Publications by authors named "Gerjan Navis"

555 Publications

Ultra-processed food and incident type 2 diabetes: studying the underlying consumption patterns to unravel the health effects of this heterogeneous food category in the prospective Lifelines cohort.

BMC Med 2022 01 13;20(1). Epub 2022 Jan 13.

Department of Internal Medicine, Division Nephrology (AA52), University Medical Center Groningen, P.O. Box 30 001, 9700RB, Groningen, The Netherlands.

Background: The overall consumption of ultra-processed food (UPF) has previously been associated with type 2 diabetes. However, due to the substantial heterogeneity of this food category, in terms of their nutritional composition and product type, it remains unclear whether previous results apply to all underlying consumption patterns of UPF.

Methods: Of 70,421 participants (35-70 years, 58.6% women) from the Lifelines cohort study, dietary intake was assessed with a food frequency questionnaire. UPF was identified according to the NOVA classification. Principal component analysis (PCA) was performed to derive UPF consumption patterns. The associations of UPF and adherence to UPF consumption patterns with incidence of type 2 diabetes were studied with logistic regression analyses adjusted for age, sex, diet quality, energy intake, alcohol intake, physical activity, TV watching time, smoking status, and educational level.

Results: During a median follow-up of 41 months, a 10% increment in UPF consumption was associated with a 25% higher risk of developing type 2 diabetes (1128 cases; OR 1.25 [95% CI 1.16, 1.34]). PCA revealed four habitual UPF consumption patterns. A pattern high in cold savory snacks (OR 1.16 [95% CI 1.09, 1.22]) and a pattern high in warm savory snacks (OR 1.15 [95% CI 1.08, 1.21]) were associated with an increased risk of incident type 2 diabetes; a pattern high in traditional Dutch cuisine was not associated with type 2 diabetes incidence (OR 1.05 [95% CI 0.97, 1.14]), while a pattern high in sweet snacks and pastries was inversely associated with type 2 diabetes incidence (OR 0.82 [95% CI 0.76, 0.89]).

Conclusions: The heterogeneity of UPF as a general food category is reflected by the discrepancy in associations between four distinct UPF consumption patterns and incident type 2 diabetes. For better public health prevention, research is encouraged to further clarify how different UPF consumption patterns are related to type 2 diabetes.
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http://dx.doi.org/10.1186/s12916-021-02200-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8756643PMC
January 2022

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

Int J Epidemiol 2022 Jan;50(6):1959-1969

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8743118PMC
January 2022

Co-Creation of a Multi-Component Health Literacy Intervention Targeting Both Patients with Mild to Severe Chronic Kidney Disease and Health Care Professionals.

Int J Environ Res Public Health 2021 12 18;18(24). Epub 2021 Dec 18.

Department of Health Sciences, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands.

Limited health literacy (LHL) is common in chronic kidney disease (CKD) patients and frequently associated with worse self-management. Multi-component interventions targeted at patients and healthcare professionals (HCPs) are recommended, but evidence is limited. Therefore, this study aims to determine the objectives and strategies of such an intervention, and to develop, produce and evaluate it. For this purpose, we included CKD patients with LHL ( = 19), HCPs ( = 15), educators ( = 3) and students ( = 4) from general practices, nephrology clinics and universities in an Intervention Mapping (IM) process. The determined intervention objectives especially address the patients' competences in maintaining self-management in the long term, and communication competences of patients and HCPs. Patients preferred visual strategies and strategies supporting discussion of needs and barriers during consultations to written and digital strategies. Moreover, they preferred an individual approach to group meetings. We produced a four-component intervention, consisting of a visually attractive website and topic-based brochures, consultation cards for patients, and training on LHL for HCPs. Evaluation revealed that the intervention was useful, comprehensible and fitting for patients' needs. Healthcare organizations need to use visual strategies more in patient education, be careful with digitalization and group meetings, and train HCPs to improve care for patients with LHL. Large-scale research on the effectiveness of similar HL interventions is needed.
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http://dx.doi.org/10.3390/ijerph182413354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8704507PMC
December 2021

Plasma sodium, extracellular fluid volume, and blood pressure in healthy men.

Physiol Rep 2021 12;9(24):e15103

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

In the general population we recently reported a consistent association between plasma sodium and volume markers, suggesting that individuals with higher plasma sodium have higher extracellular fluid volume (ECFV). To test this hypothesis, we analyzed the association between plasma sodium and directly measured ECFV (iothalamate distribution volume) in healthy men. Second, we studied whether plasma sodium is associated with blood pressure. We analyzed data from 70 men (age 24 ± 7 years) at the end of two 7-day periods on a low-sodium diet (LS, 50 mmol Na/24 h) and a high-sodium diet (HS, 200 mmol Na/24 h), respectively. The association of plasma sodium with blood pressure was assessed in the combined data of the different sodium intakes by linear mixed effects models. A positive univariable association between plasma sodium and ECFV was found during HS (β = 0.24, p = 0.042) and LS (β = 0.23, p = 0.058), respectively. Individual values of plasma sodium on LS and HS diet were strongly correlated (β = 0.68, p < 0.001), as were values for ECFV (β = 0.54, p < 0.001). In the combined data set plasma sodium level was significantly associated with ECFV (B [SE] = 0.10 [0.04], p = 0.02), and systolic blood pressure (SBP, B [SE] = 0.73 [0.26], p = 0.006), independent of ECFV. In conclusion, plasma sodium concentration is positively associated with ECFV on both LS and HS intake. Our data confirm and extend prior data on individual regulation of plasma sodium and suggest that this is associated with individuality of the regulation of ECFV. Finally, plasma sodium level is associated with SBP, independent of ECFV and diet.
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http://dx.doi.org/10.14814/phy2.15103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8683787PMC
December 2021

Cohort Profile Update: Lifelines, a three-generation cohort study and biobank.

Int J Epidemiol 2021 Dec 13. Epub 2021 Dec 13.

Lifelines Cohort Study, Roden, The Netherlands.

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http://dx.doi.org/10.1093/ije/dyab257DOI Listing
December 2021

Plasma Lead Concentration and Risk of Late Kidney Allograft Failure: Findings From the TransplantLines Biobank and Cohort Studies.

Am J Kidney Dis 2021 Dec 3. Epub 2021 Dec 3.

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

Rationale & Objective: Heavy metals are known to induce kidney damage and recent studies have linked minor exposures to cadmium and arsenic with increased risk of kidney allograft failure, yet the potential association of lead (Pb) with late graft failure in kidney transplant recipients (KTR) remains unknown.

Study Design: Prospective cohort study in the Netherlands.

Setting & Participants: We studied outpatient KTR (n=670) with a functioning graft for ≥1 year recruited at a university setting (2008-2011, NCT02811835) and followed, on average, for 4.9 (IQR, 3.4‒5.5) years. Additionally, end-stage kidney disease patients (n=46) enrolled in the ongoing TransplantLines Cohort and Biobank Study (2016-2017, NCT03272841) were studied at admission for transplantation and at 3, 6, 12, and 24 months after transplantation.

Exposure: Plasma Pb was log transformed to estimate the association with outcomes per doubling of plasma Pb concentration and also considered categorically as tertiles of the Pb distribution.

Outcome: Kidney graft failure (restart of dialysis or re-transplantation) with the competing event of death with a functioning graft.

Analytical Approach: Multivariable-adjusted cause-specific hazards models where follow-up of KTR who died with a functioning graft was censored.

Results: Median baseline plasma Pb was 0.31 (IQR, 0.22─0.45) μg/L among all KTRs. During follow-up, 78 (12%) KTR developed graft failure. Higher plasma Pb was associated with increased risk of graft failure (HR 1.59, 95% CI 1.14‒2.21 per doubling; P=0.006) independent of age, sex, transplant characteristics, eGFR, proteinuria, smoking status, alcohol intake, and plasma concentrations of cadmium and arsenic. These findings remained materially unchanged after additional adjustment for dietary intake and were consistent with those of analyses examining Pb categorically. In serial measurements, plasma Pb was significantly higher at admission for transplantation than at 3-months post-transplant (P=0.001), after which it remained stable over 2 years of follow-up (P=0.2).

Limitations: Observational study design.

Conclusions: Pretransplant plasma Pb concentrations, which fall after transplantation, are associated with increased risk of late kidney allograft failure. These findings warrant further studies to evaluate whether preventive or therapeutic interventions to decrease plasma Pb may represent novel risk-management strategies to decrease the rate of kidney allograft failure.
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http://dx.doi.org/10.1053/j.ajkd.2021.10.009DOI Listing
December 2021

Polyphenols and Novel Insights Into Post-kidney Transplant Complications and Cardiovascular Disease: A Narrative Review.

Front Cardiovasc Med 2021 16;8:751036. Epub 2021 Nov 16.

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

Kidney transplantation is the preferred treatment for end-stage kidney disease. It is, however, not devoid of complications. Delayed graft function related to ischemia-reperfusion injury (IRI), calcineurin inhibitor (CNI) nephrotoxicity, diabetes, and a particularly high-rate cardiovascular disease (CVD) risk, represent important complications following kidney transplantation. Oxidative stress and chronic low-grade inflammation are mechanisms of disease incompletely abrogated in stable kidney transplant recipient (KTR), contributing to the occurrence of these complications. Polyphenols, bioactive compounds with recognized antioxidant and anti-inflammatory properties have been strongly associated with prevention of CVD in the general population and have been shown to decrease IRI and antagonize CNI nephrotoxicity in animal experimental models, therefore they may have a role in prevention of complications in KTR. This narrative review aims to summarize and discuss current evidence on different polyphenols for prevention of complications, particularly prevention of CVD in KTR, pointing toward the need of further studies with potential clinical impact.
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http://dx.doi.org/10.3389/fcvm.2021.751036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8635050PMC
November 2021

Clinical and Dietary Determinants of Muscle Mass in Patients with Type 2 Diabetes: Data from the Diabetes and Lifestyle Cohort Twente.

J Clin Med 2021 Nov 10;10(22). Epub 2021 Nov 10.

Department of Internal Medicine/Nephrology, ZGT Hospital, 7609 PP Almelo, The Netherlands.

Low muscle mass in patients with type 2 diabetes is associated with a progressively higher risk of morbidity and mortality. The aim of this study was to identify modifiable targets for intervention of muscle mass in type 2 diabetes. Cross-sectional analyses were performed in 375 patients of the Diabetes and Lifestyle Cohort Twente-1 study. Muscle mass was estimated by 24 h urinary creatinine excretion rate (CER, mmol/24 h). Patients were divided in sex-stratified tertiles of CER. To study determinants of CER, multivariable linear regression analyses were performed. Protein intake was determined by Maroni formula and by a semi-quantitative Food Frequency Questionnaire. The mean CER was 16.1 ± 4.8 mmol/24 h and 10.9 ± 2.9 mmol/24 h in men and women, respectively. Lower CER was significantly associated with older age ( < 0.001) as a non-modifiable risk factor, whereas higher BMI ( = 0.015) and lower dietary protein intake (both methods < 0.001) were identified as modifiable risk factors for lower CER. Overall body mass index (BMI) was high, even in the lowest CER tertile the mean BMI was 30.9 kg/m, mainly driven by someone's body weight ( = 0.004) instead of someone's height ( = 0.58). In the total population, 28% did not achieve adequate protein intake of >0.8 g/kg/day, with the highest percentage in the lowest CER tertile (52%, < 0.001). Among patients with type 2 diabetes treated in secondary care, higher BMI and low dietary protein intake are modifiable risk factors for lower muscle mass. Considering the risk associated with low muscle mass, intervention may be useful. To that purpose, dietary protein intake and BMI are potential targets for intervention.
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http://dx.doi.org/10.3390/jcm10225227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8623198PMC
November 2021

Airflow Limitation, Fatigue, and Health-Related Quality of Life in Kidney Transplant Recipients.

Clin J Am Soc Nephrol 2021 11;16(11):1686-1694

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

Background And Objectives: Many kidney transplant recipients suffer from fatigue and poor health-related quality of life. Airflow limitation may be an underappreciated comorbidity among kidney transplant recipients, which could contribute to fatigue and lower health-related quality of life in this population. In this study, we compared the prevalence of airflow limitation between kidney transplant recipients and healthy controls and investigated associations of airflow limitation with fatigue and health-related quality of life in kidney transplant recipients.

Design, Setting, Participants, & Measurements: Data from the ongoing TransplantLines Biobank and Cohort study were used. Airflow limitation was defined as forced exhaled volume in 1 second less than the fifth percentile of the general population. Fatigue and health-related quality of life were assessed using checklist individual strength 20 revised (CIS20-R) and Short Form-36 (SF-36) questionnaires.

Results: A total of 539 kidney transplant recipients (58% men; mean age 56±13 years) and 244 healthy controls (45% men; mean age 57±10 years) were included. Prevalence of airflow limitation was higher in kidney transplant recipients than in healthy controls (133 [25%] versus 25 [10%]). In multinomial regression models, airflow limitation was independently associated with fatigue severity (odds ratio moderate fatigue, 1.68; 95% confidence interval, 0.92 to 3.09 and odds ratio severe fatigue, 2.51; 95% confidence interval, 1.39 to 4.55; =0.007) and lower physical health-related quality of life (-0.11 SDs; 95% confidence interval, -0.19 to -0.02; =0.01) in kidney transplant recipients. In exploratory mediation analyses, fatigue accounted for 79% of the association of airflow limitation with physical health-related quality of life.

Conclusions: Airflow limitation is common among kidney transplant recipients. Its occurrence is associated with more than two times higher risk of severe fatigue, and it is associated with lower physical health-related quality of life. Mediation analyses suggest that airflow limitation causes fatigue, which in turn, decreases physical health-related quality of life.

Clinical Trial Registry Name And Registration Number: TransplantLines: The Transplantation Biobank, NCT03272841 PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_11_08_CJN06600521.mp3.
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http://dx.doi.org/10.2215/CJN.06600521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8729428PMC
November 2021

High-Normal Protein Intake Is Not Associated With Faster Renal Function Deterioration in Patients With Type 2 Diabetes: A Prospective Analysis in the DIALECT Cohort.

Diabetes Care 2022 Jan;45(1):35-41

1Department of Internal Medicine/Nephrology, Ziekenhuis Groep Twente, Almelo, the Netherlands.

Objective: To study the prospective association between dietary protein intake and renal function deterioration in patients with type 2 diabetes (T2D).

Research Design And Methods: Prospective analyses were performed in data of 382 patients of the Diabetes and Lifestyle Cohort Twente (DIALECT) study. Dietary protein intake was determined by the Maroni equation from 24-h urinary urea excretion. Renal function deterioration was defined as need for renal replacement therapy or a persistent increase of ≥50% in serum creatinine. Cox proportional hazards models were used to calculate hazard ratios (HRs) for the association between dietary protein intake and renal function deterioration. Threshold levels represent the dietary protein intake at which there was a significantly increased and reduced hazard of renal function deterioration.

Results: Renal function deterioration occurred in 53 patients (14%), with a median follow-up duration of 6 (interquartile range 5-9) years. Mean dietary protein intake was 91 ± 27 g/day (1.22 ± 0.33 g/kg ideal body weight/day). Dietary protein intake was inversely associated with renal function deterioration (HR 0.62 [95% CI 0.44-0.90]). Patients with an intake <92 g/day had an increased hazard for renal function deterioration (HR 1.44 [95% CI 1.00-2.06]), while patients with an intake >163 g/day had a decreased hazard for renal function deterioration (HR 0.42 [95% CI 0.18-1.00]). Regarding dietary protein intake per kilogram body weight, patients with an intake <1.08 g/kg/day had an increased hazard for renal function deterioration (HR 1.63 [95% CI 1.00-2.65]).

Conclusions: In patients with T2D, unrestricted dietary protein intake was not associated with an increased hazard of renal function deterioration. Therefore, substituting carbohydrates with dietary protein is not contraindicated as a part of T2D management, although it may have a positive effect on body weight while minimizing loss of muscle mass.
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http://dx.doi.org/10.2337/dc21-1211DOI Listing
January 2022

Low Circulating Concentrations of Very Long Chain Saturated Fatty Acids Are Associated with High Risk of Mortality in Kidney Transplant Recipients.

Nutrients 2021 Sep 26;13(10). Epub 2021 Sep 26.

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

Kidney transplant recipients (KTR) are at increased risk of mortality, particularly from infectious diseases, due to lifelong immunosuppression. Although very long chain saturated fatty acids (VLSFA) have been identified as crucial for phagocytosis and clearance of infections, their association with mortality in immunocompromised patient groups has not been studied. In this prospective cohort study we included 680 outpatient KTR with a functional graft ≥1 year and 193 healthy controls. Plasma VLSFA (arachidonic acid (C20:0), behenic acid (C22:0) and lignoceric acid (C24:0)) were measured by gas chromatography coupled with a flame ionization detector. Cox regression analyses was used to prospectively study the associations of VLSFA with all-cause and cause-specific mortality. All studied VLSFA were significantly lower in KTR compared to healthy controls (all < 0.001). During a median (interquartile range) follow-up of 5.6 (5.2-6.3) years, 146 (21%) KTR died, of which 41 (28%) died due to infectious diseases. In KTR, C22:0 was inversely associated with risk of all-cause mortality, with a HR (95% CI) per 1-SD-increment of 0.79 (0.64-0.99), independent of adjustment for potential confounders. All studied VLSFA were particularly strongly associated with mortality from infectious causes, with respective HRs for C20:0, C22:0 and C24:0 of 0.53 (0.35-0.82), 0.48 (0.30-0.75), and 0.51 (0.33-0.80), independent of potential confounders. VLSFA are inversely associated with infectious disease mortality in KTR after adjustment, including HDL-cholesterol. Further studies are needed to assess the effect of VLSFA-containing foods on the risk of infectious diseases in immunocompromised patient groups.
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http://dx.doi.org/10.3390/nu13103383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8540190PMC
September 2021

Boron Intake and decreased risk of mortality in kidney transplant recipients.

Eur J Nutr 2021 Oct 22. Epub 2021 Oct 22.

Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen and University of Groningen, Post Box 30.001, 9700 RB, Groningen, The Netherlands.

Purpose: In a search for potentially modifiable factors to improve long-term outcome among kidney transplant recipients (KTR), we hypothesized that boron exposure is associated with improved long-term outcome in KTR.

Methods: We determined 24 h urinary boron excretion using inductively coupled plasma mass spectrometry as a measure of boron exposure in 693 stable KTR (57% male, mean age 53y), enrolled in the TransplantLines Food and Nutrition Biobank and Cohort Study. Dietary intake was assessed using validated food-frequency questionnaires.

Results: Linear regression analyses showed that dietary intake of fruit, wine and nuts were key determinants of boron excretion. In addition, boron excretion was negatively correlated with homocysteine and inflammatory parameters. In total, 73 (32%), 47 (20%) and 30 (13%) KTR died among the lowest, middle and highest tertiles of 24 h urinary boron excretion, respectively (P < 0.001). Cox regression analyses showed that high boron excretion was strongly associated with lower risk of mortality, independent of age, sex, estimated glomerular filtration rate and history of cardiovascular disease (HR per doubling: 0.51, 95% CI: 0.40 to 0.66, P < 0.001).

Conclusion: Boron may be an overlooked target to improve long-term survival among KTR and potentially other patients, likely through pathways other than inflammation or the methionine-homocysteine cycle that were previously suggested. Interventional trials are warranted to confirm the potential of dietary boron supplementation in KTR and other patient populations.
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http://dx.doi.org/10.1007/s00394-021-02702-0DOI Listing
October 2021

Malnutrition Universal Screening Tool and Patient-Generated Subjective Global Assessment Short Form and their predictive validity in hospitalized patients.

Clin Nutr ESPEN 2021 10 3;45:252-261. Epub 2021 Sep 3.

Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Internal Zip Code AA52, PO Box 30.001, 9700 RB, Groningen, the Netherlands.

Background And Aims: Malnutrition screening is a first step in the nutrition care process for hospitalized patients, to identify those at risk of malnutrition and associated worse outcome, preceding further assessment and intervention. Frequently used malnutrition screening tools including the Malnutrition Universal Screening Tool (MUST) mainly screen for characteristics of malnutrition, while the Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF) additionally includes risk factors for development of malnutrition, yielding a higher percentage of patients at risk. To investigate whether this translates into higher risk of worse outcome, we aimed to determine the predictive validity of MUST and PG-SGA SF for prolonged hospitalization >8 days, readmission, and mortality <6 months after hospital discharge.

Methods: In this observational study, MUST was performed according to university hospital protocol. Additional screening using PG-SGA SF was performed within 24 h of hospital admission (high risk: MUST ≥ 2, PG_SGA SF ≥ 9). Associations of MUST and PG-SGA SF with outcomes were analyzed by logistic- and Cox PH-regression.

Results: Of 430 patients analyzed (age 58 ± 16 years, 53% male, BMI 26.9 ± 5.5 kg/m), MUST and PG-SGA SF identified 32 and 80 at high risk, respectively. One-hundred-eight patients had prolonged hospitalization, 109 were readmitted and 20 died. High risk by MUST was associated with mortality (HR = 3.9; 95% CI 1.3-12.2, P = 0.02), but not with other endpoints. High risk by PG-SGA SF was associated with prolonged hospitalization (OR = 2.5; 95% CI 1.3-5.0, P = 0.009), readmission (HR = 1.9; 95% CI 1.1-3.2, P = 0.03), and mortality (HR = 34.8; 95% CI 4.2-289.3, P = 0.001), independent of age, sex, hospital ward and previous hospitalization <6 months. In the 363/430 patients classified as low risk by MUST, high risk by PG-SGA SF was independently associated with higher risk of readmission (HR = 1.9; 95% CI 1.0-3.5, P = 0.04) and mortality (HR = 19.5; 95% CI 2.0-189.4, P = 0.01).

Conclusions: Whereas high malnutrition risk by MUST was only associated with mortality, PG-SGA SF was associated with higher risk of prolonged hospitalization, readmission, and mortality. In patients considered as low risk by MUST, high malnutrition risk by PG-SGA SF was also predictive of worse outcome. Our findings support the use of PG-SGA SF in routine care to identify patients at risk of malnutrition and worse outcome, and enable proactive interventions.
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http://dx.doi.org/10.1016/j.clnesp.2021.08.015DOI Listing
October 2021

Diminished antiproteinuric effect of the angiotensin receptor blocker losartan during high potassium intake in patients with CKD.

Clin Kidney J 2021 Oct 5;14(10):2170-2176. Epub 2021 Feb 5.

Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands.

Background: Angiotensin II type 1 receptor blockers (ARBs) lower blood pressure (BP) and proteinuria and reduce renal disease progression in many-but not all-patients. Reduction of dietary sodium intake improves these effects of ARBs. Dietary potassium intake affects BP and proteinuria. We set out to address the effect of potassium intake on BP and proteinuria response to losartan in non-diabetic proteinuric chronic kidney disease (CKD) patients.

Methods: We performed a analysis of a placebo-controlled interventional cross-over study in 33 non-diabetic proteinuric patients (baseline mean arterial pressure and proteinuria: 105 mmHg and 3.8 g/day, respectively). Patients were treated for 6 weeks with placebo, losartan and losartan/hydrochlorothiazide (HCT), combined with a habitual (∼200 mmol/day) and low-sodium (LS) diet (<100 mmol/day), in randomized order. To analyse the effects of potassium intake, we categorized patients based on median split of 24-h urinary potassium excretion, reflecting potassium intake.

Results: Mean potassium intake was stable during all six treatment periods. Losartan and losartan/HCT lowered BP and proteinuria in all treatment groups. Patients with high potassium intake showed no difference in the BP effects compared with patients with low potassium intake. The antiproteinuric response to losartan monotherapy and losartan combined with HCT during the habitual sodium diet was significantly diminished in patients with high potassium intake (20% versus 41%, P=0.011; and 48% versus 64%, P=0.036). These differences in antiproteinuric response abolished when shifting to the LS diet.

Conclusions: In proteinuric CKD patients, the proteinuria, but not BP-lowering response to losartan during a habitual high-sodium diet was hampered during high potassium intake. Differences disappeared after sodium status change by LS diet.
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http://dx.doi.org/10.1093/ckj/sfab031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483678PMC
October 2021

New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race.

N Engl J Med 2021 11 23;385(19):1737-1749. Epub 2021 Sep 23.

From the Division of Nephrology (L.A.I., S.J.C., A.S.L.) and the Institute for Clinical Research and Health Policy Studies (H.T.), Tufts Medical Center, Tufts Clinical and Translational Science Institute, Tufts University (H.T.), the Section on Genetics and Epidemiology, Joslin Diabetes Center (A.D.), and the Department of Medicine, Harvard Medical School (A.D.) - all in Boston; the Renal-Electrolyte and Hypertension Division, Perelman School of Medicine (N.D.E.), and the Departments of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics (W.Y.), University of Pennsylvania, Philadelphia; the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health and the Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Medical Institutions (J.C., D.W., Y.S., M.E.G., E.S., S.H.B.), the Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine (D.C.C., M.E.G.), and the Department of Medicine, Division of Nephrology, University of Maryland School of Medicine (R.K.) - all in Baltimore; the Kidney Health Research Collaborative, San Francisco Veterans Affairs (VA) Medical Center and University of California, San Francisco (M.M.E., M.G.S.), the Division of Nephrology, Department of Medicine, San Francisco VA Health Care System and University of California, San Francisco (M.M.E.), and the Department of Medicine, Priscilla Chan and Mark Zuckerberg San Francisco General Hospital and University of California, San Francisco (N.R.P.) - all in San Francisco; the Clinical Trial Unit, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (M.F.); the Division of Biostatistics, Department of Population Health Sciences, University of Utah Health, Salt Lake City (T.G.); the Department of Clinical Chemistry and Pharmacology, Institute of Laboratory Medicine, Lund University, Lund, Sweden (A.G.); the Faculty of Medicine, University of Iceland, Reykjavik, and the Icelandic Heart Association, Kopavogur - both in Iceland (V.G.); the Departments of Medicine and Epidemiology, University of Alabama at Birmingham, Birmingham (O.M.G.); the Departments of Laboratory Medicine and Pathology (A.B.K., J.C.S.), Pediatrics (M.M.), and Medicine (M.M.), University of Minnesota, Minneapolis, and the Division of Nephrology and Hypertension, Mayo Clinic, Rochester (A.D.R., V.E.T.) - all in Minnesota; the Faculty of Medical Sciences, University Medical Center Groningen, Groningen, the Netherlands (G.N.); the Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ (R.G.N.); the Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland (E.D.P.); Rush University Medical Center, Chicago (R.R.); and Steno Diabetes Center Copenhagen and the Department of Clinical Medicine, University of Copenhagen - both in Copenhagen (P.R.).

Background: Current equations for estimated glomerular filtration rate (eGFR) that use serum creatinine or cystatin C incorporate age, sex, and race to estimate measured GFR. However, race in eGFR equations is a social and not a biologic construct.

Methods: We developed new eGFR equations without race using data from two development data sets: 10 studies (8254 participants, 31.5% Black) for serum creatinine and 13 studies (5352 participants, 39.7% Black) for both serum creatinine and cystatin C. In a validation data set of 12 studies (4050 participants, 14.3% Black), we compared the accuracy of new eGFR equations to measured GFR. We projected the prevalence of chronic kidney disease (CKD) and GFR stages in a sample of U.S. adults, using current and new equations.

Results: In the validation data set, the current creatinine equation that uses age, sex, and race overestimated measured GFR in Blacks (median, 3.7 ml per minute per 1.73 m of body-surface area; 95% confidence interval [CI], 1.8 to 5.4) and to a lesser degree in non-Blacks (median, 0.5 ml per minute per 1.73 m; 95% CI, 0.0 to 0.9). When the adjustment for Black race was omitted from the current eGFR equation, measured GFR in Blacks was underestimated (median, 7.1 ml per minute per 1.73 m; 95% CI, 5.9 to 8.8). A new equation using age and sex and omitting race underestimated measured GFR in Blacks (median, 3.6 ml per minute per 1.73 m; 95% CI, 1.8 to 5.5) and overestimated measured GFR in non-Blacks (median, 3.9 ml per minute per 1.73 m; 95% CI, 3.4 to 4.4). For all equations, 85% or more of the eGFRs for Blacks and non-Blacks were within 30% of measured GFR. New creatinine-cystatin C equations without race were more accurate than new creatinine equations, with smaller differences between race groups. As compared with the current creatinine equation, the new creatinine equations, but not the new creatinine-cystatin C equations, increased population estimates of CKD prevalence among Blacks and yielded similar or lower prevalence among non-Blacks.

Conclusions: New eGFR equations that incorporate creatinine and cystatin C but omit race are more accurate and led to smaller differences between Black participants and non-Black participants than new equations without race with either creatinine or cystatin C alone. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).
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http://dx.doi.org/10.1056/NEJMoa2102953DOI Listing
November 2021

Diet quality and incident chronic kidney disease in the general population: The Lifelines Cohort Study.

Clin Nutr 2021 09 6;40(9):5099-5105. Epub 2021 Aug 6.

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

Rationale & Aims: Healthy dietary patterns have been associated with a lower risk of chronic kidney disease (CKD). We aimed to investigate the association of a fully food-based diet quality score assessed by the Lifelines Diet Score (LLDS) with either incident CKD or eGFR decline in the general population.

Methods: For this study, data from a prospective general population-based Lifelines cohort in the Northern Netherlands was used. Diet was assessed with a 110-item food frequency questionnaire at baseline. The LLDS, based on international evidence for diet-disease relations at the food group level, was calculated to assess diet quality. For the analysis, the score was divided into tertiles. Logistic regression was performed to evaluate the association of the LLDS at baseline with either incident CKD (eGFR <60 mL/min/1.73 m) or a ≥20% eGFR decline at the second study visit, adjusted for relevant confounders.

Results: A total of 78 346 participants free of CKD at baseline were included. During a mean (SD) follow-up of 3.6 ± 0.9 years, 2071 (2.6%) participants developed CKD and 7611 (9.7%) had a ≥20% eGFR decline. Participants in the highest tertile of LLDS had a lower risk of incident CKD (fully adjusted OR 0.83, [95% CI: 0.72-0.96]) and ≥20% eGFR decline (fully adjusted OR 0.80, [95% CI: 0.75-0.86]), compared with those in the lowest tertile. Similar dose-response associations were observed in continuous LLDS.

Conclusions: Higher adherence to a high-quality diet was associated with a lower risk of incident CKD or ≥20% eGFR decline in the general population.
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http://dx.doi.org/10.1016/j.clnu.2021.07.033DOI Listing
September 2021

Mahalanobis distance, a novel statistical proxy of homeostasis loss is longitudinally associated with risk of type 2 diabetes.

EBioMedicine 2021 Sep 20;71:103550. Epub 2021 Aug 20.

Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen 9713 GZ, the Netherlands.

Background: The potential role of individual plasma biomarkers in the pathogenesis of type 2 diabetes (T2D) has been broadly studied, but the impact of biomarkers interaction remains underexplored. Recently, the Mahalanobis distance (MD) of plasma biomarkers has been proposed as a proxy of physiological dysregulation. Here we aimed to investigate whether the MD calculated from circulating biomarkers is prospectively associated with development of T2D.

Methods: We calculated the MD of the Principal Components (PCs) integrating the information of 32 circulating biomarkers (comprising inflammation, glycemic, lipid, microbiome and one-carbon metabolism) measured in 6247 participants of the PREVEND study without T2D at baseline. Cox proportional-hazards regression analyses were performed to study the association of MD with T2D development.

Findings: After a median follow-up of 7·3 years, 312 subjects developed T2D. The overall MD (mean (SD)) was higher in subjects who developed T2D compared to those who did not: 35·65 (26·67) and 30.75 (27·57), respectively (P = 0·002). The highest hazard ratio (HR) was obtained using the MD calculated from the first 31 PCs (per 1 log-unit increment) (1·72 (95% CI 1·42,2·07), P < 0·001). Such associations remained after the adjustment for age, sex, plasma glucose, parental history of T2D, lipids, blood pressure medication, and BMI (HR 1·37 (95% CI 1·11,1·70), P = 0·004).

Interpretation: Our results are in line with the premise that MD represents an estimate of homeostasis loss. This study suggests that MD is able to provide information about physiological dysregulation also in the pathogenesis of T2D.

Funding: The Dutch Kidney Foundation (Grant E.033).
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http://dx.doi.org/10.1016/j.ebiom.2021.103550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379628PMC
September 2021

Glucose Regulation Beyond HbA in Type 2 Diabetes Treated With Insulin: Real-World Evidence From the DIALECT-2 Cohort.

Diabetes Care 2021 Jul 22. Epub 2021 Jul 22.

Division of Nephrology, Department of Internal Medicine, Ziekenhuisgroep Twente, Almelo and Hengelo, the Netherlands.

Objective: To investigate glucose variations associated with glycated hemoglobin (HbA) in insulin-treated patients with type 2 diabetes.

Research Design And Methods: Patients included in Diabetes and Lifestyle Cohort Twente (DIALECT)-2 ( = 79) were grouped into three HbA categories: low, intermediate, and high (≤53, 54-62, and ≥63 mmol/mol or ≤7, 7.1-7.8, and ≥7.9%, respectively). Blood glucose time in range (TIR), time below range (TBR), time above range (TAR), glucose variability parameters, day and night duration, and frequency of TBR and TAR episodes were determined by continuous glucose monitoring (CGM) using the FreeStyle Libre sensor and compared between HbA categories.

Results: CGM was performed for a median (interquartile range) of 10 (7-12) days/patient. TIR was not different for low and intermediate HbA categories (76.8% [68.3-88.2] vs. 76.0% [72.5.0-80.1]), whereas in the low category, TBR was higher and TAR lower (7.7% [2.4-19.1] vs. 0.7% [0.3-6.1] and 8.2% [5.7-17.6] vs. 20.4% [11.6-27.0], respectively, < 0.05). Patients in the highest HbA category had lower TIR (52.7% [40.9-67.3]) and higher TAR (44.1% [27.8-57.0]) than the other HbA categories ( < 0.05), but did not have less TBR during the night. All patients had more (0.06 ± 0.06/h vs. 0.03 ± 0.03/h; = 0.002) and longer (88.0 [45.0-195.5] vs. 53.4 [34.4-82.8] minutes; < 0.001) TBR episodes during the night than during the day.

Conclusions: In this study, a high HbA did not reduce the occurrence of nocturnal hypoglycemia, and low HbA was not associated with the highest TIR. Optimal personalization of glycemic control requires the use of newer tools, including CGM-derived parameters.
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http://dx.doi.org/10.2337/dc20-2241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8740938PMC
July 2021

Blood lipids-related dietary patterns derived from reduced rank regression are associated with incident type 2 diabetes.

Clin Nutr 2021 07 11;40(7):4712-4719. Epub 2021 May 11.

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

Background & Aims: Blood lipids play a critical role in the pathogenesis of type 2 diabetes, and they are closely related to dietary factors. However, the associations between blood lipids-related dietary patterns and risk of type 2 diabetes are controversial and not fully clear. In this study, we aimed to derive dietary patterns that explained variation in blood lipids and to investigate their associations with incident type 2 diabetes.

Methods: The analysis was based on 39,000 women and 25,777 men participating in the Lifelines cohort study (aged 18-65 years, mean 43.2 years for women and 43.5 years for men). Dietary intake was measured using a 110-item semi-quantitative food frequency questionnaire. Reduced rank regression was used to derive dietary patterns with blood lipids (HDL-cholesterol, LDL-cholesterol, triglycerides, total cholesterol, and total cholesterol:HDL-cholesterol ratio) as response variables for women and men separately. The first dietary pattern identified for each sex was selected because they explained the largest variance in blood lipids. The associations between the identified dietary patterns and incident type 2 diabetes were subsequently investigated using multivariate logistic regression models. All analyses were performed separately for women and men.

Results: During an average follow-up of 43 months, 479 new cases (incidence 0.74%) of type 2 diabetes were identified. Using reduced rank regression, we identified two sex-specific blood lipids-associated dietary patterns characterized by high intake of sugary beverages, added sugar, and low intake of vegetables, fruits, tea, and nuts/seeds. These two sex-specific dietary patterns were similar in food groups but differed in factor loadings. High dietary pattern scores were associated with increased risk of type 2 diabetes after adjustment for age, total energy intake, body mass index, waist-hip ratio, and blood pressure (ORs for the fifth quintile [Q5] using the first quintile [Q1] as reference, 1.87 [95% CI 1.23, 2.83] for women [P-trend < 0.001], and 1.72 [95% CI 1.11, 2.66] for men [P-trend = 0.018]). The associations were attenuated but remained significant after further adjustment for lifestyle and socio-economic factors.

Conclusions: Dietary patterns associated with adverse blood lipids are associated with incidence of type 2 diabetes. The present study provides new insights in optimizing blood lipids for the prevention of type 2 diabetes through dietary approaches.
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http://dx.doi.org/10.1016/j.clnu.2021.04.046DOI Listing
July 2021

Net Endogenous Acid Excretion and Kidney Allograft Outcomes.

Clin J Am Soc Nephrol 2021 09 16;16(9):1398-1406. Epub 2021 Jun 16.

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

Background And Objectives: High dietary acid load may accelerate a decline in kidney function. We prospectively investigated whether dietary acid load is associated with graft outcomes in kidney transplant recipients, and whether venous bicarbonate mediates this association.

Design, Setting, Participants, & Measurements: We used data from 642 kidney transplant recipients with a functioning graft ≥1 year after transplantation. Net endogenous acid production was estimated using food frequency questionnaires and, alternatively, 24-hour urinary urea and potassium excretion to estimate net endogenous acid production. We defined the composite kidney end point as a doubling of plasma creatinine or graft failure. Multivariable Cox regression analyses, adjusted for potential confounders, were used to study the associations of dietary acid load with the kidney end point. We evaluated potential mediation effects of venous bicarbonate, urinary bicarbonate excretion, urinary ammonium excretion, titratable acid excretion, and net acid excretion on the association between net endogenous acid production and the kidney end point.

Results: The median net endogenous acid production using food frequency questionnaires and net endogenous acid production using urinary excretion were 40 (interquartile range, 35-45) and 54 (interquartile range, 44-66) mEq/day, respectively. During a median follow-up of 5.3 years (interquartile range, 4.1-6.0), 121 (19%) participants reached the kidney end point. After multivariable adjustment, net endogenous acid production using food frequency questionnaires and net endogenous acid production using urinary excretion (per SD higher) were independently associated with higher risk for kidney end point (hazard ratio, 1.33; 95% confidence interval, 1.12 to 1.57, =0.001 and hazard ratio, 1.44; 95% confidence interval, 1.24 to 1.69, <0.001, respectively). Baseline venous bicarbonate mediated 20% of the association between net endogenous acid production using food frequency questionnaires and the kidney end point. Baseline venous bicarbonate, urinary ammonium excretion, and net acid excretion mediated 25%, -14%, and -18%, respectively, of the association between net endogenous acid production using urinary excretion and the kidney end point.

Conclusions: Higher dietary acid load was associated with a higher risk of doubling of plasma creatinine or graft failure, and this association was partly mediated by venous bicarbonate, urinary ammonium, and net acid excretion.
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http://dx.doi.org/10.2215/CJN.00780121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8729579PMC
September 2021

Physical activity and 4-year changes in body weight in 52,498 non-obese people: the Lifelines cohort.

Int J Behav Nutr Phys Act 2021 06 7;18(1):75. Epub 2021 Jun 7.

Department of Epidemiology (FA40), Unit of Lifestyle Medicine in Obesity and Diabetes, University Medical Center Groningen, University of Groningen, P.O. Box 30 001, 9700, RB, Groningen, the Netherlands.

Objectives: We investigated associations between leisure-time physical activity (LTPA) at different intensities (moderate and vigorous or moderate-to-vigorous) and prospective weight gain in non-obese people. We also examined whether these associations were independent of other lifestyle factors and changes in muscle mass and whether they were age-dependent and changed over a person's life course.

Methods: The data were extracted from the Lifelines cohort study (N = 52,498; 43.5% men) and excluded obese individuals (BMI > 30 kg/m). We used the validated SQUASH questionnaire to estimate moderate-to-vigorous (MVPA; MET≥4), moderate (MPA; MET between 4 and 6.5) and vigorous PA (VPA; MET≥6.5). Body weight was objectively measured, and changes were standardized to a 4-year period. Separate analyses, adjusted for age, educational level, diet, smoking, alcohol consumption and changes in creatinine excretion (a marker of muscle mass), were performed for men and women.

Results: The average weight gain was + 0.45 ± 0.03 kg in women. Relative to each reference groups (No-MVPA, No-MPA and No-VPA), MVPA (Beta (95%CI): - 0.34 kg (- 0.56;-0.13)), MPA (- 0.32 kg (- 0.54;-0.10)) and VPA (- 0.30 kg (- 0.43;-0.18)) were associated with less gain in body weight in women after adjusting for potential confounders, described above. These associations were dose-dependent when physically active individuals were divided in tertiles. Beta-coefficients (95%CI) for the lowest, middle, and highest MVPA tertiles relative to the 'No-MVPA' were, respectively, - 0.24 (- 0.47;-0.02), - 0.31 (- 0.53;-0.08), and - 0.38 (- 0.61;-0.16) kg. The average weight gain in men was + 0.13 ± 0.03 kg, and only VPA, not MPA was associated with less body weight gain. Beta-coefficients (95%CI) for the VPA tertiles relative to the 'No-VPA' group were, respectively, - 0.25 (- 0.42;-0.09), - 0.19 (- 0.38;-0.01) and - 0.20 (- 0.38;-0.02) kg. However, after adjusting for potential confounders, the association was no longer significant in men. The potential benefits of leisure-time PA were age-stratified and mainly observed in younger adults (men < 35 years) or stronger with younger age (women < 55 years).

Conclusion: Higher leisure-time MVPA, MPA, and VPA were associated with less weight gain in women < 55 years. In younger men (< 35 years), only VPA was associated with less weight gain.
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http://dx.doi.org/10.1186/s12966-021-01141-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186174PMC
June 2021

Meat intake and risk of mortality and graft failure in kidney transplant recipients.

Am J Clin Nutr 2021 10;114(4):1505-1517

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

Background: It is unknown whether meat intake is beneficial for long-term patient and graft survival in kidney transplant recipients (KTR).

Objectives: We first investigated the association of the previously described meat intake biomarkers 1-methylhistidine and 3-methylhistidine with intake of white and red meat as estimated from a validated food frequency questionnaire (FFQ). Second, we investigated the association of the meat intake biomarkers with long-term outcomes in KTR.

Methods: We measured 24-h urinary excretion of 1-methylhistidine and 3-methylhistidine by validated assays in a cohort of 678 clinically stable KTR. Cross-sectional associations were assessed by linear regression. We used Cox regression analyses to prospectively study associations of log2-transformed biomarkers with mortality and graft failure.

Results: Urinary 1-methylhistidine and 3-methylhistidine excretion values were median: 282; interquartile range (IQR): 132-598 µmol/24 h and median: 231; IQR: 175-306 µmol/24 h, respectively. Urinary 1-methylhistidine was associated with white meat intake [standardized β (st β): 0.20; 95% CI: 0.12, 0.28; P < 0.001], whereas urinary 3-methylhistidine was associated with red meat intake (st β: 0.30; 95% CI: 0.23, 0.38; P < 0.001). During median follow-up for 5.4 (IQR: 4.9-6.1) y, 145 (21%) died and 83 (12%) developed graft failure. Urinary 3-methylhistidine was inversely associated with mortality independently of potential confounders (HR per doubling: 0.55; 95% CI: 0.42, 0.72; P < 0.001). Both urinary 1-methylhistidine and urinary 3-methylhistidine were inversely associated with graft failure independent of potential confounders (HR per doubling: 0.84; 95% CI: 0.73, 0.96; P = 0.01; and 0.59; 95% CI: 0.41, 0.85; P = 0.004, respectively).

Conclusions: High urinary 3-methylhistidine, reflecting higher red meat intake, is independently associated with lower risk of mortality. High urinary concentrations of both 1- and 3-methylhistidine, of which the former reflects higher white meat intake, are independently associated with lower risk of graft failure in KTR. Future intervention studies are warranted to study the effect of high meat intake on mortality and graft failure in KTR, using these biomarkers.
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http://dx.doi.org/10.1093/ajcn/nqab185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488867PMC
October 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

Do Uncontrolled Hypertension, Diabetes, Dyslipidemia, and Obesity Mediate the Relationship Between Health Literacy and Chronic Kidney Disease Complications?

Int J Environ Res Public Health 2021 05 14;18(10). Epub 2021 May 14.

Department of Health Sciences, Community and Occupational Medicine, University Medical Center Groningen, Hanzeplein 1, 9700RB Groningen, The Netherlands.

Health literacy is the ability to deal with information related to one's health. Patients with low health literacy and chronic diseases, such as chronic kidney disease (CKD), have poor disease-management skills, which could lead to complications. We used logistic regressions and structural equational modeling to assess whether low health literacy is associated with the development of cardiovascular disease and mortality in patients with CKD, and whether this association is mediated by the presence of uncontrolled hypertension, diabetes, dyslipidemia, obesity, or albuminuria. Data from 2742 adult participants with CKD from the Lifelines study were analyzed at baseline and after approximately four years. Low health literacy was associated with cardiovascular disease and mortality in the crude models, with OR and 95%CI of 1.93 (1.46 to 2.55) and 1.59 (1.08 to 2.36), respectively. After adjustment for age and sex, low health literacy was only associated with cardiovascular disease (OR 1.76 (1.31 to 2.23)). This association was mediated by uncontrolled diabetes (27.1%) and obesity (8.0%). Low health literacy is associated with the development of cardiovascular disease after adjustment for age and sex, and this association is mediated by uncontrolled diabetes and obesity.
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http://dx.doi.org/10.3390/ijerph18105235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157126PMC
May 2021

A longitudinal qualitative study to explore and optimize self-management in mild to end stage chronic kidney disease patients with limited health literacy: Perspectives of patients and health care professionals.

Patient Educ Couns 2022 Jan 13;105(1):88-104. Epub 2021 May 13.

University Medical Centre Groningen, Department of Health Sciences, Groningen, The Netherlands.

Objectives: Limited health literacy (LHL) is associated with faster kidney deterioration. Health care professionals (HCPs) promote self-management to maintain kidney function, which is difficult for patients with LHL. Evidence lacks on perceived barriers and best strategies to optimize their self-management. Our study aims to explore experiences with and barriers for self-management from the perspectives of LHL patients and HCPs to identify strategies to optimize self-management.

Methods: We performed a longitudinal qualitative study with semi-structured in-depth interviews and focus group discussions among CKD patients and LHL (n = 24) and HCPs (n = 37) from general practices and hospitals.

Results: Four themes arose among patients: (1) CKD elusiveness, (2) suboptimal intake of knowledge (3) not taking a front-seat role, and (4) maintaining change. Among HCPs, three themes emerged: (1) not recognizing HL problems, (2) lacking effective strategies, and (3) health care barriers.

Conclusion: We suggest three routes to optimize self-management: providing earlier information, applying person-centered strategies to maintain changes, and improving competencies of HCPs.

Practice Implications: HCPs need to explain CKD self-management better to prevent kidney deterioration. New interventions, based on behavioral approaches, are needed to optimize self-management. HCPs need training to improve recognition and support of LHL patients.
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http://dx.doi.org/10.1016/j.pec.2021.05.016DOI Listing
January 2022

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

J Am Heart Assoc 2021 06 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483531PMC
June 2021

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

Liver Int 2021 10 8;41(10):2371-2382. Epub 2021 Jun 8.

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8518486PMC
October 2021

Associations of Diet Quality and All-Cause Mortality Across Levels of Cardiometabolic Health and Disease: A 7.6-Year Prospective Analysis From the Dutch Lifelines Cohort.

Diabetes Care 2021 05 7;44(5):1228-1235. Epub 2021 May 7.

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

Objective: To simultaneously investigate the association of diet quality and all-cause mortality in groups with varying cardiometabolic diseases (CMDs) at baseline.

Research Design And Methods: From the population-based Lifelines cohort, 40,892 non-underweight participants aged ≥50 years with data on diet quality and confounding factors were included (enrollment 2006-2013). From food-frequency questionnaire data, tertiles of the Lifelines Diet Score were calculated (T1 poorest, T3 best diet quality). Four CMD categories were defined: ) CMD free, ) type 2 diabetes, ) one cardiovascular disease (CVD), ) two or more CMDs. Months when deaths occurred were obtained from municipal registries up until November 2019. Multivariable Cox proportional hazards models were applied for the total population and stratified by CMD categories.

Results: After a median follow-up of 7.6 years, 1,438 participants died. Diet quality and CMD categories were independently associated with all-cause mortality in crude and adjusted models ( < 0.001). A dose-response relationship of diet quality with all-cause mortality was observed in the total population ( < 0.001, T2 vs. T3 = 1.22 [1.07-1.41], T1 vs. T3 = 1.57 [1.37-1.80]). In stratified analyses, the association was significant for CMD-free individuals (T1 vs. T3 = 1.63 [1.38-1.93]) and for patients with type 2 diabetes (1.87 [1.17-3.00]) but not for patients with one CVD (1.39 [0.93-2.08]) or multiple CMDs (1.19 [0.80-1.76]).

Conclusions: A high-quality diet can potentially lower all-cause mortality risk in the majority of the aging population. Its effect may be greatest for CMD-free individuals and patients with type 2 diabetes. Tailored dietary guidelines may be required for patients with extensive histories of CMDs.
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http://dx.doi.org/10.2337/dc20-2709DOI Listing
May 2021

Prediction of Incident Cancers in the Lifelines Population-Based Cohort.

Cancers (Basel) 2021 04 28;13(9). Epub 2021 Apr 28.

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

Cancer incidence is rising, and accurate prediction of incident cancers could be relevant to understanding and reducing cancer incidence. The aim of this study was to develop machine learning (ML) models that could predict an incident diagnosis of cancer. Participants without any history of cancer within the Lifelines population-based cohort were followed for a median of 7 years. Data were available for 116,188 cancer-free participants and 4232 incident cancer cases. At baseline, socioeconomic, lifestyle, and clinical variables were assessed. The main outcome was an incident cancer during follow-up (excluding skin cancer), based on linkage with the national pathology registry. The performance of three ML algorithms was evaluated using supervised binary classification to identify incident cancers among participants. Elastic net regularization and Gini index were used for variables selection. An overall area under the receiver operator curve (AUC) <0.75 was obtained, the highest AUC value was for prostate cancer (random forest AUC = 0.82 (95% CI 0.77-0.87), logistic regression AUC = 0.81 (95% CI 0.76-0.86), and support vector machines AUC = 0.83 (95% CI 0.78-0.88), respectively); age was the most important predictor in these models. Linear and non-linear ML algorithms including socioeconomic, lifestyle, and clinical variables produced a moderate predictive performance of incident cancers in the Lifelines cohort.
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http://dx.doi.org/10.3390/cancers13092133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125183PMC
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
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