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This article examines the relationship between albuminuria (a marker of chronic kidney disease) and the occurrence of cancer. The study analyzes data from a Dutch population-based cohort and identifies potential factors that explain the connection between albuminuria and cancer. The researchers find that markers of systemic inflammation, oxidative stress, and kidney function partially mediate the association between albuminuria and overall cancer incidence. The study provides valuable insights into the mechanisms linking albuminuria and cancer, suggesting that inflammation may play a role in cancer development in individuals with albuminuria. Further research is needed to explore other potential factors and pathways. [Extracted from the article]

Background Chronic kidney disease (CKD) is believed to be associated with an increased risk for cancer, especially urinary tract cancer. However, previous studies predominantly focused on the association of decreased estimated glomerular filtration rate (eGFR) with cancer. In this study, we investigated the association of albuminuria with cancer incidence, adjusted for eGFR. Methods We included 8490 subjects in the Prevention of Renal and Vascular End-stage Disease (PREVEND) observational study. Urinary albumin excretion (UAE) was measured in two 24-hour urine specimens at baseline. Primary outcomes were the incidence of overall and urinary tract cancer. Secondary outcomes were the incidence of other site-specific cancers, and mortality due to overall, urinary tract, and other site-specific cancers. Results Median baseline UAE was 9.4 (IQR, 6.3–17.8) mg/24 h. During a median follow-up of 17.7 years, 1341 subjects developed cancer (of which 177 were urinary tract cancers). After multivariable adjustment including eGFR, every doubling of UAE was associated with a 6% (hazard ratios (HR), 1.06, 95% confidence intervals (CI), 1.02–1.10), and 14% (HR, 1.14, 95% CI, 1.04–1.24) higher risk of overall and urinary tract cancer incidence, respectively. Except for lung and hematological cancer, no associations were found between UAE and the incidence of other site-specific cancer. Doubling of UAE was also associated with a higher risk of mortality due to overall and lung cancer. Conclusions Higher albuminuria is associated with a higher incidence of overall, urinary tract, lung, and hematological cancer, and with a higher risk of mortality due to overall and lung cancers, independent of baseline eGFR. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is associated with mitochondrial damage. Circulating mitochondrial metabolites may be elevated in NAFLD but their associations with liver damage is not known. This study aimed to assess the association of key mitochondrial metabolites with the degree of liver fibrosis in the context of NAFLD and nonalcoholic steatohepatitis (NASH). Cross-sectional analyses were performed on two cohorts of biopsy-proven NAFLD and/or NASH subjects. The association of circulating mitochondrial metabolite concentrations with liver fibrosis was assessed using linear regression analysis. In the single-center cohort of NAFLD subjects (n = 187), the mean age was 54.9 ±13.0 years, 40.1% were female and 86.1% were White. Type 2 diabetes (51.3%), hypertension (43.9%) and obesity (72.2%) were prevalent. Those with high citrate had a higher proportion of moderate/significant liver fibrosis (stage F ≥ 2) (68.4 vs. 39.6%, p = 0.001) and advanced fibrosis (stage F ≥ 3) (31.6 vs. 13.6%, p = 0.01). Citrate was associated with liver fibrosis independent of age, sex, NAFLD activity score and metabolic syndrome (per 1 SD increase: β = 0.19, 95% CI: 0.03–0.35, p = 0.02). This association was also observed in a cohort of NASH subjects (n = 176) (β = 0.21, 95% CI: 0.07–0.36, p = 0.005). The association of citrate with liver fibrosis was observed in males (p = 0.005) but not females (p = 0.41). In conclusion, circulating citrate is elevated and associated with liver fibrosis, particularly in male subjects with NAFLD and NASH. Mitochondrial function may be a target to consider for reducing the progression of liver fibrosis and NASH. [ABSTRACT FROM AUTHOR]

Context: Thyroid function status has effects on the development of atherosclerotic cardiovascular disease by affecting lipid metabolism, but associations of high-density lipoprotein (HDL) particle concentrations and subfractions with thyroid hormone levels within the reference range remain elusive. Objective: The aim of the present study was to determine the associations of free triiodothyronine (FT3), free thyroxine (FT4) and thyroidstimulating hormone (TSH) levels with HDL particle characteristics in euthyroid individuals. Methods: This cross-sectional study on the associations of thyroid hormones with HDL particle concentrations, HDL subfractions, and HDL particle size included 5844 euthyroid individuals (FT3, FT4, and TSH levels within the reference range and no medication use affecting thyroid function), participating in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study. HDL particles and subfractions were measured by nuclear magnetic resonance using an optimized version of the NMR LipoProfile Test (LP4). Results: In multivariable linear regression analyses, FT3 was positively associated with total HDL particle concentration (std.β = 0.14; P < 0.001) and with small (std.β = 0.13; P < 0.001) and medium-sized HDL particles (std.β = 0.05; P = 0.001). Conversely, FT3 was inversely associated with large HDL particles (std.β = −0.07; P < 0.001) and with HDL particle size (std.β = −0.08; P < 0.001). Such associations with FT4 or reciprocally with TSH were less pronounced or nonsignificant. Conclusion: In euthyroid individuals, higher FT3 is cross-sectionally associated with higher total HDL particle concentration and with lower HDL particle size. These associations may be relevant to better understand the role of HDL in thyroid function–associated atherosclerotic cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent, paralleling the obesity epidemic. Ketone bodies are produced in the liver, but it is currently uncertain whether circulating ketone bodies are increased in the context of NAFLD. We investigated the association between NAFLD and circulating ketone bodies and determined the extent to which NAFLD and circulating ketone bodies are associated with all‐cause mortality. Methods: Plasma ketone bodies were measured by nuclear magnetic resonance spectroscopy in participants of the general population‐based PREVEND study. A fatty liver index (FLI) ≥60 was regarded as a proxy of NAFLD. Associations of an elevated FLI and ketone bodies with all‐cause mortality were investigated using Cox regression analyses. Results: The study included 6,297 participants aged 54 ± 12 years, of whom 1,970 (31%) had elevated FLI. Participants with elevated FLI had higher total ketone bodies (194 [153‐259] vs 170 [133‐243] µmol/L; P <.001) than participants without elevated FLI. During 7.9 [7.8‐8.9] years of follow‐up, 387 (6%) participants died. An elevated FLI was independently associated with an increased risk of mortality (HR: 1.34 [1.06‐1.70]; P =.02). Higher total ketone bodies were also associated with an increased mortality risk (HR per doubling: 1.29 [1.12‐1.49]; P <.001). Mediation analysis suggested that the association of elevated FLI with all‐cause mortality was in part mediated by ketone bodies (proportion mediated: 10%, P <.001). Conclusion: Circulating ketone bodies were increased in participants with suspected NAFLD. Both suspected NAFLD and higher circulating ketone bodies are associated with an increased risk of all‐cause mortality. [ABSTRACT FROM AUTHOR]

Branched chain amino acids (BCAA) are implicated in the pathogenesis of cardiometabolic diseases conceivably by affecting insulin resistance and mitochondrial dysfunction. Circulating BCAA levels may predict (subclinical) atherosclerosis, diabetes and hypertension development but the factors involved in BCAA regulation are incompletely understood. Given the key role of thyroid hormones on many metabolic processes including protein metabolism, we aimed to determine effects of thyroid dysfunction on circulating BCAA. Effects of short-term profound hypothyroidism on plasma BCAA were determined in 17 patients who had undergone total thyroidectomy for differentiated thyroid carcinoma. Patients were studied during hypothyroidism, i.e. after thyroidectomy, and after thyroid hormone supplementation. Plasma BCAA (sum of valine, leucine and isoleucine) and alanine were measured by nuclear magnetic resonance spectroscopy. During hypothyroidism (median thyroid-stimulating hormone 81 (IQR 67–120.5) mU/L), plasma BCAA were lower (255 (IQR 222–289) µmol/L) compared to a euthyroid reference population (n = 5579; 377 µmol/L (2.5th to 97.5th percentile 258–548), p < 0.001). After 20 weeks of thyroid hormone supplementation (thyroid-stimulating hormone 0.03 (IQR 0.01–0.14 mU/L) plasma BCAA had increased (328 (IQR 272–392) µmol/L, p =.001), but plasma alanine concentrations were unaltered (p =.50). Changes in body weight in response to thyroid hormone supplementation were correlated with changes in plasma BCAA (r = 0.721 p =.001, but not with changes in cholesterol or glucose (p >.80). In conclusion, plasma BCAA concentrations are lower during short-term profound hypothyroidism in humans, and increase in response to thyroid hormone supplementation. Changes in BCAA and in body weight after reversal of the hypothyroid state appear to be interrelated. [ABSTRACT FROM AUTHOR]

Abstract Objective Elevated circulating levels of pro-inflammatory biomarkers are associated with adverse health effects, but the extent to which enhanced low-grade inflammation influences remaining life expectancy (LE) is uncertain. GlycA is a novel pro-inflammatory marker. We determined effects of GlycA and high sensitivity C-reactive protein (hsCRP) on LE. Methods GlycA and hsCRP were determined in 5526 subjects. LE was compared in the upper quartile of both GlycA and hsCRP vs. the respective lower three quartiles combined, adjusted for LE of individuals in the Dutch general population of the same birth cohort and sex. Results Median follow up was 8.5 years [interquartile range 7.9–9.0], during which 348 (6.3%) subjects had deceased. LE at the end of follow up was lower in the highest vs. the lower three quartiles of GlycA (P <.001) and hsCRP (P <.001). Both men as well as women in the highest GlycA quartile had reduced LE vs. the lowest three quartiles combined (P <.001 and P =.02). For hsCRP, this was only observed in men (P <.001) but not in women (P =.67). Conclusions This population-based cohort study demonstrates that higher plasma levels of GlycA were associated with reduced LE in men and women. With regard to hsCRP this only applied to men. Highlights • GlycA is a nuclear magnetic resonance spectroscopy-measured glycoprotein biomarker. • GlycA is strongly correlated with hsCRP and related to adverse health effects. • Higher plasma levels of GlycA were associated with reduced life expectancy. [ABSTRACT FROM AUTHOR]

Background: Primary aldosteronism (PA) may confer increased cardiovascular risk beyond effects on systemic blood pressure, but contributing mechanisms remain incompletely understood. We compared plasma (apo)lipoproteins and lipoprotein particle characteristics, GlycA, a pro‐inflammatory glycoprotein biomarker of enhanced chronic inflammation, and plasma total branched‐chain amino acids (BCAA), measured using nuclear magnetic resonance (NMR) spectroscopy, between patients with PA, control subjects without hypertension, subjects with untreated hypertension and subjects with treated hypertension. Methods: Twenty PA patients were individually matched with 2819 control subjects without hypertension, 501 subjects with untreated hypertension and 878 subjects with treated hypertension participating in the PREVEND (Prevention of Renal and Vascular End‐Stage Disease) cohort study with respect to age, sex, body mass index, smoking and statin use. The Vantera® Clinical Analyzer was used to determine NMR‐based laboratory parameters. Results: Total cholesterol, low‐density lipoprotein cholesterol (LDL‐C), high‐density lipoprotein cholesterol (HDL‐C), apolipoprotein (apo) B, apolipoprotein A‐I (apoA‐I), LDL particle and HDL particle concentrations were all decreased in PA subjects vs control subjects and subjects with untreated hypertension (P < 0.016). Triglycerides (TG) and triglyceride‐rich lipoprotein (TRL) concentrations were lower in PA subjects vs subjects with (untreated) hypertension. GlycA was increased in PA vs the three comparator groups (P < 0.016). Total BCAA concentrations were unaltered in PA. Conclusions: Primary aldosteronism is associated with lower concentrations of LDL and HDL particles and to some extent also with lower TG and TRL particle concentrations. PA is also characterized by increased GlycA levels, indicating enhanced low‐grade chronic inflammation. Low HDL particle concentrations and increased GlycA could contribute to accelerated cardiovascular disease development in PA. [ABSTRACT FROM AUTHOR]

Abstract: Background: Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent condition which contributes to atherogenic apolipoprotein B dyslipoproteinemias. Lecithin:cholesterol acyltransferase (LCAT) and phospholipid transfer protein (PLTP) are both synthesized by the liver and are important in lipid metabolism. Here, we interrogated the impact of NAFLD on plasma LCAT and PLTP activities. Methods: Plasma LCAT activity (exogenous substrate assay) and PLTP activity (phospholipid vesicles‐HDL assay) were determined in 348 subjects (279 men; 81 subjects with type 2 diabetes (T2DM); 123 with metabolic syndrome (MetS)). A Fatty Liver Index (FLI) ≥60 was used as a proxy of NAFLD. Insulin resistance was determined by homoeostasis model assessment (HOMA‐IR). Results: A total of 147 participants had an FLI ≥60 coinciding with T2DM and MetS (P < 0.001 for each). Plasma LCAT activity and PLTP activity were on average 12% and 5% higher, respectively, in subjects with an FLI ≥ 60 (P < 0.001 for each). In age‐ and sex‐adjusted partial linear regression analysis, LCAT activity and PLTP activity were positively related to various obesity measures and HOMA‐IR (P < 0.001 for each). In multivariable linear regression analyses adjusted for age and sex, LCAT activity was associated with an FLI ≥ 60 independent of T2DM and MetS, the waist/hip ratio, or HOMA‐IR (β = 0.307 to 0.366, P < 0001 for all models). PLTP activity was also associated with an FLI ≥ 60 independent of these variables (β = 0.151 to 0223, P = 0.013 to 0.001). Conclusion: NAFLD, as inferred from an FLI≥60, confers higher plasma LCAT and to a lesser extent PLTP activity, even when taking account of T2DM, MetS, central obesity and insulin resistance. [ABSTRACT FROM AUTHOR]

Background: Functional properties of high density lipoproteins (HDL) are increasingly recognized to play a physiological role in atheroprotection. Type 2 diabetes mellitus (T2DM) is characterized by low HDL cholesterol, but the effect of chronic hyperglycemia on the anti-inflammatory capacity of HDL, a metric of HDL function, is unclear. Therefore, the aim of the present study was to establish the impact of T2DM on the HDL anti-inflammatory capacity, taking paraoxonase-1 (PON-1) activity and low grade inflammation into account. Methods: The HDL anti-inflammatory capacity, determined as the ability to suppress tumor necrosis factor-α (TNF-α) induced vascular cell adhesion molecule-1 (VCAM-1) mRNA expression in endothelial cells in vitro (higher values indicate lower anti-inflammatory capacity), PON-1 (arylesterase) activity, hs-C-reactive protein (hs-CRP), serum amyloid A (SAA) and TNF-α were compared in 40 subjects with T2DM (no insulin or statin treatment) and 36 non-diabetic subjects. Results: T2DM was associated with impaired HDL anti-inflammatory capacity (3.18 vs 1.05 fold increase in VCAM-1 mRNA expression; P < 0.001), coinciding with decreased HDL cholesterol (P = 0.001), apolipoprotein A-I (P = 0.038) and PON-1 activity (P = 0.023), as well as increased hs-CRP (P = 0.043) and TNF-α (P = 0.005). In all subjects combined, age- and sex-adjusted multivariable linear regression analysis demonstrated that impaired HDL anti-inflammatory capacity was associated with hyperglycemia (β = 0.499, P < 0.001), lower PON-1 activity (β = - 0.192, P = 0.030) and higher hs-CRP (β = 0.220, P = 0.016). Conclusions: The HDL anti-inflammatory capacity is substantially impaired in T2DM, at least partly attributable to the degree of hyperglycemia, decreased PON-1 activity and enhanced low grade chronic inflammation. Decreased antiinflammatory protection capacity of HDL conceivably contributes to the increased atherosclerosis risk associated with T2DM. [ABSTRACT FROM AUTHOR]

Supplementation with n-3 fatty acids may improve long-term outcomes of renal transplant recipients (RTR). Recent evidence suggests that EPA and DHA have different outcomes compared with α-linolenic acid (ALA). We examined the prospective associations of EPA–DHA and ALA intakes with graft failure and all-cause mortality in 637 RTR. During 3·1 years (interquartile range 2·7, 3·8) of follow-up, forty-one developed graft failure and sixty-seven died. In age- and sex-adjusted analyses, EPA–DHA and ALA intakes were not associated with graft failure. EPA–DHA intake was not significantly associated with mortality (hazard ratio (HR) 0·79; 95% CI 0·54, 1·15 per 0·1 energy% difference). ALA intake was significantly associated with mortality (HR 1·17; 95% CI 1·04, 1·31 per 0·1 energy% difference). This association remained following adjustments for BMI, proteinuria and intakes of fat, carbohydrate and protein. RTR in the highest tertile of ALA intake exhibited about 2-fold higher mortality risk (HR 2·21; 95% CI 1·23, 3·97) compared with the lowest tertile. In conclusion, ALA intake may be associated with increased mortality in RTR. Future RCT are needed to confirm these results. [ABSTRACT FROM AUTHOR]

Background: The choline metabolite, betaine, plays a role in lipid metabolism, and may predict the development of cardiovascular disease and type 2 diabetes mellitus (T2DM). Phospholipid transfer protein (PLTP) and lecithin: cholesterol acyltransferase (LCAT) require phosphatidylcholine as substrate, raising the possibility that there is an intricate relationship of these protein factors with choline metabolism. Here we determined the relationships of PLTP and LCAT activity with betaine in subjects with and without T2DM. Methods: Plasma betaine (nuclear magnetic resonance spectroscopy), PLTP activity (liposome-vesicle HDL system), LCAT activity (exogenous substrate assay) and (apo)lipoproteins were measured in 65 type 2 diabetic (T2DM) and in 55 non-diabetic subjects. Results: PLTP and LCAT activity were elevated in T2DM (p < 0.05), whereas the difference in betaine was not significant. In age-, sex- and diabetes status-controlled correlation analysis, betaine was inversely correlated with triglycerides and positively with HDL cholesterol (p < 0.05 to 0.01). PLTP and LCAT activity were positively correlated with triglycerides and inversely with HDL cholesterol (p < 0.05 to 0.001). PLTP (r = -0.245, p = 0.006) and LCAT activity (r = -0.195, p = 0.035) were correlated inversely with betaine. The inverse association of PLTP activity with betaine remained significant after additional adjustment for body mass index and lipoprotein variables (ß = -0.179, p = 0.034), whereas its association with LCAT activity lost significance (ß = -0.056, p = 0.44). Conclusions: Betaine may influence lipoprotein metabolism via an effect on PLTP activity. [ABSTRACT FROM AUTHOR]

The physiological function initially attributed to the oligosaccharide moieties or glycans on inflammatory glycoproteins was to improve protein stability. However, it is now clear that glycans play a prominent role in glycoprotein structure and function and in some cases contribute to disease states. In fact, glycan processing contributes to pathogenicity not only in autoimmune disorders but also in atherosclerotic cardiovascular disease, diabetes and malignancy. While most clinical laboratory tests measure circulating levels of inflammatory proteins, newly developed diagnostic and prognostic tests are harvesting the information that can be gleaned by measuring the amount or structure of the attached glycans, which may be unique to individuals as well as various diseases. As such, these newer glycan-based tests may provide future means for more personalized approaches to patient stratification and improved patient care. Here we will discuss recent progress in high-throughput laboratory methods for glycomics (i.e. the study of glycan structures) and glycoprotein quantification by methods such as mass spectrometry and nuclear magnetic resonance spectroscopy. We will also review the clinical utility of glycoprotein and glycan measurements in the prediction of common low-grade inflammatory disorders including cardiovascular disease, diabetes and cancer, as well as for monitoring autoimmune disease activity. [ABSTRACT FROM AUTHOR]

Background: The extent to which dietary sodium intake may confer alterations in the inflammatory status is unclear. GlycA is a novel proton nuclear magnetic resonance spectroscopy-measured biomarker of systemic inflammation, which is associated with the development of cardiovascular disease and diabetes. Objective: We determined associations of the inflammatory markers GlycA and high-sensitivity C-reactive protein (hsCRP) with 24-h sodium excretion. Design: A cross-sectional, population-based study was performed in 3935 subjects who were not using an antihypertensive medication, lipid-lowering drugs, or a glucose-lowering treatment. Urinary sodium excretion was calculated as the mean of two 24-h urine excretions. Linear regression models were used, with 24-h sodium excretion as an independent variable and GlycA or ln hsCRP as a dependent variable. Results: The mean ± SD sodium excretion was 143.0 ± 53.4 mmol/24 h. The GlycA concentration was 343.6 ± 58.7 mmol/L, and the geometric mean of the hsCRP concentration was 1.20 mg/L (95% CI: 1.16, 1.25 mg/L). In age- and sex-adjusted analyses, GlycA and ln hsCRP were not significantly associated with 24-h sodium excretion [B: 1.23 (95% CI: -0.67, 3.13; P = 0.21) and 0.03 (95% CI: -0.004, 0.07; P = 0.08), respectively, per 1-SD increase]. After additional adjustment for body mass index (BMI), both GlycA (B: -2.76; 95% CI: -4.65, -0.86; P = 0.004) and ln hsCRP (B: -0.07; 95% CI: -0.11, -0.04; P < 0.001) were inversely associated with 24-h sodium excretion. These associations were similar if adjustment was performed for waist circumference instead of BMI or if additional adjustment was performed for relevant clinical and laboratory variables and were particularly present in men. Conclusions: The proinflammatory biomarkers GlycA and hsCRP are inversely related to higher 24-h sodium excretion when taking into account the variation in adiposity. These inverse relations remain present after taking into account other covariates. [ABSTRACT FROM AUTHOR]

Background GlycA is a recently developed glycoprotein biomarker of systemic inflammation that may be predictive of incident type 2 diabetes mellitus (T2DM). Methods Analytical performance of the GlycA test, measured on the Vantera® Clinical Analyzer, was evaluated. To test its prospective association with T2DM, GlycA was measured in 4524 individuals from the PREVEND study and a survival analysis was performed with a mean follow-up period of 7.3 y. Results Imprecision for the GlycA test ranged from 1.3–2.3% and linearity was established between 150 and 1588 μmol/l. During the follow-up period, 220 new T2DM cases were ascertained. In analyses adjusted for relevant covariates, GlycA was associated with incident T2DM; hazard ratio (HR) for the highest vs. lowest quartile 1.77 [95% Confidence Interval (CI): 1.10–2.86, P = 0.01], whereas the association of high sensitivity C-reactive protein (hsCRP) with T2DM was not significant. GlycA remained associated with incident T2DM after additional adjustment for hsCRP; HR 1.71 [1.00–2.92, P = 0.04]. A multivariable adjusted analysis of dichotomized subgroups showed that the hazard for incident T2DM was highest in the subgroup with high GlycA and low hsCRP (P = 0.03). Conclusions The performance characteristics of the GlycA test reveal that it is suitable for clinical applications, including assessment of the risk of future T2DM. [ABSTRACT FROM AUTHOR]

Objective: GlycA is a novel nuclear magnetic resonance spectroscopy-measured biomarker of systemic inflammation. We determined whether GlycA is associated with incident cardiovascular disease (CVD) in men and women, examined whether this association with CVD is modified by renal function, and compared this association with high sensitivity C-reactive protein (hsCRP). Research design and methods: A prospective cohort study was performed among 4,759 subjects (PREVEND study) without a history of CVD and cancer. Incident CVD was defined as the combined endpoint of cardiovascular morbidity and mortality. Cox regression analyses were used to examine associations of baseline GlycA and hsCRP with CVD. Results: 298 first CVD events occurred during a median follow-up of 8.5 years. After adjustment for clinical and lipid measures the hazard ratio (HR) for CVD risk in the highest GlycA quartile was 1.58 (95% CI, 1.05–2.37, P for trend = 0.004). This association was similar after further adjustment for renal function (estimated glomerular filtration rate and urinary albumin excretion). After additional adjustment for hsCRP, GlycA was still associated with incident CVD (HR: 1.16 per SD change (95% CI, 1.01–1.33), P = 0.04). Similar results were obtained for hsCRP (HR per SD change after adjustment for GlycA: 1.17 (95% CI 1.17 (95% CI, 1.01–3.60), P = 0.04). CVD risk was highest in subjects with simultaneously higher GlycA and hsCRP (fully adjusted HR: 1.79 (95% CI, 1.31–2.46), P<0.001). Conclusion: GlycA is associated with CVD risk in men and women, independent of renal function. The association of GlycA with incident CVD is as strong as that of hsCRP. [ABSTRACT FROM AUTHOR]

Detailed information regarding lipoprotein concentrations and subfractions in cirrhotic patients before and after orthotopic liver transplantation (OLT) is lacking. Lipoprotein-Z (LP-Z) is a recently characterised abnormal, hepatotoxic free cholesterol-rich low-density lipoprotein (LDL)-like lipoprotein. We determined the lipoprotein profiles, including LP-Z, in cirrhotic patients and OLT recipients and assessed the prognostic significance of LP-Z on the OLT waiting list. We performed analyses in cirrhotic transplant candidates and non-cirrhotic OLT recipients. A population-based cohort was used as reference. The setting was a University hospital. Lipoprotein particle concentrations and subfractions were measured by nuclear magnetic resonance spectroscopy. In the cirrhotic patients (N = 130), most measures of triglyceride-rich lipoproteins (TRL), LDL, and high-density lipoproteins (HDL) were much lower compared to the OLT recipients (N = 372) and controls (N = 6027) (p < 0.01). In the OLT recipients, many lipoprotein variables were modestly lower, but HDL-cholesterol, triglycerides, and TRL and HDL size were greater vs. the control population. LP-Z was measurable in 40 cirrhotic patients and 3 OLT recipients (30.8% vs. 0.8%, p < 0.001). The cirrhotic patients with measurable LP-Z levels had profoundly lower HDL-cholesterol and particle concentrations (p < 0.001), and worse Child Pugh Turcotte classifications and MELD scores. The presence of LP-Z (adjusted for age, sex, and MELD score) predicted worse survival in cirrhotic patients (HR per 1 LnSD increment: 1.11, 95%CI 1.03–1.19, p = 0.003). In conclusion, cirrhotic patients have considerably lower plasma concentrations of all major lipoprotein classes with changes in lipoprotein subfraction distribution. After OLT, these lipoprotein abnormalities are in part reversed. LP-Z is associated with cirrhosis. Its presence may translate in disturbed HDL metabolism and worse survival. [ABSTRACT FROM AUTHOR]

Background: The Dietary Approach to Stop Hypertension (DASH) and potassium supplementation have been shown to reduce the risk of death with a functioning graft (DWFG) and renal graft failure in renal transplant recipients (RTR). Unfortunately, a key problem for patients is the adherence to these diets. The aim of this study is to evaluate the cost-effectiveness and budget impact of higher adherence to either the DASH or potassium supplementation. Methods: A Markov model was used to simulate the life course of 1000 RTR in the Netherlands. A societal perspective with a lifetime time horizon was used. The potential effect of improvement of dietary adherence was modelled in different scenarios. The primary outcomes are the incremental cost-effectiveness ratio (ICER) and the budget impact. Results: In the base case, improved adherence to the DASH diet saved 27,934,786 and gained 1880 quality-adjusted life years (QALYs). Improved adherence to potassium supplementation saved €1,217,803 and gained 2901 QALYs. Both resulted in dominant ICERs. The budget impact over a five-year period for the entire Dutch RTR population was €8,144,693. Conclusion: Improving dietary adherence in RTR is likely to be cost-saving and highly likely to be cost-effective compared to the current standard of care in the Netherlands. [ABSTRACT FROM AUTHOR]

Objective: Evaluate the ability of a newly developed diabetes risk score, the Diabetes Risk Index (DRI), to predict incident type 2 diabetes mellitus (T2D) in a large adult population. Methods: The DRI was developed by combining the Lipoprotein Insulin Resistance Index (LP-IR), calculated from 6 lipoprotein subspecies and size parameters, and the branched chain amino acids, valine and leucine, all of which have been shown previously to be associated with future T2D. DRI scores were calculated in a total of 6134 nondiabetic men and women in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) Study. Cox proportional hazards regression was used to evaluate the association of DRI scores with incident T2D. Results: During a median follow-up of 8.5 years, 306 new T2D cases were ascertained. In analyses adjusted for age and sex, there was a significant association between DRI scores and incident T2D with the hazard ratio (HR) for the highest versus lowest quartile being 12.07 (95% confidence interval: 6.97–20.89, p < 0.001). After additional adjustment for body mass index (BMI), family history of T2D, alcohol consumption, diastolic blood pressure, total cholesterol, triglycerides, HDL cholesterol and HOMA-IR, the HR was attenuated but remained significant (HR 3.20 (1.73–5.95), p = 0.001). Similar results were obtained when DRI was analyzed as HR per 1 SD increase (HR 1.37 (1.14–1.65), p < 0.001). The Kaplan–Meier plot demonstrated that patients in the highest quartile of DRI scores presented at higher risk (p-value for log-rank test <0.001). Conclusions: Higher DRI scores are associated with an increased risk of T2D. The association is independent of clinical risk factors for T2D including HOMA-IR, BMI and conventional lipids. [ABSTRACT FROM AUTHOR]

Objective: Evaluate the ability of the Diabetes Risk Index (DRI) to predict incident type 2 diabetes mellitus (T2DM) in a large cohort. Methods: The DRI was developed by combining the 6 lipoprotein subfractions in the Lipoprotein Insulin Resistance Index (LP-IR) and the branched chain amino acids valine and leucine, all of which have been shown previously to be associated with future T2DM. DRI scores were calculated in a total of 6134 nondiabetic men and women in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) Study. Cox proportional hazards regression was used to evaluate the association of DRI scores with incident T2DM. Results: During a median follow-up of 8.5 years, 306 new T2DM cases were ascertained. In analyses adjusted for age and sex, there was a significant association between DRI scores and incident T2DM with the hazard ratio (HR) for the highest versus lowest tertile being 7.49 (95% confidence interval: 5.01-11.19), P <0.001. After additional adjustment for BMI, family history of T2DM, alcohol consumption, diastolic blood pressure, total cholesterol, triglycerides, HDL cholesterol and HOMA-IR, the HR was attenuated but remained significant (HR 1.67 [1.01-2.76], P = 0.04). Similar results were obtained when DRI was analyzed as HR per 1 SD increase (HR 1.37 [1.14-1.65], P = 0.001). The Kaplan-Meier plot demonstrated that patients in the highest tertile of DRI scores presented at higher risk (p-value for log-rank test <0.001). Conclusions: Higher DRI scores are associated with an increased risk of T2DM. The association is independent of clinical risk factors for T2DM including HOMA-IR, BMI and conventional lipids. Disclosure: J. Flores-Guerrero: None. M.A. Connelly: Employee; Self; LabCorp. I.Y. Shalaurova: None. E.G. Gruppen: None. J.D. Otvos: Employee; Self; LabCorp. R.P.F. Dullaart: None. S.J.I. Bakker: None. [ABSTRACT FROM AUTHOR]

Post-transplant diabetes mellitus (PTDM) is a serious complication in renal transplant recipients. Branched-chain amino acids (BCAAs) are involved in the pathogenesis of insulin resistance. We determined the association of plasma BCAAs with PTDM and included adult renal transplant recipients (≥18 y) with a functioning graft for ≥1 year in this cross-sectional cohort study with prospective follow-up. Plasma BCAAs were measured in 518 subjects using nuclear magnetic resonance spectroscopy. We excluded subjects with a history of diabetes, leaving 368 non-diabetic renal transplant recipients eligible for analyses. Cox proportional hazards analyses were used to assess the association of BCAAs with the development of PTDM. Mean age was 51.1 ± 13.6 y (53.6% men) and plasma BCAA was 377.6 ± 82.5 µM. During median follow-up of 5.3 (IQR, 4.2–6.0) y, 38 (9.8%) patients developed PTDM. BCAAs were associated with a higher risk of developing PTDM (HR: 1.43, 95% CI 1.08–1.89) per SD change (p = 0.01), independent of age and sex. Adjustment for other potential confounders did not significantly change this association, although adjustment for HbA1c eliminated it. The association was mediated to a considerable extent (53%) by HbA1c. The association was also modified by HbA1c; BCAAs were only associated with renal transplant recipients without prediabetes (HbA1c < 5.7%). In conclusion, high concentrations of plasma BCAAs are associated with developing PTDM in renal transplant recipients. Alterations in BCAAs may represent an early predictive biomarker for PTDM. [ABSTRACT FROM AUTHOR]

A higher sodium intake is conceivably associated with insulin resistant conditions like obesity, but associations of non-alcoholic fatty liver disease (NAFLD) with a higher sodium intake determined by 24 hours (24 h) urine collections are still unclear. Dietary sodium intake was measured by sodium excretion in two complete consecutive 24 h urine collections in 6132 participants of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort. Fatty Liver Index (FLI) ≥60 and Hepatic Steatosis Index (HSI) >36 were used as proxies of suspected NAFLD. 1936 (31.6%) participants had an FLI ≥60, coinciding with the increased prevalence of type 2 diabetes (T2D), metabolic syndrome, hypertension and history of cardiovascular disease. Sodium intake was higher in participants with an FLI ≥60 (163.63 ± 61.81 mmol/24 h vs. 136.76 ± 50.90 mmol/24 h, p < 0.001), with increasing incidence in ascending quartile categories of sodium intake (p < 0.001). Multivariably, an FLI ≥60 was positively associated with a higher sodium intake when taking account for T2D, a positive cardiovascular history, hypertension, alcohol intake, smoking and medication use (odds ratio (OR) 1.54, 95% confidence interval (CI) 1.44–1.64, p < 0.001). Additional adjustment for the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) diminished this association (OR 1.30, 95% CI 1.21–1.41, p < 0.001). HSI >36 showed similar results. Associations remained essentially unaltered after adjustment for body surface area or waist/hip ratio. In conclusion, suspected NAFLD is a feature of higher sodium intake. Insulin resistance-related processes may contribute to the association of NAFLD with sodium intake. [ABSTRACT FROM AUTHOR]

Background: Gut microbiota-related metabolites, trimethylamine-N-oxide (TMAO), choline, and betaine, have been shown to be associated with cardiovascular disease (CVD) risk. Moreover, lower plasma betaine concentrations have been reported in subjects with type 2 diabetes mellitus (T2DM). However, few studies have explored the association of betaine with incident T2DM, especially in the general population. The goals of this study were to evaluate the performance of a newly developed betaine assay and to prospectively explore the potential clinical associations of betaine and future risk of T2DM in a large population-based cohort. Methods: We developed a high-throughput, nuclear magnetic resonance (NMR) spectroscopy procedure for acquiring spectra that allow for the accurate quantification of plasma/serum betaine and TMAO. Assay performance for betaine quantification was assessed and Cox proportional hazards regression was employed to evaluate the association of betaine with incident T2DM in 4336 participants in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. Results: Betaine assay results were linear (y = 1.02X − 3.75) over a wide range of concentrations (26.0–1135 µM). The limit of blank (LOB), limit of detection (LOD) and limit of quantitation (LOQ) were 6.4, 8.9, and 13.2 µM, respectively. Coefficients of variation for intra- and inter-assay precision ranged from 1.5–4.3% and 2.5–5.5%, respectively. Deming regression analysis of results produced by NMR and liquid chromatography coupled to tandem mass spectrometry(LC-MS/MS) revealed an R2 value of 0.94 (Y = 1.08x – 1.89) and a small bias for higher values by NMR. The reference interval, in a cohort of apparently healthy adult participants (n = 501), was determined to be 23.8 to 74.7 µM (mean of 42.9 ± 12.6 µM). In the PREVEND study (n = 4336, excluding subjects with T2DM at baseline), higher betaine was associated with older age and lower body mass index, total cholesterol, triglycerides, and hsCRP. During a median follow-up of 7.3 (interquartile range (IQR), 5.9–7.7) years, 224 new T2DM cases were ascertained. Cox proportional hazards regression models revealed that the highest tertile of betaine was associated with a lower incidence of T2DM. Hazard ratio (HR) for the crude model was 0.61 (95% CI: 0.44–0.85, p = 0.004). The association remained significant even after adjusting for multiple clinical covariates and T2DM risk factors, including fasting glucose. HR for the fully-adjusted model was 0.50 (95% CI: 0.32–0.80, p = 0.003). Conclusions: The newly developed NMR-based betaine assay exhibits performance characteristics that are consistent with usage in the clinical laboratory. Betaine levels may be useful for assessing the risk of future T2DM. [ABSTRACT FROM AUTHOR]