Publications by authors named "Stephan J L Bakker"

721 Publications

Pretransplant characteristics of kidney transplant recipients that predict posttransplant outcome.

Front Immunol 2022 25;13:945288. Epub 2022 Jul 25.

Nordic Bioscience, Herlev, Denmark.

Better characterization of the potential kidney transplant recipient using novel biomarkers, for example, pretransplant plasma endotrophin, will lead to improved outcome after transplantation. This mini-review will focus on current knowledge about pretransplant recipients' characteristics, biomarkers, and immunology. Clinical characteristics of recipients including age, obesity, blood pressure, comorbidities, and estimated survival scores have been introduced for prediction of recipient and allograft survival. The pretransplant immunologic risk assessment include histocompatibility leukocyte antigens (HLAs), anti-HLA donor-specific antibodies, HLA-DQ mismatch, and non-HLA antibodies. Recently, there has been the hope that pretransplant determination of markers can further improve the prediction of posttransplant complications, both short-term and long-term outcomes including rejections, allograft loss, and mortality. Higher pretransplant plasma endotrophin levels were independently associated with posttransplant acute allograft injury in three prospective European cohorts. Elevated numbers of non-synonymous single-nucleotide polymorphism mismatch have been associated with increased allograft loss in a multivariable analysis. It is concluded that there is a need for integration of clinical characteristics and novel molecular and immunological markers to improve future transplant medicine to reach better diagnostic decisions tailored to the individual patient.
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http://dx.doi.org/10.3389/fimmu.2022.945288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9357871PMC
July 2022

Sex differences in associations of comorbidities with incident cardiovascular disease: focus on absolute risk.

Eur Heart J Open 2022 Mar 14;2(2):oeac017. Epub 2022 Mar 14.

Department of Cardiology, University of Groningen, University Medical Center Groningen, AB43, Hanzeplein 1, Groningen 9713 GZ, the Netherlands.

Aim: To examine sex differences in associations of obesity, type-2 diabetes, hypertension, and atrial fibrillation (AF) with incident cardiovascular disease (CVD), focusing on absolute risk measures.

Methods And Results: We included a total of 7994 individuals (mean age 49.1 years; 51.2% women) without prior CVD from the PREVEND (Prevention of Renal and Vascular End-stage Disease) cohort with a median follow-up of 12.5 years. Using Poisson regression, we calculated the increase in absolute as well as relative CVD risk associated with a comorbidity using incidence rate differences (IRD = IR-IR) and incidence rate ratios (IRR = IR/IR), respectively. Sex differences were presented as women-to-men differences (WMD = IRD-IRD) and women-to-men ratios (WMR = IRR/IRR). Absolute CVD risk was lower in women than in men (IR: 6.73 vs. IR: 14.58 per 1000 person-years). While increase in absolute CVD risk associated with prevalent hypertension was lower in women than in men [WMD: -6.12, 95% confidence interval: (-9.84 to -2.40), = 0.001], increase in absolute CVD risk associated with prevalent obesity [WMD: -4.25 (-9.11 to 0.61), = 0.087], type-2 diabetes [WMD: -1.04 (-14.36 to 12.29), = 0.879] and AF [WMD: 18.39 (-39.65 to 76.43), = 0.535] did not significantly differ between the sexes. Using relative risk measures, prevalent hypertension [WMR: 1.49%, 95% confidence interval: (1.12-1.99), = 0.006], type-2 diabetes [WMR: 1.73 (1.09-2.73), = 0.019], and AF [WMR: 2.53 (1.12-5.70), = 0.025] were all associated with higher CVD risk in women than in men.

Conclusion: Increase in absolute risk of developing CVD is higher in hypertensive men than in hypertensive women, but no substantial sex-related differences were observed among individuals with obesity, type-2 diabetes and AF. On a relative risk scale, comorbidities, in general, confer a higher CVD risk in women than in men.
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http://dx.doi.org/10.1093/ehjopen/oeac017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9242082PMC
March 2022

Circulating de novo lipogenesis fatty acids and all-cause mortality in a prospective Dutch population cohort.

J Clin Lipidol 2022 Jul 19. Epub 2022 Jul 19.

Certe Medical Diagnostics and Advice, Medical Center Leeuwarden, Leeuwarden, the Netherlands (Dr Riphagen).

Background: Circulating fatty acids (FA) from de novo lipogenesis (DNL) are associated with all-cause mortality in individuals with elevated CVD risk. However, compared to FA early in the DNL synthetic pathway, cis-vaccenic acid, one of the FA distal in the DNL synthetic pathway, has rarely been studied in a general population cohort. We hypothesized that circulating cis-vaccenic acid is more strongly related to all-cause mortality than other circulating DNL-related FA.

Objectives: The primary and secondary objectives of this study were to investigate the prospective associations of plasma levels of cis-vaccenic acid and other DNL-related FA with all-cause mortality in a general population, respectively.

Methods: We included 850 participants (mean ± SD age 53 ± 15 years) from the Dutch Lifelines cohort study. Circulating levels of palmitic (C16:0), palmitoleic (C16:1n7), cis-vaccenic (cis-C18:1n7), stearic (C18:0), oleic acid (C18:1n9) in plasma phospholipids (PL) and triglycerides (TG) were measured by gas chromatography. The associations of circulating cis-C18:1n7 and other DNL-related FA with all-cause mortality were assessed using Cox regression analyses.

Results: During a median follow-up of 9.3 (IQR: 5.4-10.8) years, 34 (4.0%) participants had died. In plasma PL, a 1-SD increase in cis-C18:1n7 was associated with an increased risk of all-cause mortality in univariate and multivariate models (p<0.02 for all), with a HR [95% CI] of 1.60 [1.13-2.25] after adjustment for age and sex.

Conclusions: Circulating plasma PL cis-C18:1n7 was associated with a higher risk for all-cause mortality. More studies are needed in different cohorts to verify and validate our results.
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http://dx.doi.org/10.1016/j.jacl.2022.07.003DOI Listing
July 2022

Adherence to Statin Therapy and Attainment of LDL Cholesterol Targets in an Outpatient Population of Type 2 Diabetes Patients: Analysis in the DIAbetes and LifEstyle Cohort Twente (DIALECT).

Front Pharmacol 2022 12;13:888110. Epub 2022 Jul 12.

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

To assess adherence to statin therapy and its association with sociodemographic data, medical characteristics, LDLc levels, and LDLc target attainment in real-world T2D patients treated in secondary care. Cross-sectional analyses were performed on baseline data of 393 patients in the DIAbetes and LifEstyle Cohort Twente (DIALECT). The medication possession ratio (MPR), calculated with pharmacy dispensing data, was used to determine adherence to statins for an intended period of 24 months. Statins were included in the analyses if they were used for at least six consecutive months with at least three dispenses. Adherence was defined as an MPR ≥80%. Associations with adherence were assessed using descriptive statistics and binary logistic regression. Overall, 80% of the patients had a statin prescription and of those, 89% were adherent. The proportion of patients who reached LDLc targets of ≤2.5 mmol/L and <1.8 mmol/L differed significantly between the adherent, nonadherent and non-statin group (90% vs. 74% vs. 46%; < 0.01 and 56% vs. 26% vs. 6%; < 0.01, respectively). Serum LDLc levels were lower in the adherent versus the nonadherent and non-statin group (1.76 ± 0.60 vs. 2.23 ± 0.90 vs. 2.71 ± 0.67 mmol/L; < 0.01). Higher HbA1c levels were independently associated with nonadherence (OR: 1.05, 95% CI 1.01-1.08; < 0.01). Mediation adherence (OR: 2.88, 95% CI 1.04-7.97; = 0.041) and lower BMI (OR: 0.88, 95% CI 0.81-0.96; < 0.01) were independently associated with attaining the LDLc target of ≤2.5 mmol/L. In patients with T2D treated in secondary care, statin adherence was relatively high and was associated with significantly lower LDLc levels. It is important to identify nonadherence as it appeared an important determinant of failure to reach LDLc targets. The finding that many patients who failed to attain LDLc targets did not receive statin treatment offers an opportunity to improve diabetes care.
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http://dx.doi.org/10.3389/fphar.2022.888110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9315395PMC
July 2022

Amino Acid Homeostasis and Fatigue in Chronic Hemodialysis Patients.

Nutrients 2022 Jul 8;14(14). Epub 2022 Jul 8.

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

Patients dependent on chronic hemodialysis treatment are prone to malnutrition, at least in part due to insufficient nutrient intake, metabolic derangements, and chronic inflammation. Losses of amino acids during hemodialysis may be an important additional contributor. In this study, we assessed changes in plasma amino acid concentrations during hemodialysis, quantified intradialytic amino acid losses, and investigated whether plasma amino acid concentrations and amino acid losses by hemodialysis and urinary excretion are associated with fatigue. The study included a total of 59 hemodialysis patients (65 ± 15 years, 63% male) and 33 healthy kidney donors as controls (54 ± 10 years, 45% male). Total plasma essential amino acid concentration before hemodialysis was lower in hemodialysis patients compared with controls ( = 0.006), while total non-essential amino acid concentration did not differ. Daily amino acid losses were 4.0 ± 1.3 g/24 h for hemodialysis patients and 0.6 ± 0.3 g/24 h for controls. Expressed as proportion of protein intake, daily amino acid losses of hemodialysis patients were 6.7 ± 2.4% of the total protein intake, compared to 0.7 ± 0.3% for controls ( < 0.001). Multivariable regression analyses demonstrated that hemodialysis efficacy (Kt/V) was the primary determinant of amino acid losses (Std. β = 0.51; < 0.001). In logistic regression analyses, higher plasma proline concentrations were associated with higher odds of severe fatigue (OR (95% CI) per SD increment: 3.0 (1.3; 9.3); = 0.03), while higher taurine concentrations were associated with lower odds of severe fatigue (OR (95% CI) per log2 increment: 0.3 (0.1; 0.7); = 0.01). Similarly, higher daily taurine losses were also associated with lower odds of severe fatigue (OR (95% CI) per log2 increment: 0.64 (0.42; 0.93); = 0.03). Lastly, a higher protein intake was associated with lower odds of severe fatigue (OR (95% CI) per SD increment: 0.2 (0.04; 0.5); = 0.007). Future studies are warranted to investigate the mechanisms underlying these associations and investigate the potential of taurine supplementation.
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http://dx.doi.org/10.3390/nu14142810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9318329PMC
July 2022

Fasting Proinsulin Independently Predicts Incident Type 2 Diabetes in the General Population.

J Pers Med 2022 Jul 12;12(7). Epub 2022 Jul 12.

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

Fasting proinsulin levels may serve as a marker of β-cell dysfunction and predict type 2 diabetes (T2D) development. Kidneys have been found to be a major site for the degradation of proinsulin. We aimed to evaluate the predictive value of proinsulin for the risk of incident T2D added to a base model of clinical predictors and examined potential effect modification by variables related to kidney function. Proinsulin was measured in plasma with U-PLEX platform using ELISA immunoassay. We included 5001 participants without T2D at baseline and during a median follow up of 7.2 years; 271 participants developed T2D. Higher levels of proinsulin were associated with increased risk of T2D independent of glucose, insulin, C-peptide, and other clinical factors (hazard ratio (HR): 1.28; per 1 SD increase 95% confidence interval (CI): 1.08-1.52). Harrell's C-index for the Framingham offspring risk score was improved with the addition of proinsulin ( = 0.019). Furthermore, we found effect modification by hypertension ( = 0.019), eGFR ( = 0.020) and urinary albumin excretion ( = 0.034), consistent with an association only present in participants with hypertension or kidney dysfunction. Higher fasting proinsulin level is an independent predictor of incident T2D in the general population, particularly in participants with hypertension or kidney dysfunction.
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http://dx.doi.org/10.3390/jpm12071131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9323856PMC
July 2022

Fibroblast Growth Factor 23 and Risk of New Onset Heart Failure With Preserved or Reduced Ejection Fraction: The PREVEND Study.

J Am Heart Assoc 2022 Aug 25;11(15):e024952. Epub 2022 Jul 25.

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

Background The role of fibroblast growth factor 23 (FGF23) in the development of new-onset heart failure (HF) with reduced (HFrEF) or preserved ejection fraction (HFpEF) in the general population is unknown. Therefore, we set out to investigate associations of C-terminal FGF23 with development of new-onset HF and, more specifically, with HFrEF or HFpEF in a large, prospective, population-based cohort. Methods and Results We studied 6830 participants (aged 53.8±12.1 years; 49.7% men; estimated glomerular filtration rate, 93.1±15.7 mL/min per 1.73 m) in the community-based PREVEND (Prevention of Renal and Vascular End-Stage Disease) study who were free of HF at baseline. Cross-sectional multivariable linear regression analysis showed that ferritin (standardized β, -0.24; <0.001) and estimated glomerular filtration rate (standardized β, -0.13; <0.001) were the strongest independent correlates of FGF23. Multivariable Cox proportional hazard regression was used to study the association between baseline FGF23 and incident HF, HFrEF (ejection fraction ≤40%) or HFpEF (ejection fraction ≥50%). After median follow-up of 7.4 [IQR 6.9-7.9] years, 227 individuals (3.3%) developed new-onset HF, of whom 132 had HFrEF and 88 had HFpEF. A higher FGF23 level was associated with an increased risk of incident HF (fully adjusted hazard ratio, 1.29 [95% CI, 1.06-1.57]) and with an increased risk of incident HFrEF (fully adjusted hazard ratio, 1.31 [95% CI, 1.01-1.69]). The association between FGF23 and incident HFpEF lost statistical significance after multivariable adjustment (hazard ratio, 1.22 [95% CI, 0.87-1.71]). Conclusions Higher FGF23 is independently associated with new-onset HFrEF in analyses fully adjusted for cardiovascular risk factors and other potential confounders. The association between FGF23 and incident HFpEF lost statistical significance upon multivariable adjustment.
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http://dx.doi.org/10.1161/JAHA.121.024952DOI Listing
August 2022

Impact of measured versus estimated glomerular filtration rate-based screening on living kidney donor characteristics: A study of multiple cohorts.

PLoS One 2022 7;17(7):e0270827. Epub 2022 Jul 7.

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

Background: Most transplant centers in the Netherlands use estimated glomerular filtration rate (eGFR) for evaluation of potential living kidney donors. Whereas eGFR often underestimates GFR, especially in healthy donors, measured GFR (mGFR) allows more precise kidney function assessment, and therefore holds potential to increase the living donor pool. We hypothesized that mGFR-based donor screening leads to acceptance of donors with lower pre-donation eGFR than eGFR-based screening.

Methods: In this longitudinal cohort study, we compared eGFR (CKD-EPI) before donation in one center using mGFR-based screening (mGFR-cohort, n = 250) with two centers using eGFR-based screening (eGFR-cohort1, n = 466 and eGFR-cohort2, n = 160). We also compared differences in eGFR at five years after donation.

Results: Donor age was similar among the cohorts (mean±standard deviation (SD) mGFR-cohort 53±10 years, eGFR-cohort1 52±13 years, P = 0.16 vs. mGFR-cohort, and eGFR-cohort2 53±9 years, P = 0.61 vs. mGFR-cohort). Estimated GFR underestimated mGFR by 10±12 mL/min/1.73m2 (mean±SD), with more underestimation in younger donors. In the overall cohorts, mean±SD pre-donation eGFR was lower in the mGFR-cohort (91±13 mL/min/1.73m2) than in eGFR-cohort1 (93±15 mL/min/1.73m2, P<0.05) and eGFR-cohort2 (94±12 mL/min/1.73m2, P<0.05). However, these differences disappeared when focusing on more recent years, which can be explained by acceptance of more older donors with lower pre-donation eGFR over time in both eGFR-cohorts. Five years post-donation, mean±SD eGFR was similar among the centers (mGFR-cohort 62±12 mL/min/1.73m2, eGFR-cohort1 61±14 mL/min/1.73m2, eGFR-cohort2 62±11 mL/min/1.73m2, P = 0.76 and 0.95 vs. mGFR-cohort respectively). In the mGFR-cohort, 38 (22%) donors were excluded from donation due to insufficient mGFR with mean±SD mGFR of 71±9 mL/min/1.73m2.

Conclusions: Despite the known underestimation of mGFR by eGFR, we did not show that the routine use of mGFR in donor screening leads to inclusion of donors with a lower pre-donation eGFR. Therefore eGFR-based screening will be sufficient for the majority of the donors. Future studies should investigate whether there is a group (e.g. young donors with insufficient eGFR) that might benefit from confirmatory mGFR testing.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0270827PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9262218PMC
July 2022

Prediction of measured GFR after living kidney donation from pre-donation parameters.

Nephrol Dial Transplant 2022 Jun 22. Epub 2022 Jun 22.

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

Background: One of the challenges in living kidney donor screening is to estimate remaining kidney function after donation. Here we developed a new model to predict post-donation measured GFR from pre-donation serum creatinine, age and sex.

Methods: In the prospective development cohort (TransplantLines, n = 511) several prediction models were constructed and tested for accuracy, precision, and predictive capacity for short- and long-term post-donation 125I-iothalamate mGFR. The model with optimal performance was further tested in specific high-risk subgroups (pre-donation eGFR < 90 mL/min/1.73m2, a declining 5-year post-donation mGFR slope or age > 65 years), and validated in internal (n = 509) and external (Mayo Clinic, n = 1087) cohorts.

Results: In the development cohort, pre-donation eGFR was 86 ± 14 mL/min/1.73m2, and post-donation mGFR 64 ± 11 mL/min/1.73m2. Donors with a pre-donation eGFR ≥ 90 mL/min/1.73m2 (present in 43%) had mean post-donation mGFR of 69 ± 10 mL/min/1.73m2, and 5% of these donors reached an mGFR < 55 mL/min/1.73m2. A model using pre-donation serum creatinine, age and sex performed optimally, predicting mGFR with good accuracy (mean bias 2.56 mL/min/1.73m2, R2 = 0.29, RMSE = 11.61) and precision (bias interquartile range (IQR) 14 mL/min/1.73m2) in the external validation cohort. This model also performed good in donors with pre-donation eGFR < 90 mL/min/1.73m2 (bias 0.35 mL/min/1.73m2 and IQR 10 mL/min/1.73m2), in donors with negative post-donation mGFR slope (bias 4.75 mL/min/1.73m2 and IQR 13 mL/min/1.73m2) and in donors > 65 years (bias 0.003 mL/min/1.73m2 and IQR 9 mL/min/1.73m2).

Conclusions: We developed a novel post-donation mGFR prediction model based on pre-donation serum creatinine, age, and sex.
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http://dx.doi.org/10.1093/ndt/gfac202DOI Listing
June 2022

Associations of 24 h urinary excretions of α- and γ-carboxyethyl hydroxychroman with plasma α- and γ-tocopherol and dietary vitamin E intake in older adults: the Lifelines-MINUTHE Study.

Eur J Nutr 2022 Jun 19. Epub 2022 Jun 19.

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

Background: Urinary metabolites of vitamin E, i.e., α- and γ-carboxyethyl hydroxychroman (α- and γ-CEHC), have gained increasing attention and have been proposed as novel biomarkers of vitamin E intake and status. However, there are insufficient data on the relationship of plasma α-tocopherol and γ-tocopherol and dietary vitamin E intake with 24 h urinary excretions of α- and γ-CEHC.

Objectives: We aimed to (1) investigate the associations of urinary α- and γ-CEHC/creatinine ratios and 24 h urinary excretions of α- and γ-CEHC with plasma α- and γ-tocopherol, respectively; (2) investigate the associations of urinary α- and γ-CEHC/creatinine ratios and 24 h urinary excretions of α- and γ-CEHC with dietary vitamin E intake, and we hypothesize that 24 h urinary excretions of α- and γ-CEHC will better correlate with vitamin E intake than urinary α- and γ-CEHC/creatinine ratios.

Design: 24 h Urine and plasma samples were collected from 1519 participants (60-75 years, male: 50%) included in the Lifelines-MINUTHE Study for the assessments of urinary α- and γ-CEHC/creatinine ratios and 24 h urinary excretions of α- and γ-CEHC, and plasma α- and γ-tocopherol. Among those participants, dietary vitamin E intake data from 387 participants were available from an externally validated Flower-Food Frequency Questionnaire (FFQ). The associations of plasma α- and γ-tocopherol, dietary vitamin E intake, with urinary α- and γ-CEHC were assessed using multivariate linear regressions.

Results: 24 h Urinary excretion of α-CEHC (median (IQR): 0.9 (0.3-2.4) µmol) was less than that of γ-CEHC (median (IQR): 1.5 (0.5-3.5) µmol). After adjustment for covariates, we found that 24 h urinary α-CEHC excretion and urinary α-CEHC/creatinine ratio were both positively associated with plasma α-tocopherol (std.beta: 0.06, p = 0.02; std.beta: 0.06, p = 0.01, respectively). Furthermore, the sum of 24 h urinary α- and γ-CEHC excretions was positively associated with dietary vitamin E intake (std.beta: 0.08; p = 0.03), whereas there was no relation between urinary α- and γ-CEHC/creatinine ratios and vitamin E intake. No association was observed neither between plasma α- and γ-tocopherol and dietary vitamin E intake, nor between urinary γ-CEHC and plasma γ-tocopherol.

Conclusion: Our study confirmed our hypothesis that 24 h urinary α- and γ-CEHC excretions would be a better marker for dietary vitamin E intake than urinary α- and γ-CEHC/creatinine ratios. Considering that both 24 h urinary α- and γ-CEHC excretions and α- and γ-CEHC/creatinine ratios were also associated with plasma α-tocopherol status, we suggest that 24 h urinary α- and γ-CEHC excretions could be used to assess overall vitamin E status.
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http://dx.doi.org/10.1007/s00394-022-02918-8DOI Listing
June 2022

Normal fasting triglyceride levels and incident type 2 diabetes in the general population.

Cardiovasc Diabetol 2022 Jun 18;21(1):111. Epub 2022 Jun 18.

Division of Clinical Chemistry, Department of Laboratory Medicine (LABMED), Karolinska Institutet, H5, Alfred Nobels Alle 8, S-141 83, Stockholm, Sweden.

Background: Type 2 diabetes is increasing worldwide. Traditionally, only hypertriglyceridemia is considered a risk factor. We investigated whether also normal triglycerides prospectively associate with incident type 2 diabetes in healthy subjects.

Methods: Incident type 2 diabetes was determined in healthy individuals with normal triglyceride levels from a prospective longitudinal cohort study (PREVEND, n = 2085, 11.4-year median follow-up).

Results: Type 2 diabetes incidence was 3.8%. In linear regression analysis baseline insulin, HOMA-IR, total cholesterol, HDL cholesterol, eGFR, systolic blood pressure (all p < 0.001), glucose, age and creatinine (all p < 0.01) independently associated with triglycerides within the normal range, comparable to what would be expected from associations with increased triglycerides. In Kaplan-Meier analysis sex-stratified tertiles of normal triglycerides prospectively associated with de novo type 2 diabetes (p < 0.001). Cox regression confirmed a significant prospective association independent of HOMA-IR [HR (95% CI), 1.39 (1.12, 1.74), p = 0.002] and several other recognized risk factors.

Conclusions: Even in healthy subjects without metabolic syndrome increasing triglyceride levels within the normal range confer a continuous increase in type 2 diabetes incidence. These data indicate that virtually everyone could potentially benefit from triglyceride lowering, further encouraging implementation of lifestyle changes in the general population.
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http://dx.doi.org/10.1186/s12933-022-01530-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9206357PMC
June 2022

Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies.

Kidney Int 2022 Jun 16. Epub 2022 Jun 16.

The George Institute for Global Health, University of New South Wales, Sydney, Australia.

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.
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http://dx.doi.org/10.1016/j.kint.2022.05.021DOI Listing
June 2022

Employment and ability to work after kidney transplantation in the Netherlands: The impact of preemptive versus non-preemptive kidney transplantation.

Clin Transplant 2022 Jun 18:e14757. Epub 2022 Jun 18.

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

Background: Work can have a major positive impact on health and wellbeing. Employment of kidney transplant recipients (KTR) of working age is much lower than in the general population. The first aim of this study was to examine the impact of a preemptive kidney transplantation (PKT) on employment, in addition to other possible influencing factors. The second aim was to explore differences in work ability, absenteeism and work performance among employed KTR with different types of transplantations.

Methods: A cross-sectional survey study was conducted between 2018 and 2019 in nine Dutch hospitals. PKT as potential predictor of employment was examined. Furthermore, work ability, absenteeism and loss of work performance were compared between employed preemptive recipients with a living donor (L-PKT) and non-preemptive recipients with a living donor (L-nPKT) and with a deceased donor (D-nPKT).

Results: Two hundred and twenty four KTR participated; 71% reported having paid work. Paid work was more common among PKT recipients (82% vs. 65% in L-nPKT and 55% in D-nPKT) and recipients who were younger (OR .950, 95%CI .913-.989), had no comorbidities (1 comorbidity: OR .397, 95%CI .167-.942; 2 comorbidities: OR .347, 95%CI .142-.844), had less fatigue (OR .974, 95%CI .962-.987) and had mentally demanding work tasks (only in comparison with physically demanding tasks, OR .342, 95%CI .145-.806). If recipients were employed, D-nPKT recipients worked fewer hours (mean 24.6±11.3 vs. PKT 31.1±9.6, L-nPKT 30.1±9.5) and D-nPKT and L-nPKT recipients received more often supplemental disability benefits (32 and 33.3%, respectively) compared to PKT recipients (9.9%). No differences were found for self-reported ability to work, sick leave (absenteeism) and loss of work performance with the exception of limitations in functioning at work.

Conclusions: Preemptive kidney transplantation recipients with a kidney from a living donor are employed more often, work more hours per week (only in comparison with D-nPKT) and have a partial disability benefit less often than nPKT recipients. More knowledge regarding treatments supporting sustainable participation in the labor force is needed as work has a positive impact on recipients' health and wellbeing and is also beneficial for society as a whole.
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http://dx.doi.org/10.1111/ctr.14757DOI Listing
June 2022

Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals.

Commun Biol 2022 Jun 13;5(1):580. Epub 2022 Jun 13.

Division of Kidney, Urologic and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.

Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n = 178,691, n = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
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http://dx.doi.org/10.1038/s42003-022-03448-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9192715PMC
June 2022

Decreased haemoglobin levels are associated with lower muscle mass and strength in kidney transplant recipients.

J Cachexia Sarcopenia Muscle 2022 Jun 3. Epub 2022 Jun 3.

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

Background: Post-transplant anaemia and reduced muscle mass and strength are highly prevalent in kidney transplant recipients (KTRs). Decreased haemoglobin levels, a marker of anaemia, could adversely affect muscle mass and strength through multiple mechanisms, among others, through diminished tissue oxygenation. We aimed to investigate the association between haemoglobin levels with muscle mass and strength in KTRs.

Methods: We included stable KTRs from the TransplantLines Biobank and Cohort study with a functional graft ≥1 year post-transplantation. Muscle mass was assessed using 24 h urinary creatinine excretion rate (CER) and bioelectrical impedance analysis (BIA). Muscle strength was assessed with a handgrip strength test using a dynamometer and, in a subgroup (n = 290), with the five-times sit-to-stand (FTSTS) test. We used multivariable linear and logistic regression analyses to investigate the associations of haemoglobin levels with muscle mass and strength.

Results: In 871 included KTRs [median age 58 (interquartile range (IQR), 48-66)] years; 60% men; eGFR 51 ± 18 mL/min/1.73 m ) who were 3.5 (1.0-10.2) years post-transplantation, the mean serum haemoglobin level was 13.9 ± 1.8 g/dL in men and 12.8 ± 1.5 g/dL in women. Lower haemoglobin levels were independently associated with a lower CER (std. β = 0.07, P = 0.01), BIA-derived skeletal muscle mass (std. β = 0.22, P < 0.001), handgrip strength (std. β = 0.15, P < 0.001), and worse FTSTS test scores (std. β = -0.17, P = 0.02). KTRs in the lowest age-specific and sex-specific quartile of haemoglobin levels had an increased risk of being in the worst age-specific and sex-specific quartile of CER (fully adjusted OR, 2.09; 95% CI 1.15-3.77; P = 0.02), handgrip strength (fully adjusted OR, 3.30; 95% CI 1.95-5.59; P < 0.001), and FTSTS test score (fully adjusted OR, 7.21; 95% CI 2.59-20.05; P < 0.001).

Conclusions: Low haemoglobin levels are strongly associated with decreased muscle mass and strength in KTRs. Future investigation will need to investigate whether maintaining higher haemoglobin levels may improve muscle mass and strength in KTRs.
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http://dx.doi.org/10.1002/jcsm.12999DOI Listing
June 2022

Nitric oxide and long-term outcomes after kidney transplantation: Results of the TransplantLines cohort study.

Nitric Oxide 2022 08 2;125-126:1-11. Epub 2022 Jun 2.

Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, the Netherlands. Electronic address:

Impaired endogenous nitric oxide (NO) production may contribute to graft failure and premature mortality in kidney transplant recipients (KTR). We investigated potential associations of 24-h urinary NOx (NO + NO) excretion (uNOx) with long-term outcomes. uNOx was determined by HPLC and GC-MS in 698 KTR and in 132 kidney donors before and after donation. Additionally, we measured urinary nitroso species (RXNO) by gas-phase chemiluminescence. Median uNOx was lower in KTR compared to kidney donors (688 [393-1076] vs. 1301 [868-1863] before donation and 1312 [982-1853] μmol/24 h after donation, P < 0.001). During median follow-up of 5.4 [4.8-6.1] years, 150 KTR died (61 due to cardiovascular disease) and 83 experienced graft failure. uNOx was inversely associated with all-cause mortality (HR per doubling of uNOx: 0.84 [95% CI 0.75-0.93], P < 0.001) and cardiovascular mortality (HR 0.78 [95% CI 0.67-0.92], P = 0.002). The association of uNOx with graft failure was lost when adjusted for renal function (HR per doubling of uNOx: 0.89 [95% CI 0.76-1.05], P = 0.17). There were no significant associations of urinary RXNO with outcomes. Our study suggests that KTR have lower NO production than healthy subjects and that lower uNOx is associated with a higher risk of all-cause and cardiovascular mortality.
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http://dx.doi.org/10.1016/j.niox.2022.05.005DOI Listing
August 2022

Systemic oxidative stress associates with new-onset hypertension in the general population.

Free Radic Biol Med 2022 Jul 28;187:123-131. Epub 2022 May 28.

Department of Internal Medicine, Division of Vascular Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Electronic address:

Background: Oxidative stress is known to be involved in the development of hypertension, but accurate redox biomarkers predicting the risk of developing hypertension are scarce. Serum free sulfhydryl groups (R-SH, free thiols) have been shown to accurately reflect systemic oxidative stress in various conditions. In this study, we aimed to investigate associations between serum free thiols and the risk of developing new-onset hypertension in a population-based cohort study.

Methods: Subjects (n = 3,575) who participated in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, a prospective, population-based cohort study in the Netherlands, were included. Baseline protein-adjusted serum free thiols were studied for their associations with the development of hypertension, defined as a systolic blood pressure (SBP) of at least 140 mmHg, a diastolic blood pressure (DBP) of at least 90 mmHg, or the first usage of antihypertensive medication. Subjects with hypertension at baseline were excluded from the study.

Results: Mean protein-adjusted serum free thiols at baseline was 5.16 μmol/g of protein (range: 1.62-8.41 μmol/g). Protein-adjusted serum free thiols were significantly associated with the risk of incident hypertension (hazard ratio [HR] per doubling 0.60 [95% confidence interval [CI]: 0.49-0.72, P < 0.001), also after adjustment for age and sex (HR 0.81 [95% CI: 0.66-0.91], P < 0.05), but not after additional adjustment for relevant confounding factors (HR 0.90 [95% CI: 0.70-1.15], P = 0.382).

Conclusion: Higher levels of serum free thiols, i.e. less oxidative stress, are associated with a decreased risk of developing incident hypertension in subjects from the general population.
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http://dx.doi.org/10.1016/j.freeradbiomed.2022.05.020DOI Listing
July 2022

Untargeted 'SWATH' mass spectrometry-based metabolomics for studying chronic and intermittent exposure to xenobiotics in cohort studies.

Food Chem Toxicol 2022 Jul 27;165:113188. Epub 2022 May 27.

Life Sciences Mass Spectrometry, Department of Inorganic and Analytical Chemistry, University of Geneva, Quai Ernest Ansermet 24, 1211, Geneva, Switzerland. Electronic address:

Humans are exposed to numerous chemicals daily, for example through nutrition, therapies, and lifestyle choices, which may exert beneficial or toxicological responses. In cohort studies, exposures are frequently assessed using questionnaires, although mass spectrometry-based metabolomics has recently emerged as complementary technique capable of yielding molecular evidence of exposures. Corresponding data processing workflows, however, have been mostly developed for detecting (omnipresent) endogenous metabolites, whereas detection of exogenous chemicals would benefit from fit-for-purpose strategies. In this work, we describe novel strategies for improved exposure detection and their application to data from an untargeted metabolomics study on urine samples from the TransplantLines Food and Nutrition Biobank and Cohort Study (NCT identifier 'NCT02811835'), which includes kidney transplant recipients, potential living kidney donors, and living kidney donors (post-donation). Specifically, we describe a reference spectra generation workflow using exposure-positive samples to detect more and also previously-undetected chronic exposures, and we present a novel approach to establish detection limits based on targeted signal extraction for more reliable and lower-level detection of intermittent exposures. These approaches can contribute to unlocking additional exposure-related information from small-molecule profiling datasets thus increasing data usefulness in metabolomics research and in environmental, food, clinical, and forensic toxicology.
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http://dx.doi.org/10.1016/j.fct.2022.113188DOI Listing
July 2022

Influence of carnosine and carnosinase-1 on diabetes-induced afferent arteriole vasodilation: implications for glomerular hemodynamics.

Am J Physiol Renal Physiol 2022 07 30;323(1):F69-F80. Epub 2022 May 30.

Department of Nephrology, University Medical Centre Groningen and University of Groningen, Groningen, The Netherlands.

Dysregulation in glomerular hemodynamics favors hyperfiltration in diabetic kidney disease (DKD). Although carnosine supplementation ameliorates features of DKD, its effect on glomerular vasoregulation is not known. We assessed the influence of carnosine and carnosinase-1 (CN1) on afferent glomerular arteriole vasodilation and its association with glomerular size, hypertrophy, and nephrin expression in diabetic BTBR mice. Two cohorts of mice including appropriate controls were studied: i.e., diabetic mice that received oral carnosine supplementation () and human (h)CN1 transgenic (TG) diabetic mice (). The lumen area ratio (LAR) of the afferent arterioles and glomerular parameters were measured by conventional histology. Three-dimensional analysis using a tissue clearing strategy was also used. In both cohorts, LAR was significantly larger in diabetic BTBR versus nondiabetic BTBR mice (0.41 ± 0.05 vs. 0.26 ± 0.07, < 0.0001 and 0.42 ± 0.06 vs. 0.29 ± 0.04, < 0.0001) and associated with glomerular size (: = 0.55, = 0.001 and : = 0.89, < 0.0001). LAR was partially normalized by oral carnosine supplementation (0.34 ± 0.05 vs. 0.41 ± 0.05, = 0.004) but did not differ between hCN1 TG and wild-type BTBR mice. In hCN1 TG mice, serum CN1 concentrations correlated with LAR ( = 0.90, = 0.006). Diabetic mice displayed decreased nephrin expression and increased glomerular hypertrophy. This was not significantly different in hCN1 TG BTBR mice ( = 0.06 and = 0.08, respectively). In conclusion, carnosine and CN1 may affect intraglomerular pressure in an opposing manner through the regulation of afferent arteriolar tone. This study corroborates previous findings on the role of carnosine in the progression of DKD. Dysregulation in glomerular hemodynamics favors hyperfiltration in diabetic kidney disease (DKD). Although carnosine supplementation ameliorates features of DKD, its effect on glomerular vasoregulation is not known. We assessed the influence of carnosine and carnosinase-1 (CN1) on afferent glomerular arteriole vasodilation and its association with glomerular size, hypertrophy, and nephrin expression in diabetic BTBR mice. Our results provide evidence that carnosine feeding and CN1 overexpression likely affect intraglomerular pressure through vasoregulation of the afferent arteriole.
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http://dx.doi.org/10.1152/ajprenal.00232.2021DOI Listing
July 2022

Muscle mass and estimates of renal function: a longitudinal cohort study.

J Cachexia Sarcopenia Muscle 2022 May 21. Epub 2022 May 21.

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

Background: Creatinine is the most widely used test to estimate the glomerular filtration rate (GFR), but muscle mass as key determinant of creatinine next to renal function may confound such estimates. We explored effects of 24-h height-indexed creatinine excretion rate (CER index) on GFR estimated with creatinine (eGFR ), muscle mass-independent cystatin C (eGFR ), and the combination of creatinine and cystatin C (eGFR ) and predicted probabilities of discordant classification given age, sex, and CER index.

Methods: We included 8076 adults enrolled in the PREVEND study. Discordant classification was defined as not having eGFR  <60 mL/min per 1.73 m when eGFR was <60 mL/min/1.73 m . Baseline effects of age and sex on CER index were quantified with linear models using generalized least squares. Baseline effects of CER index on eGFR were quantified with quantile regression and logistic regression. Effects of annual changes in CER index on trajectories of eGFR were quantified with linear mixed-effects models. Missing observations in covariates were multiply imputed.

Results: Mean (SD) CER index was 8.0 (1.7) and 6.1 (1.3) mmol/24 h per meter in male and female participants, respectively (P  < 0.001). In male participants, baseline CER index increased until 45 years of age followed by a gradual decrease, whereas a gradual decrease across the entire range of age was observed in female participants. For a 70-year-old male participant with low muscle mass (CER index of 2 mmol/24 h per meter), predicted baseline eGFR and eGFR disagreed by 24.7 mL/min/1.73 m (and 30.1 mL/min/1.73 m when creatinine was not corrected for race). Percentages (95% CI) of discordant classification in male and female participants aged 60 years and older with low muscle mass were 18.5% (14.8-22.1%) and 15.2% (11.4-18.5%), respectively. For a 70-year-old male participant who lost muscle during follow-up, eGFR and eGFR disagreed by 1.5, 5.0, 8.5, and 12.0 mL/min/1.73 m (and 6.7, 10.7, 13.5, and 15.9 mL/min/1.73 m when creatinine was not corrected for race) at baseline, 5 years, 10 years, and 15 years of follow-up, respectively.

Conclusions: Low muscle mass may cause considerable overestimation of single measurements of eGFR . Muscle wasting may cause spurious overestimation of repeatedly measured eGFR . Implementing muscle mass-independent markers for estimating renal function, like cystatin C as superior alternative to creatinine, is crucial to accurately assess renal function in settings of low muscle mass or muscle wasting. This would also eliminate the negative consequences of current race-based approaches.
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http://dx.doi.org/10.1002/jcsm.12969DOI Listing
May 2022

High plasma levels of betaine, a trimethylamine N-Oxide-related metabolite, are associated with the severity of cirrhosis.

Liver Int 2022 May 18. Epub 2022 May 18.

Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background And Aims: The gut microbiome-related metabolites betaine and trimethylamine N-oxide (TMAO) affect major health issues. In cirrhosis, betaine metabolism may be diminished because of impaired hepatic betaine homocysteine methyltransferase activity, whereas TMAO generation from trimethylamine may be altered because of impaired hepatic flavin monooxygenase expression. Here, we determined plasma betaine and TMAO levels in patients with end-stage liver disease and assessed their relationships with liver disease severity.

Methods: Plasma betaine and TMAO concentrations were measured by nuclear magnetic resonance spectroscopy in 129 cirrhotic patients (TransplantLines cohort study; NCT03272841) and compared with levels from 4837 participants of the PREVEND cohort study. Disease severity was assessed by Child-Pugh-Turcotte (CPT) classification and Model for End-stage Liver Disease (MELD) score.

Results: Plasma betaine was on average 60% higher (p < .001), whereas TMAO was not significantly lower in cirrhotic patients vs. PREVEND population (p = .44). After liver transplantation (n = 13), betaine decreased (p = .017; p = .36 vs. PREVEND population), whereas TMAO levels tended to increase (p = .085) to higher levels than in the PREVEND population (p = .003). Betaine levels were positively associated with the CPT stage and MELD score (both p < .001). The association with the MELD score remained in the fully adjusted analysis (p < .001). The association of TMAO with the MELD score did not reach significance (p = .11). Neither betaine nor TMAO levels were associated with mortality on the waiting list for liver transplantation (adjusted p = .78 and p = .44, respectively).

Conclusion: Plasma betaine levels are elevated in cirrhotic patients in parallel with disease severity and decrease after liver transplantation.
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http://dx.doi.org/10.1111/liv.15310DOI Listing
May 2022

Urinary Potassium Excretion and Mortality Risk in Community-Dwelling Individuals with and without obesity.

Am J Clin Nutr 2022 May 17. Epub 2022 May 17.

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

Background: Potassium intake has been shown to be inversely associated with blood pressure and premature mortality. Previous studies suggested that the association between potassium intake and blood pressure is modified by obesity, but whether obesity similarly influences the association between potassium intake and mortality is unclear.

Objectives: To investigate whether potassium intake, reflected by 24-hour urinary excretion, is associated with all-cause mortality, and to explore potential effect modification by obesity.

Methods: We performed a prospective cohort study in community-dwelling individuals. The association between urinary potassium excretion and all-cause mortality was investigated by multivariable Cox regression. We performed multiplicative interaction analysis and subgroup analyses according to BMI and waist circumference.

Results: In 8,533 individuals (50% male) mean age was 50 ± 13 years, mean urinary potassium excretion was 71±21 mmol/24 hrs, median BMI was 25.6 (IQR 23.1-28.4) kg/m2 and mean waist circumference was 89±13 cm. During follow-up of 18.4 [IQR 13.5-18.8] years, 1,663 participants died. Low urinary potassium excretion (1st vs. 3rd sex-specific quintile) was associated with an increased mortality risk (fully adjusted HR 1.38 [95% CI 1.18, 1.61], P < 0.001, irrespective of body dimensions (Range of HR for all body dimensions 1.36 to 1.70, all P < 0.05). High urinary potassium excretion (5th vs. 3rd quintile) was associated with increased mortality risk in participants with obesity (BMI ≥30 kg/m2; HR 1.52 [1.00, 2.30]), but not in participants without obesity (BMI <25 kg/m2; HR 0.89 [0.62, 1.26]) (P-interaction = 0.001).

Conclusions: Low potassium intake was associated with increased mortality risk in community-dwelling individuals. In individuals with obesity, high potassium intake was also associated with increased mortality risk.
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http://dx.doi.org/10.1093/ajcn/nqac137DOI Listing
May 2022

Nuclear Magnetic Resonance-Measured Ionized Magnesium Is Inversely Associated with Type 2 Diabetes in the Insulin Resistance Atherosclerosis Study.

Nutrients 2022 Apr 25;14(9). Epub 2022 Apr 25.

Laboratory Corporation of America Holdings (Labcorp), Morrisville, NC 27560, USA.

The aims were to optimize a nuclear magnetic resonance (NMR)-based assay for quantifying ionized or free magnesium and investigate its association with type 2 diabetes (T2D). A high-throughput, ionized magnesium assay was optimized and evaluated. Plasma magnesium was quantified, and associations with T2D were ascertained in Insulin Resistance Atherosclerosis Study (IRAS) participants. Coefficients of variation for the ionized magnesium assay ranged from 0.7-1.5% for intra-assay and 4.2-4.7% for inter-assay precision. In IRAS (n = 1342), ionized magnesium was significantly lower in subjects with prediabetes and T2D than in normoglycemic subjects, and lower in participants with T2D than those with prediabetes ( < 0.0001). Cross-sectional regression analyses revealed that magnesium was associated with T2D at baseline in models adjusted for multiple clinical risk factors ( = 0.032). This association appeared to be modified by sex, in such a way that the associations were present in women (OR = 0.54 (95% CI 0.37-0.79), = 0.0015) and not in men (OR = 0.98 (95% CI 0.71-1.35), = 0.90). Longitudinal regression analyses revealed an inverse association between magnesium and future T2D in the total population ( = 0.035) that was attenuated by LP-IR ( = 0.22). No interactions were detected between magnesium and age, race, BMI, glucose, insulin, triglycerides, or LPIR for the prospective association with future T2D. However, a significant interaction between magnesium and sex was present, now with a trend for an association in men (OR = 0.75 (95% CI 0.55-1.02), = 0.065 and absence of an association in women (OR = 1.01 (0.76-1.33), = 0.97). Conclusions: lower ionized magnesium, as measured by an NMR-based assay optimized for accuracy and precision, was associated cross-sectionally with T2D at baseline and longitudinally with incident T2D in IRAS.
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http://dx.doi.org/10.3390/nu14091792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9103587PMC
April 2022

Association of Cardiometabolic Disease With Cancer in the Community.

JACC CardioOncol 2022 Mar 15;4(1):69-81. Epub 2022 Mar 15.

Cardiovascular Institute and Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

Background: Obesity and cardiometabolic dysfunction have been associated with cancer risk and severity. Underlying mechanisms remain unclear.

Objectives: The aim of this study was to examine associations of obesity and related cardiometabolic traits with incident cancer.

Methods: FHS (Framingham Heart Study) and PREVEND (Prevention of Renal and Vascular End-Stage Disease) study participants without prevalent cancer were studied, examining associations of obesity, body mass index (BMI), waist circumference, visceral adipose tissue (VAT) and subcutaneous adipose tissue depots, and C-reactive protein (CRP) with future cancer in Cox models.

Results: Among 20,667 participants (mean age 50 years, 53% women), 2,619 cancer events were observed over a median follow-up duration of 15 years. Obesity was associated with increased risk for future gastrointestinal (HR: 1.30; 95% CI: 1.05-1.60), gynecologic (HR: 1.62; 95% CI: 1.08-2.45), and breast (HR: 1.32; 95% CI: 1.05-1.66) cancer and lower risk for lung cancer (HR: 0.62; 95% CI: 0.44-0.87). Similarly, waist circumference was associated with increased risk for overall, gastrointestinal, and gynecologic but not lung cancer. VAT but not subcutaneous adipose tissue was associated with risk for overall cancer (HR: 1.22; 95% CI: 1.05-1.43), lung cancer (HR: 1.92; 95% CI: 1.01-3.66), and melanoma (HR: 1.56; 95% CI: 1.02-2.38) independent of BMI. Last, higher CRP levels were associated with higher risk for overall, colorectal, and lung cancer ( < 0.05 for all).

Conclusions: Obesity and abdominal adiposity are associated with future risk for specific cancers (eg, gastrointestinal, gynecologic). Although obesity was associated with lower risk for lung cancer, greater VAT and CRP were associated with higher lung cancer risk after adjusting for BMI.
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http://dx.doi.org/10.1016/j.jaccao.2022.01.095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9040108PMC
March 2022

Reference intervals for Sysmex XN hematological parameters as assessed in the Dutch Lifelines cohort.

Clin Chem Lab Med 2022 05 2;60(6):907-920. Epub 2022 May 2.

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

Objectives: Our aim was to derive reference intervals for all Sysmex XN hematology analyzer parameters. The rationale behind the study was the lack of reference intervals for the XN analyzer cell population data (CPD) and functional parameters.

Methods: Fresh fasting blood samples from 18,484 participants in the Dutch Lifelines study were analyzed using two automated XN analyzers. Structured health questionnaire data were used to select a subgroup of 15,803 apparently healthy individuals for inclusion in the reference population. The Latent Abnormal Values Exclusion (LAVE) approach was used to reduce the influence of latent diseases in the reference population on the resulting reference intervals. We applied analysis of variance to judge the need for partitioning of the reference intervals by sex or age.

Results: We report reference intervals for 105 XN analyzer hematological parameters with and without applying LAVE. Sex-related partitioning was required for red blood cells, (RBC, RBC-O), hemoglobin (HGB, HGB-O), hematocrit (HCT), mean corpuscular hemoglobin concentration (MCHC), reticulocyte production index (RPI), and side scattered light intensity of the red blood cell population in the RET channel (RBC-Z). Partitioning for age was not warranted. Body mass index (BMI) and smoking had moderate influence on a minority of the parameters.

Conclusions: We provide reference intervals for all Sysmex XN analyzer routine, CPD and functional parameters, using a direct approach in a large cohort in the Netherlands.
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http://dx.doi.org/10.1515/cclm-2022-0094DOI Listing
May 2022

Plasma phosphate and all-cause mortality in individuals with and without type 2 diabetes: the Dutch population-based lifelines cohort study.

Cardiovasc Diabetol 2022 04 27;21(1):61. Epub 2022 Apr 27.

Department of Medicine, Division of Nephrology, University Medical Centre Groningen, University of Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands.

Introduction: Individuals with type 2 diabetes have a substantially elevated cardiovascular risk. A higher plasma phosphate level promotes vascular calcification, which may adversely affect outcomes in individuals with type 2 diabetes. We hypothesized that the association between plasma phosphate and all-cause mortality is stronger in individuals with type 2 diabetes, compared to those without diabetes.

Methods: We analysed the association between plasma phosphate and all-cause mortality in the Dutch population-based Lifelines cohort and in subgroups with and without type 2 diabetes, using multivariable Cox regression adjusted for potential confounders. Effect modification was tested using multiplicative interaction terms.

Results: We included 57,170 individuals with 9.4 [8.8-10.4] years follow-up. Individuals within the highest phosphate tertile (range 1.00-1.83 mmol/L) were at higher risk of all-cause mortality (fully adjusted HR 1.18 [95% CI 1.02-1.36], p = 0.02), compared with the intermediate tertile (range 0.85-0.99 mmol/L). We found significant effect modification by baseline type 2 diabetes status (p-interaction = 0.003). Within the type 2 diabetes subgroup (N = 1790), individuals within the highest plasma phosphate tertile had an increased mortality risk (HR 1.73 [95% CI 1.10-2.72], p = 0.02 vs intermediate tertile). In individuals without diabetes at baseline (N = 55,380), phosphate was not associated with mortality (HR 1.12 [95% CI 0.96-1.31], p = 0.14). Results were similar after excluding individuals with eGFR < 60 mL/min/1.73 m.

Discussion: High-normal plasma phosphate levels were associated with all-cause mortality in individuals with type 2 diabetes. The association was weaker and non-significant in those without diabetes. Measurement of phosphate levels should be considered in type 2 diabetes; whether lowering phosphate levels can improve health outcomes in diabetes requires further study.
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http://dx.doi.org/10.1186/s12933-022-01499-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9047280PMC
April 2022

Ultra-processed foods and risk of all-cause mortality in renal transplant recipients.

Am J Clin Nutr 2022 06;115(6):1646-1657

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

Background: Renal transplant recipients (RTRs) have a 6-fold higher risk of mortality than age- and sex-matched controls. Whether high consumption of ultra-processed foods is associated with survival in RTRs is unknown.

Objectives: We aimed to study the association between high consumption of ultra-processed foods and all-cause mortality in stable RTRs.

Methods: We conducted a prospective cohort study in adult RTRs with a stable graft. Dietary intake was assessed using a validated 177-item FFQ. Food items were categorized according to the NOVA classification system and the proportion ultra-processed foods comprised of total food weight per day was calculated.

Results: We included 632 stable RTRs (mean ± SD age: 53.0 ± 12.7 y, 57% men). Mean ± SD consumption of ultra-processed foods was 721 ± 341 g/d (28% of total weight of food intake), whereas the intake of unprocessed and minimally processed foods, processed culinary ingredients, and processed foods accounted for 57%, 1%, and 14%, respectively. During median follow-up of 5.4 y [IQR: 4.9-6.0 y], 129 (20%) RTRs died. In Cox regression analyses, ultra-processed foods were associated with all-cause mortality (HR per doubling of percentage of total weight: 2.13; 95% CI: 1.46, 3.10; P < 0.001), independently of potential confounders. This association was independent from the quality of the overall dietary pattern, expressed by the Mediterranean Diet Score (MDS) or Dietary Approaches to Stop Hypertension (DASH) score. When analyzing ultra-processed foods by groups, only sugar-sweetened beverages (HR: 1.21; 95% CI: 1.05, 1.39; P = 0.007), desserts (HR: 1.24; 95% CI: 1.02, 1.49; P = 0.03), and processed meats (HR: 1.87; 95% CI: 1.22, 2.86; P = 0.004) were associated with all-cause mortality.

Conclusions: Consumption of ultra-processed foods, in particular sugar-sweetened beverages, desserts, and processed meats, is associated with a higher risk of all-cause mortality after renal transplantation, independently of low adherence to high-quality dietary patterns, such as the Mediterranean diet and the DASH diet.This trial was registered at clinicaltrials.gov as NCT02811835.
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http://dx.doi.org/10.1093/ajcn/nqac053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9170470PMC
June 2022

Association of Endogenous Erythropoietin Levels and Iron Status With Cognitive Functioning in the General Population.

Front Aging Neurosci 2022 8;14:862856. Epub 2022 Apr 8.

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

Background: Emerging data suggest that erythropoietin (EPO) promotes neural plasticity and that iron homeostasis is needed to maintain normal physiological brain function. Cognitive functioning could therefore be influenced by endogenous EPO levels and disturbances in iron status.

Objective: To determine whether endogenous EPO levels and disturbances in iron status are associated with alterations in cognitive functioning in the general population.

Materials And Methods: Community-dwelling individuals from the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study, a general population-based cohort in Groningen, Netherlands, were surveyed between 2003 and 2006. Additionally, endogenous EPO levels and iron status, consisting of serum iron, transferrin, ferritin, and transferrin saturation were analyzed. Cognitive function was assessed by scores on the Ruff Figural Fluency Test (RFFT), as a reflection of executive function, and the Visual Association Test (VAT), as a reflection of associative memory.

Results: Among 851 participants (57% males; mean age 60 ± 13 years), higher endogenous EPO levels were independently associated with an improved cognitive function, reflected by RFFT scores (ß = 0.09, = 0.008). In multivariable backward linear regression analysis, EPO levels were among the most important modifiable determinants of RFFT scores (ß = 0.09, = 0.002), but not of VAT scores. Of the iron status parameters, only serum ferritin levels were inversely associated with cognitive function, reflected by VAT scores, in multivariable logistic regression analysis (odds ratio, 0.77; 95% confidence interval 0.63-0.95; = 0.02 for high performance on VAT, i.e., ≥11 points). No association between iron status parameters and RFFT scores was identified.

Conclusion: The findings suggest that endogenous EPO levels and serum ferritin levels are associated with specific cognitive functioning tests in the general population. Higher EPO levels are associated with better RFFT scores, implying better executive function. Serum ferritin levels, but not other iron status parameters, were inversely associated with high performance on the VAT score, implying a reduced ability to create new memories and recall recent past. Further research is warranted to unravel underlying mechanisms and possible benefits of therapeutic interventions.
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http://dx.doi.org/10.3389/fnagi.2022.862856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9024369PMC
April 2022
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