ≥1.9 mmol/L (HR 0.46; 95% CI 0.30-0.70; < 0.001; = 0.01) and among KTR with HDL cholesterol ≥0.91 mmol/L (HR 0.56; 95% CI 0.38-0.84; = 0.01; = 0.04). These findings remained materially unchanged in multivariable-adjusted analyses (donor, recipient, and transplant characteristics, including estimated glomerular filtration rate and proteinuria), were consistent in categorical analyses according to tertiles of plasma vitamin C, and robust after exclusion of outliers. Plasma vitamin C in outpatient KTR is inversely associated with risk of late graft failure. Whether plasma vitamin C‒targeted therapeutic strategies represent novel opportunities to ease important burden of graft failure necessitates further studies.
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http://dx.doi.org/10.3390/antiox10050631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143099PMC
April 2021

Modelling the Cost-Effectiveness of Implementing a Dietary Intervention in Renal Transplant Recipients.

Nutrients 2021 Apr 2;13(4). Epub 2021 Apr 2.

Department of Nephrology, University Medical Center Groningen (UMCG), University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.

Background: The Dietary Approach to Stop Hypertension (DASH) and potassium supplementation have been shown to reduce the risk of death with a functioning graft (DWFG) and renal graft failure in renal transplant recipients (RTR). Unfortunately, a key problem for patients is the adherence to these diets. The aim of this study is to evaluate the cost-effectiveness and budget impact of higher adherence to either the DASH or potassium supplementation.

Methods: A Markov model was used to simulate the life course of 1000 RTR in the Netherlands. A societal perspective with a lifetime time horizon was used. The potential effect of improvement of dietary adherence was modelled in different scenarios. The primary outcomes are the incremental cost-effectiveness ratio (ICER) and the budget impact.

Results: In the base case, improved adherence to the DASH diet saved 27,934,786 and gained 1880 quality-adjusted life years (QALYs). Improved adherence to potassium supplementation saved €1,217,803 and gained 2901 QALYs. Both resulted in dominant ICERs. The budget impact over a five-year period for the entire Dutch RTR population was €8,144,693.

Conclusion: Improving dietary adherence in RTR is likely to be cost-saving and highly likely to be cost-effective compared to the current standard of care in the Netherlands.
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http://dx.doi.org/10.3390/nu13041175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066697PMC
April 2021

Separate and combined effects of individual and neighbourhood socio-economic disadvantage on health-related lifestyle risk factors: a multilevel analysis.

Int J Epidemiol 2021 Apr 24. Epub 2021 Apr 24.

Department of Internal Medicine, Division of Nephrology, University Medical Centre Groningen, Groningen, The Netherlands.

Background: Socio-economic disadvantage at both individual and neighbourhood levels has been found to be associated with single lifestyle risk factors. However, it is unknown to what extent their combined effects contribute to a broad lifestyle profile. We aimed to (i) investigate the associations of individual socio-economic disadvantage (ISED) and neighbourhood socio-economic disadvantage (NSED) in relation to an extended score of health-related lifestyle risk factors (lifestyle risk index); and to (ii) investigate whether NSED modified the association between ISED and the lifestyle risk index.

Methods: Of 77 244 participants [median age (IQR): 46 (40-53) years] from the Lifelines cohort study in the northern Netherlands, we calculated a lifestyle risk index by scoring the lifestyle risk factors including smoking status, alcohol consumption, diet quality, physical activity, TV-watching time and sleep time. A higher lifestyle risk index was indicative of an unhealthier lifestyle. Composite scores of ISED and NSED based on a variety of socio-economic indicators were calculated separately. Linear mixed-effect models were used to examine the association of ISED and NSED with the lifestyle risk index and to investigate whether NSED modified the association between ISED and the lifestyle risk index by including an interaction term between ISED and NSED.

Results: Both ISED and NSED were associated with an unhealthier lifestyle, because ISED and NSED were both positively associated with the lifestyle risk index {highest quartile [Q4] ISED beta-coefficient [95% confidence interval (CI)]: 0.64 [0.62-0.66], P < 0.001; highest quintile [Q5] NSED beta-coefficient [95% CI]: 0.17 [0.14-0.21], P < 0.001} after adjustment for age, sex and body mass index. In addition, a positive interaction was found between NSED and ISED on the lifestyle risk index (beta-coefficient 0.016, 95% CI: 0.011-0.021, Pinteraction < 0.001), which indicated that NSED modified the association between ISED and the lifestyle risk index; i.e. the gradient of the associations across all ISED quartiles (Q4 vs Q1) was steeper among participants residing in the most disadvantaged neighbourhoods compared with those who resided in the less disadvantaged neighbourhoods.

Conclusions: Our findings suggest that public health initiatives addressing lifestyle-related socio-economic health differences should not only target individuals, but also consider neighbourhood factors.
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http://dx.doi.org/10.1093/ije/dyab079DOI Listing
April 2021

Biochemical Urine Testing of Medication Adherence and Its Association With Clinical Markers in an Outpatient Population of Type 2 Diabetes Patients: Analysis in the DIAbetes and LifEstyle Cohort Twente (DIALECT).

Diabetes Care 2021 Apr 23. Epub 2021 Apr 23.

Department of Internal Medicine/Nephrology, Ziekenhuis Groep Twente, Almelo, the Netherlands.

Objective: To assess adherence to the three main drug classes in real-world patients with type 2 diabetes using biochemical urine testing, and to determine the association of nonadherence with baseline demographics, treatment targets, and complications.

Research Design And Methods: Analyses were performed of baseline data on 457 patients in the DIAbetes and LifEstyle Cohort Twente (DIALECT) study. Adherence to oral antidiabetics (OADs), antihypertensives, and statins was determined by analyzing baseline urine samples using liquid chromatography-tandem mass spectrometry. Primary outcomes were microvascular and macrovascular complications and treatment targets of LDL cholesterol, HbA, and blood pressure. These were assessed cross-sectionally at baseline.

Results: Overall, 89.3% of patients were identified as adherent. Adherence rates to OADs, antihypertensives, and statins were 95.7, 92.0, and 95.5%, respectively. The prevalence of microvascular (81.6 vs. 66.2%; = 0.029) and macrovascular complications (55.1 vs. 37.0%; = 0.014) was significantly higher in nonadherent patients. The percentage of patients who reached an LDL cholesterol target of ≤2.5 mmol/L was lower (67.4 vs. 81.1%; = 0.029) in nonadherent patients. Binary logistic regression indicated that higher BMI, current smoking, elevated serum LDL cholesterol, high HbA, presence of diabetic kidney disease, and presence of macrovascular disease were associated with nonadherence.

Conclusions: Although medication adherence of real-world type 2 diabetes patients managed in specialist care was relatively high, the prevalence of microvascular and macrovascular complications was significantly higher in nonadherent patients, and treatment targets were reached less frequently. This emphasizes the importance of objective detection and tailored interventions to improve adherence.
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http://dx.doi.org/10.2337/dc20-2533DOI Listing
April 2021

The emerging plasma biomarker Dickkopf-3 (DKK3) and its association with renal and cardiovascular disease in the general population.

Sci Rep 2021 Apr 21;11(1):8642. Epub 2021 Apr 21.

Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen, 9713 GZ, The Netherlands.

Dickkopf-3 (DKK3) is an emerging biomarker for cardiovascular disease (CVD) and chronic kidney disease (CKD). Herein, baseline DKK3 plasma levels were measured in 8420 subjects from the Prevention of Renal and Vascular ENd-stage Disease (PREVEND) cohort, a large general population cohort, using enzyme-linked immunosorbent assays. Associations with clinical variables and outcomes were analysed. Median DKK3 level was 32.8 ng/ml (28.0-39.0). In multivariable linear regression analysis, the strongest correlates for plasma DKK3 were age, body mass index and estimated glomerular filtration rate (eGFR). At baseline, 564 (6.7%) subjects had CVD (defined as a myocardial infarction and/or cerebrovascular accident) and 1361 (16.2%) subjects had CKD (defined as eGFR < 60 ml/min/1.73m and/or urinary albumin excretion (UAE) > 30 mg/24 h). Of subjects with known CVD and CKD follow-up status (respectively 7828 and 5548), 669 (8.5%) developed CVD and 951 (17.1%) developed CKD (median follow-up respectively 12.5 and 10.2 years). Crude logistic regression analysis revealed that DKK3 levels were associated with prevalent CVD (Odds ratio: 2.14 [1.76-2.61] per DKK3 doubling, P < 0.001) and CKD (Odds ratio: 1.84 [1.59-2.13] per DKK3 doubling, P < 0.001). In crude Cox proportional hazard regression analysis, higher DKK3 levels were associated with higher risk for new-onset CVD (Hazard ratio: 1.47 [1.13-1.91] per DKK3 doubling, P = 0.004) and CKD (Hazard ratio: 1.45, [1.25-1.69] per DKK3 doubling, P < 0.001). However, these associations remained no longer significant after correction for common clinical variables and risk factors, though independently predicted for new-onset CKD in a subgroup of subjects with the lowest UAE values. Together, DKK3 plasma levels are associated with cardiovascular risk factors, but are generally not independently associated with prevalent and new-onset CVD and CKD and only predicted for new-onset CKD in those subjects with the lowest UAE values.
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http://dx.doi.org/10.1038/s41598-021-88107-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060267PMC
April 2021

Discrepancy between self-perceived mycophenolic acid-associated diarrhea and stool water content after kidney transplantation.

Clin Transplant 2021 Apr 21:e14321. Epub 2021 Apr 21.

Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: Diarrhea is a well-known side effect of mycophenolic acid (MPA) use in kidney transplant recipients (KTRs). It is unknown whether self-reported diarrhea using the Modified Transplant Symptom Occurrence and Symptom Distress Scale (MTSOSD-59R) corresponds to stool water content and how both relate to MPA usage.

Methods: MTSOSD-59R questionnaires filled out by 700 KTRs from the TransplantLines Biobank and Cohort Study (NCT03272841) were analyzed and compared with stool water content. Stool samples (N = 345) were freeze-dried, and a water content ≥80% was considered diarrhea.

Results: Self-perceived diarrhea was reported by 46%, while stool water content ≥80% was present in 23% of KTRs. MPA use was not associated with self-perceived diarrhea (odds ratio(OR) 1.32; 95% confidence interval(CI), 0.87-1.99, p = .2), while it was associated with stool water content ≥80% (OR 2.88; 95%CI, 1.41-5.89, p = .004), independent of potential confounders. Adjustment for prior MPA discontinuation because of severe diarrhea, uncovered an association between MPA use and self-perceived diarrhea (OR 1.80; 95%CI, 1.13-2.89, p = .01).

Conclusions: These results suggest that reporting bias could add to the discrepancy between both methods for diarrhea assessment. We recommend use of objective biomarkers or more extensive questionnaires which assess information on stool frequency and stool consistency, to investigate post-transplantation diarrhea.
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http://dx.doi.org/10.1111/ctr.14321DOI Listing
April 2021

Methylglyoxal induces p53 activation and inhibits mTORC1 in human umbilical vein endothelial cells.

Sci Rep 2021 Apr 13;11(1):8004. Epub 2021 Apr 13.

Department of Nephrology, Endocrinology and Rheumatology, Fifth Department of Medicine, University Hospital Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.

Methylglyoxal (MGO), a precursor of advanced glycation end products (AGEs), is regarded as a pivotal mediator of vascular damage in patients with diabetes. We have previously reported that MGO induces transcriptional changes compatible with p53 activation in cultured human endothelial cells. To further substantiate this finding and to explore the underlying mechanisms and possible consequences of p53 activation, we aimed (1) to provide direct evidence for p53 activation in MGO-treated human umbilical vein endothelial cells (HUVECs), (2) to assess putative mechanisms by which this occurs, (3) to analyze down-stream effects on mTOR and autophagy pathways, and (4) to assess the potential benefit of carnosine herein. Exposure of HUVECs to 800 µM of MGO for 5 h induced p53 phosphorylation. This was paralleled by an increase in TUNEL and γ-H2AX positive cells, indicative for DNA damage. Compatible with p53 activation, MGO treatment resulted in cell cycle arrest, inhibition of mTORC1 and induction of autophagy. Carnosine co-treatment did not counteract MGO-driven effects. In conclusion, our results demonstrate that MGO elicits DNA damage and p53 activation in HUVECs, resulting in modulation of downstream pathways, e.g. mTORC1.
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http://dx.doi.org/10.1038/s41598-021-87561-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044125PMC
April 2021

High-Density Lipoprotein Anti-Inflammatory Capacity and Incident Cardiovascular Events.

Circulation 2021 May 12;143(20):1935-1945. Epub 2021 Apr 12.

Department of Pediatrics (C.J., J.L.C.A., U.J.F.T.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: The role of high-density lipoprotein (HDL) function in cardiovascular disease represents an important emerging concept. The present study investigated whether HDL anti-inflammatory capacity is prospectively associated with first cardiovascular events in the general population.

Methods: HDL anti-inflammatory capacity was determined as its ability to suppress TNFα (tumor necrosis factor α)-induced VCAM-1 (vascular cell adhesion molecule-1) mRNA expression in endothelial cells in vitro (results expressed as achieved percent reduction by individual HDL related to the maximum TNFα effect with no HDL present). In a nested case-control design of the PREVEND (Prevention of Renal and Vascular End Stage Disease) study, 369 cases experiencing a first cardiovascular event (combined end point of death from cardiovascular causes, ischemic heart disease, nonfatal myocardial infarction, and coronary revascularization) during a median of 10.5 years of follow-up were identified and individually matched to 369 controls with respect to age, sex, smoking status, and HDL cholesterol. Baseline samples were available in 340 cases and 340 matched controls.

Results: HDL anti-inflammatory capacity was not correlated with HDL cholesterol or hsCRP (high-sensitivity C-reactive protein). HDL anti-inflammatory capacity was significantly lower in cases compared with controls (31.6% [15.7-44.2] versus 27.0% [7.4-36.1]; <0.001) and was inversely associated with incident CVD in a fully adjusted model (odds ratio [OR] per 1 SD, 0.74 [CI, 0.61-0.90]; =0.002). Furthermore, this association was approximately similar with all individual components of the cardiovascular disease end point. The HDL anti-inflammatory was not correlated with cholesterol efflux capacity (=-0.02; >0.05). When combining these 2 HDL function metrics in 1 model, both were significantly and independently associated with incident cardiovascular disease in a fully adjusted model (efflux: OR per 1 SD, 0.74; =0.002; anti-inflammatory capacity: OR per 1 SD, 0.66; <0.001). Adding HDL anti-inflammatory capacity improved risk prediction by the Framingham risk score, with a model likelihood-ratio statistic increase from 10.50 to 20.40 (=0.002).

Conclusions: The HDL anti-inflammatory capacity, reflecting vascular protection against key steps in atherogenesis, was inversely associated with incident cardiovascular events in a general population cohort, independent of HDL cholesterol and HDL cholesterol efflux capacity. Adding HDL anti-inflammatory capacity to the Framingham risk score improves risk prediction.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050808DOI Listing
May 2021

Hypercholesterolemia in Progressive Renal Failure Is Associated with Changes in Hepatic Heparan Sulfate - PCSK9 Interaction.

J Am Soc Nephrol 2021 Jun 23;32(6):1371-1388. Epub 2021 Mar 23.

Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Background: Dyslipidemia is an important risk factor in CKD. The liver clears triglyceride-rich lipoproteins (TRL) LDL receptor (LDLR), LDLR-related protein-1 (LRP-1), and heparan sulfate proteoglycans (HSPGs), mostly syndecan-1. HSPGs also facilitate LDLR degradation by proprotein convertase subtilisin/kexin type 9 (PCSK9). Progressive renal failure affects the structure and activity of hepatic lipoprotein receptors, PCSK9, and plasma cholesterol.

Methods: Uninephrectomy- and aging-induced CKD in normotensive Wistar rats and hypertensive Munich-Wistar-Frömter (MWF) rats.

Results: Compared with 22-week-old sex- and strain-matched rats, 48-week-old uninephrectomized Wistar-CKD and MWF-CKD rats showed proteinuria, increased plasma creatinine, and hypercholesterolemia (all <0.05), which were most apparent in hypertensive MWF-CKD rats. Hepatic PCSK9 expression increased in both CKD groups (<0.05), with unusual sinusoidal localization, which was not seen in 22-week-old rats. Heparan sulfate (HS) disaccharide analysis, staining with anti-HS mAbs, and mRNA expression of HS polymerase exostosin-1 (), revealed elongated HS chains in both CKD groups. Solid-phase competition assays showed that the PCSK9 interaction with heparin-albumin (HS-proteoglycan analogue) was critically dependent on polysaccharide chain length. VLDL binding to HS from CKD livers was reduced (<0.05). Proteinuria and plasma creatinine strongly associated with plasma cholesterol, PCSK9, and HS changes.

Conclusions: Progressive CKD induces hepatic HS elongation, leading to increased interaction with PCSK9. This might reduce hepatic lipoprotein uptake and thereby induce dyslipidemia in CKD. Therefore, PCSK9/HS may be a novel target to control dyslipidemia.
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http://dx.doi.org/10.1681/ASN.2020091376DOI Listing
June 2021

Creatine homeostasis and protein energy wasting in hemodialysis patients.

J Transl Med 2021 03 20;19(1):115. Epub 2021 Mar 20.

Department of Internal Medicine, University of Groningen, University Medical Center Groningen, 9713 GZ, Groningen, The Netherlands.

Muscle wasting, low protein intake, hypoalbuminemia, low body mass, and chronic fatigue are prevalent in hemodialysis patients. Impaired creatine status may be an often overlooked, potential contributor to these symptoms. However, little is known about creatine homeostasis in hemodialysis patients. We aimed to elucidate creatine homeostasis in hemodialysis patients by assessing intradialytic plasma changes as well as intra- and interdialytic losses of arginine, guanidinoacetate, creatine and creatinine. Additionally, we investigated associations of plasma creatine concentrations with low muscle mass, low protein intake, hypoalbuminemia, low body mass index, and chronic fatigue. Arginine, guanidinoacetate, creatine and creatinine were measured in plasma, dialysate, and urinary samples of 59 hemodialysis patients. Mean age was 65 ± 15 years and 63% were male. During hemodialysis, plasma concentrations of arginine (77 ± 22 to 60 ± 19 μmol/L), guanidinoacetate (1.8 ± 0.6 to 1.0 ± 0.3 μmol/L), creatine (26 [16-41] to 21 [15-30] μmol/L) and creatinine (689 ± 207 to 257 ± 92 μmol/L) decreased (all P < 0.001). During a hemodialysis session, patients lost 1939 ± 871 μmol arginine, 37 ± 20 μmol guanidinoacetate, 719 [399-1070] μmol creatine and 15.5 ± 8.4 mmol creatinine. In sex-adjusted models, lower plasma creatine was associated with a higher odds of low muscle mass (OR per halving: 2.00 [1.05-4.14]; P = 0.04), low protein intake (OR: 2.13 [1.17-4.27]; P = 0.02), hypoalbuminemia (OR: 3.13 [1.46-8.02]; P = 0.008) and severe fatigue (OR: 3.20 [1.52-8.05]; P = 0.006). After adjustment for potential confounders, these associations remained materially unchanged. Creatine is iatrogenically removed during hemodialysis and lower plasma creatine concentrations were associated with higher odds of low muscle mass, low protein intake, hypoalbuminemia, and severe fatigue, indicating a potential role for creatine supplementation.
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http://dx.doi.org/10.1186/s12967-021-02780-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981955PMC
March 2021

Food Literacy Is Associated With Adherence to a Mediterranean-Style Diet in Kidney Transplant Recipients.

J Ren Nutr 2021 Mar 4. Epub 2021 Mar 4.

Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Objectives: Adherence to a Mediterranean-style diet is associated with improved health outcomes in kidney transplant recipients (KTR). However, poor dietary habits, including excessive sodium intake, are common in KTR, indicating difficulties with incorporating a healthy diet into daily life. Food literacy is identified as potential facilitator of a healthy diet, but the precise relationship between food literacy and dietary intake in KTR has not been investigated. This study examined food literacy levels in KTR and its association with adherence to a Mediterranean-style diet and sodium intake.

Methods: This cross-sectional study is part of the TransplantLines Cohort and Biobank Study. Food literacy was measured with the Self-Perceived Food Literacy (SPFL) questionnaire. Dietary intake assessment with food frequency questionnaires was used to calculate the Mediterranean Diet Score. Sodium intake was based on the 24-hour urinary sodium excretion rate. Associations of SPFL with Mediterranean Diet Score and sodium intake were assessed with univariable and multivariable linear regression analyses.

Results: In total, 148 KTR (age 56 [48-66]; 56% male) completed the SPFL questionnaire with a mean SPFL score of 3.63 ± 0.44. Higher SPFL was associated with a higher Mediterranean Diet Score in KTR (β = 1.51, 95% confidence interval 0.88-2.12, P ≤ .001). Although KTR with higher food literacy tended to have a lower sodium intake than those with lower food literacy (P = .08), the association of food literacy with sodium intake was not significant in a multivariable regression analysis (β = 0.52 per 10 mmol/24-hour increment, 95% confidence interval -1.79 to 2.83, P = .66).

Conclusions: Higher levels of food literacy are associated with better adherence to a Mediterranean-style diet in KTR. No association between food literacy and sodium intake was found. Further studies are needed to determine if interventions on improving food literacy contribute to a healthier diet and better long-term outcomes in KTR.
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http://dx.doi.org/10.1053/j.jrn.2020.12.010DOI Listing
March 2021

Introduction of the Grayscale Median for Ultrasound Tissue Characterization of the Transplanted Kidney.

Diagnostics (Basel) 2021 Feb 25;11(3). Epub 2021 Feb 25.

Department of Surgery, Division of Transplant Surgery, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands.

Ultrasound examination is advised for early post-kidney transplant assessment. Grayscale median (GSM) quantification is novel in the kidney transplant field, with no systematic assessment previously reported. In this prospective cohort study, we measured the post-operative GSM in a large cohort of adult kidney transplant recipients (KTR) who consecutively underwent Doppler ultrasound directly after transplantation (within 24 h), compared it with GSM in nontransplanted patients, and investigated its association with baseline and follow-up characteristics. B-mode images were used to calculate the GSM in KTR and compared with GSM data in nontransplanted patients, as simulated from summary statistics of the literature using a Mersenne twister algorithm. The association of GSM with baseline and 1-year follow-up characteristics were studied by means of linear regression analyses. In 282 KTR (54 ± 15 years old, 60% male), the median (IQR) GSM was 55 (45-69), ranging from 22 to 124 (coefficient of variation = 7.4%), without differences by type of donation ( = 0.28). GSM in KTR was significantly higher than in nontransplanted patients ( < 0.001), and associated with systolic blood pressure, history of cardiovascular disease, and donor age (std. β = 0.12, -0.20, and 0.13, respectively; < 0.05 for all). Higher early post-kidney transplant GSM was not associated with 1-year post-kidney transplant function parameters (e.g., measured and estimated glomerular filtration rate). The data provided in this study could be used as first step for further research on the application of early postoperative ultrasound in KTR.
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http://dx.doi.org/10.3390/diagnostics11030390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996582PMC
February 2021

Whole-body arginine dimethylation is associated with all-cause mortality in adult renal transplant recipients.

Amino Acids 2021 Apr 2;53(4):541-554. Epub 2021 Mar 2.

Core Unit Proteomics, Institute of Toxicology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.

Arginine residues in proteins can be singly or doubly methylated post-translationally. Proteolysis of arginine-methylated proteins provides monomethyl arginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). ADMA and SDMA are considered cardiovascular risk factors, with the underlying mechanisms being not yet fully understood. SDMA lacks appreciable metabolism and is almost completely eliminated by the kidney, whereas ADMA is extensively metabolized to dimethylamine (DMA), with a minor ADMA fraction of about 10% being excreted unchanged in the urine. Urinary DMA and ADMA are useful measures of whole-body asymmetric arginine-dimethylation, while urinary SDMA serves as a whole-body measure of symmetric arginine-dimethylation. In renal transplant recipients (RTR), we previously found that higher plasma ADMA concentrations and lower urinary ADMA and SDMA concentrations were associated with a higher risk of all-cause mortality. Yet, in this RTR collective, no data were available for urinary DMA. For the present study, we additionally measured the excretion rate of DMA in 24-h collected urine samples of the RTR and of healthy kidney donors in the cohort, with the aim to quantitate whole-body asymmetric (ADMA, DMA) and symmetric (SDMA) arginine-dimethylation. We found that lower DMA excretion rates were associated with higher all-cause mortality, yet not with cardiovascular mortality. In the healthy donors, kidney donation was associated with considerable decreases in ADMA (by - 39%, P < 0.0001) and SDMA (by - 21%, P < 0.0001) excretion rates, yet there was no significant change in DMA (by - 9%, P = 0.226) excretion rate. Our results suggest that protein-arginine dimethylation is altered in RTR compared to healthy kidney donors and that it is pronouncedly shifted from symmetric to asymmetric arginine-dimethylation, with whole-body protein-arginine dimethylation being almost unaffected.
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http://dx.doi.org/10.1007/s00726-021-02965-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107162PMC
April 2021

Systemic Oxidative Stress, Aging and the Risk of Cardiovascular Events in the General Female Population.

Front Cardiovasc Med 2021 9;8:630543. Epub 2021 Feb 9.

Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.

Menopause is associated with increased cardiovascular risk, in which oxidative stress plays a pivotal role. Systemic oxidative stress is reflected by decreased levels of free thiols (R-SH, sulfhydryl groups), which are key components of the extracellular antioxidant machinery. In this study, we investigated the relation between serum free thiols as marker of oxidative stress and the female cardiovascular phenotype, as well as potential associations with the risk of cardiovascular (CV) events in pre- and postmenopausal women from the general population. Female participants ( = 2,980) of the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort study were included. Serum free thiol concentrations were analyzed for associations with demographic, clinical, biochemical, and gynecological parameters, as well as with menopausal status and, prospectively, with the risk of CV events. Postmenopausal women had significantly reduced levels of serum free thiols (4.8 ± 1.0 vs. 5.2 ± 1.0 μmol/g, < 0.001) compared to reproductive women. In multivariable analyses, serum free thiols were significantly associated with menopausal status (OR 0.70 [0.49-0.98], = 0.039), even when adjusted for potential confounding factors, except for age ( = 0.550). Prospectively, serum free thiols were significantly associated with the risk of CV events (HR 0.52 [0.27-0.97], = 0.040), even with covariate adjustment, although this disappeared when correcting for age. In this study, we revealed serum free thiols to be strongly associated with the female cardiovascular phenotype as well as with female risk of CV events, where the influence of age itself seemed to outweigh that of female menopause. Future studies are warranted to further unravel the clinical utility of serum free thiol levels in the context of female cardiovascular risk management.
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http://dx.doi.org/10.3389/fcvm.2021.630543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900172PMC
February 2021

Reduced Vitamin K Status and Coronavirus Disease 2019: An Epiphenomenon of Impaired Kidney Function?

Clin Infect Dis 2021 Feb 25. Epub 2021 Feb 25.

Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1093/cid/ciab164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929021PMC
February 2021

Metabolic syndrome-related dietary pattern and risk of mortality in kidney transplant recipients.

Nutr Metab Cardiovasc Dis 2021 04 19;31(4):1129-1136. Epub 2021 Jan 19.

Department of Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Background And Aims: Presence of the metabolic syndrome (MetS) importantly contributes to excess mortality in kidney transplant recipients (KTRs). However, it is unclear which dietary factors drive the adverse role of MetS in KTRs. We aimed to define a dietary pattern that maximally explained the variation in MetS components, and to investigate the association between this MetS-related dietary pattern (MetS-DP) and all-cause mortality in KTRs.

Methods And Results: We included 429 adult KTRs who had a functioning graft ⩾1 year. A MetS-DP was constructed using habitual dietary intake derived from a 177-item food frequency questionnaire. We used reduced rank regression (RRR), and defined the six components of MetS (waist circumference, systolic blood pressure, diastolic blood pressure, serum triglycerides, HbA1c, and HDL cholesterol) as response variables and 48 food groups as predictor variables. We evaluated the association between the MetS-DP and all-cause mortality using multivariable Cox regression analysis. The MetS-DP was characterized by high intakes of processed meat and desserts, and low intakes of vegetables, tea, rice, fruits, milk, and meat substitutes. During a mean follow-up of 5.3 ± 1.2 years, 63 KTRs (14.7%) died. Compared to the lowest tertile of the Mets-DP score, those with the greatest adherence had a more than 3-fold higher risk of all-cause mortality (hazard ratio [HR] = 3.63; 95% confidence interval [CI], 1.70-7.74, P < 0.001), independent of potential confounders.

Conclusions: We identified a MetS-related dietary pattern which was independently associated with all-cause mortality in KTRs. The association between this dietary pattern and all-cause mortality was mediated by MetS. Clinical trial reg. no. NCT02811835.
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http://dx.doi.org/10.1016/j.numecd.2021.01.005DOI Listing
April 2021

Association of beta-hydroxybutyrate with development of heart failure: Sex differences in a Dutch population cohort.

Eur J Clin Invest 2021 May 18;51(5):e13468. Epub 2020 Dec 18.

Department of Internal Medicine, Division of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: In the failing heart, energy metabolism is shifted towards increased ketone body oxidation. Nevertheless, the association of beta-hydroxybutyrate (β-OHB) with development of heart failure (HF) remains unclear. We investigated the association between plasma β-OHB and the risk of HF in a prospective population-based cohort.

Design: Plasma β-OHB concentrations were measured in 6134 participants of the PREVEND study. Risk of incident HF with reduced (HFrEF) or preserved (HFpEF) ejection fraction was estimated using multivariable-adjusted Cox regression models.

Results: During median follow-up for 8.2 years, 227 subjects were diagnosed with HF (137 with HFrEF; 90 with HFpEF). Cox regression analyses revealed a significant association of higher β-OHB concentrations with incident HF (HR per 1 standard deviation increase, 1.40 (95% CI: 1.21-1.63; P < .001), which was largely attributable to HFrEF. In women, the hazard ratio (HR) for HFrEF per 1 standard deviation increase in β-OHB was 1.73 (95% confidence interval (CI): 1.17-2.56, P = .005) in age, BMI, type 2 diabetes, hypertension, myocardial infarction, smoking, alcohol consumption, total cholesterol, HDL-C, triglycerides, glucose, eGFR and UAE adjusted analysis. In men, in the same fully adjusted analysis, the HR was 1.14 (CI: 0.86-1.53, P = .36) (P < .01 for sex interaction). In N-terminal pro-brain natriuretic peptide (NT-proBNP)-stratified analysis, the age-adjusted association with HF was significant in women with higher NT-proBNP levels (P = .008).

Conclusions: This prospective study suggests that high plasma concentrations of β-OHB are associated with an increased risk of HFrEF, particularly in women. The mechanisms responsible for the sex differences of this association warrant further study.
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http://dx.doi.org/10.1111/eci.13468DOI Listing
May 2021