The clinical relevance of novel biomarkers as outcome parameter in adults with phenylketonuria.

Recent studies in PKU patients identified alternative biomarkers in blood using untargeted metabolomics. To test the added clinical value of these novel biomarkers, targeted metabolomics of 11 PKU biomarkers (phenylalanine, glutamyl-phenylalanine, glutamyl-glutamyl-phenylalanine, N-lactoyl-phenylalanine, N-acetyl-phenylalanine, the dipeptides phenylalanyl-phenylalanine and phenylalanyl-leucine, phenylalanine-hexose conjugate, phenyllactate, phenylpyruvate, and phenylacetate) was performed in stored serum samples of the well-defined PKU patient-COBESO cohort and a healthy control group. Serum samples of 35 PKU adults and 20 healthy age- and sex-matched controls were analyzed using ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry. Group differences were tested using the Mann-Whitney U test. Multiple linear regression analyses were performed with these biomarkers as predictors of (neuro-)cognitive functions working memory, sustained attention, inhibitory control, and mental health. Compared to healthy controls, phenylalanine, glutamyl-phenylalanine, N-lactoyl-phenylalanine, N-acetyl-phenylalanine, phenylalanine-hexose conjugate, phenyllactate, phenylpyruvate, and phenylacetate were significant elevated in PKU adults (p < 0.001). The remaining three were below limit of detection in PKU and controls. Both phenylalanine and N-lactoyl-phenylalanine were associated with DSM-VI Attention deficit/hyperactivity (R2 = 0.195, p = 0.039 and R2 = 0.335, p = 0.002, respectively) of the ASR questionnaire. In addition, N-lactoyl-phenylalanine showed significant associations with ASR DSM-VI avoidant personality (R2 = 0.265, p = 0.010), internalizing (R2 = 0.192, p = 0.046) and externalizing problems (R2 = 0.217, p = 0.029) of the ASR questionnaire and multiple aspects of the MS2D and FI tests, reflecting working memory with R2 between 0.178 (p = 0.048) and 0.204 (p = 0.033). Even though the strength of the models was not considered strong, N-lactoyl-phenylalanine outperformed phenylalanine in its association with working memory and mental health outcomes.

Caloric restriction reduces proteinuria in male rats with established nephropathy.

Reducing proteinuria is a crucial approach in preventing kidney function loss. Previous preclinical studies indicated that caloric restriction (CR) imposed at a young age protects against age-related proteinuria. However, these studies have not explored CR in established renal disease. Therefore, this study aimed to investigate the impact of CR on established proteinuria. Rats, aged 12 ± 2 weeks, were administered 2.1 mg/kg of Adriamycin. Six weeks after injection, protein excretion was measured, and a [13 N]ammonia positron emission tomography (PET) scan was conducted to assess kidney perfusion. After 7 weeks rats were divided into four groups: ad libitum (AL) and CR groups fed either a 12% or a 20% protein diet. All groups were treated for 12 weeks. Blood pressure was measured and a second PET scan was acquired at the end of the study. The animals subjected to CR exhibited a 20.3% decrease in protein excretion (p = 0.003) compared to those in the AL groups. Additionally, blood pressure in the CR group was 21.2% lower (p < 0.001) than in the AL groups. While kidney function declined over time in all groups, the 20% CR group demonstrated the smallest decline. Thus CR effectively reduces urinary protein excretion and lowers blood pressure in rats with established proteinuria.

Use of maximal dosage renin-angiotensin-aldosterone system inhibitors in a real life population of complicated type 2 diabetes - contraindications and opportunities.

OBJECTIVE: Pharmacological inhibition of the renin-angiotensin-aldosterone-system (RAASi) is the cornerstone of hypertension treatment, renoprotection and secondary prevention of cardiovascular disease in patients with type 2 diabetes. Although there is a dose-dependent effect of RAASi with optimum protection when using maximal dose, little is known on actual use of maximal dosage RAASi in clinical practice. Here we investigate prevalence of maximal dosage RAASi, and contraindications for, optimizing RAASi dosage, in patients with complicated type 2 diabetes in a real-life clinical setting. RESEARCH DESIGN AND METHODS: We performed a retrospective analysis in 668 patients included in the DIAbetes and LifEstyle Cohort Twente (DIALECT). We grouped patients according to no RAASi, submaximal RAASi and maximal RAASi use. All potassium and creatinine measurements between January 1st 2000 and date of inclusion in DIALECT were extracted from patients files. We identified determinants of maximal RAASi use vs. submaximal RAASi use with multivariate logistic regression analysis. RESULTS: Mean age was 64 ± 10 years and 61% were men. In total, 460 patients (69%) used RAASi, and 30% used maximal RAASi. Maximal RAASi use was not statistically different between different indications for RAASi (i.e. hypertension, diabetic kidney disease, coronary heart disease and cerebrovascular disease; P > 0.05). Per patient, 2 [1-4] measurements of potassium and 20 [13-31] measurements of creatinine were retrieved, retrospective follow-up time was - 3.0 [-1.4 to -5.7] years. Pre-baseline hyperkalemia > 5.0 mmol/l and acute kidney injury were found in 151 (23%) patients and 119 patients (18%), respectively. Determinants of maximal RAASi were prior acute kidney injury (OR 0.51 (0.30-0.87)), increased albuminuria (OR 1.89 (1.17-3.08)) and total number of used antihypertensives (OR 1.66 (1.33-2.06)). CONCLUSIONS: Maximal dose RAASi is used in almost one third of complicated type 2 diabetes patients in a real-life setting. The prevalence of contraindications is considerable, but relative in nature, suggesting that it is worthwhile to explore strategies aimed at maximizing RAASi while circumventing the alleged contraindications.

GlycA, a novel pro-inflammatory glycoprotein biomarker is associated with mortality: results from the PREVEND study and meta-analysis.

BACKGROUND: Chronic diseases are associated with an inflammatory response. We determined the association of two inflammatory markers, GlycA and high-sensitivity C-reactive protein (hsCRP), with overall and cause-specific mortality in a cohort of men and women. METHODS: Cox regression analyses were used to examine associations of GlycA and hsCRP with all-cause, cancer and cardiovascular mortality in 5526 subjects (PREVEND cohort; average follow-up 12.6 years). RESULTS: GlycA was associated with all-cause mortality (n = 838), independent of clinical risk factors and hsCRP (hazard ratio 1.43 [95% confidence interval (CI): 1.09-1.87] for top versus bottom quartiles). For hsCRP, the association with all-cause mortality was nonsignificant after adjustment for GlycA. GlycA and hsCRP were associated with cancer mortality in men (n = 248), but not in women (n = 132). Neither GlycA nor hsCRP was independently associated with cardiovascular mortality (n = 201). In a meta-analysis of seven population-based studies, including 8153 deaths, the pooled multivariable-adjusted relative risk of GlycA for all-cause mortality was 1.74 (95% CI: 1.40-2.17) for top versus bottom quartiles. The association of GlycA with all-cause mortality was somewhat stronger than that of hsCRP. GlycA and hsCRP were not independently associated with cardiovascular mortality. The associations of GlycA and hsCRP with cancer mortality were present in men, but not in women. CONCLUSIONS: GlycA is significantly associated with all-cause mortality. GlycA and hsCRP were each not independently associated with cardiovascular mortality. The association of GlycA and hsCRP with cancer mortality appears to be driven by men.

Correction to: Sex differences in the association between plasma copeptin and incident type 2 diabetes: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study.

The values given for copeptin levels in men in quartiles 1 and 2 (Table 1) were incorrect, and should have read.

Chronic pain after hand-assisted laparoscopic donor nephrectomy.

BACKGROUND: Data on chronic pain after kidney donation are sparse. The aim of this study was to assess the incidence of chronic pain after hand-assisted laparoscopic nephrectomy. METHODS: Living kidney donors who donated between 2011 and 2017 at the University Medical Centre Groningen were included. All patients underwent hand-assisted laparoscopic donor nephrectomy. Postdonation pain and movement disabilities were assessed using the Carolinas Comfort Scale (CCS) and a visual analogue scale (VAS). The prevalence, severity of pain and the need for analgesics were reported. RESULTS: Some 333 living kidney donors with a mean age of 56 years were included. At a median of 19 (i.q.r. 10-33) months after donation, 82 donors (24·6 per cent) had a CCS score above 0, of which 58 (71 per cent) had a CCS score of at least 2 and 57 (70 per cent) reported movement limitations. Some 110 donors (33·0 per cent) had a VAS score of more than 0. Complaints mainly occurred during bending over (12·3 per cent) and exercising (12·4 per cent). Thirty-two donors (9·7 per cent) required analgesics during follow-up between donation and the time of measurement, and six of 82 (7 per cent) reported chronic inguinal pain. In multivariable analysis, donor age (odds ratio (OR) 0·97, 95 per cent c.i. 0·95 to 0·99; P = 0·020) and length of hospital stay (OR 1·21, 1·01 to 1·51; P = 0·041) were independently associated with chronic pain. CONCLUSION: One-quarter of donors experienced chronic postdonation pain or discomfort, most of which was bothersome. Younger donors and those with a longer postoperative hospital stay had more symptoms.

Influence of prednisolone on parameters of de novo lipogenesis and indices for stearoyl-CoA- and Δ6- desaturase activity in healthy males: A Post-hoc analysis of a randomized, placebo-controlled, double-blind trial.

Glucocorticoid treatment decreases liver insulin sensitivity and may modify fatty acid metabolism. We investigated the influence of oral prednisolone on indices for de novo lipogenesis (DNLi), stearoyl-CoA desaturase (SCDi) and Δ6-desaturase (D6Di) activity in healthy males. In addition, we explored whether the changes may be associated with prednisolone-induced changes in glucose and lipid metabolism and insulin sensitivity. Thirty-two healthy young males (mean ±â€¯SD age 22 ±â€¯3 years, BMI 22.4 ±â€¯1.7 kg/m2) were allocated to receive prednisolone 7.5 mg/day (PRED7.5; n = 12), prednisolone 30 mg/day (PRED30; n = 12), or placebo (n = 8) in a randomized double-blind fashion for 2 weeks. Fatty acid compositions of plasma cholesteryl esters (CE), phospholipids (PL) and triglycerides (TG) were measured at baseline and on day 14. DNLi, SCDi and D6Di were estimated from product/precursor ratios in CE, with DNLi primary deriving from 16:1ω7/18:2ω6, SCDi from 16:1ω7/16:0 and D6Di from 22:6ω3/20:5ω3. Ratios were also assessed in PL and TG. In CE, PRED30 increased DNLi by 51.2 [95%CI 14.8; 87.6]%, increased SCDi by 48.6 [18.7; 78.5]%, and decreased D6Di by 57.7 [-91.8; -23.5]% (p ≤ 0.01 for all, compared to placebo). The prednisolone-induced increases in DNLi and SCDi were positively correlated with insulin sensitivity (r = 0.35 and 0.50, respectively). Similar results were found in PL and TG. Prednisolone dose-dependently increases DNLi and SCDi and decreases D6Di in plasma CE, PL and TG in healthy males after 2 weeks. The observed unfavorable effects on fatty acid metabolism were related to the induction of glucocorticoid-induced insulin resistance.

Trajectories of metabolic risk factors and biochemical markers prior to the onset of type 2 diabetes: the population-based longitudinal Doetinchem study.

BACKGROUND: Risk factors often develop at young age and are maintained over time, but it is not fully understood how risk factors develop over time preceding type 2 diabetes. We examined how levels and trajectories of metabolic risk factors and biochemical markers prior to diagnosis differ between persons with and without type 2 diabetes over 15-20 years. METHODS: A total of 355 incident type 2 diabetes cases (285 self-reported, 70 with random glucose ⩾11.1 mmol l-1) and 2130 controls were identified in a prospective cohort between 1987-2012. Risk factors were measured at 5-year intervals. Trajectories preceding case ascertainment were analysed using generalised estimating equations. RESULTS: Among participants with a 21-year follow-up period, those with type 2 diabetes had higher levels of metabolic risk factors and biochemical markers 15-20 years before case ascertainment. Subsequent trajectories were more unfavourable in participants with type 2 diabetes for body mass index (BMI), HDL cholesterol and glucose (P<0.01), and to a lesser extent for waist circumference, diastolic and systolic blood pressure, triglycerides, alanine aminotransferase, gamma glutamyltransferase, C-reactive protein, uric acid and estimated glomerular filtration rate compared with participants without type 2 diabetes. Among persons with type 2 diabetes, BMI increased by 5-8% over 15 years, whereas the increase among persons without type 2 diabetes was 0-2% (P<0.01). The observed differences in trajectories of metabolic risk factors and biochemical markers were largely attenuated after inclusion of BMI in the models. Results were similar for men and women. CONCLUSIONS: Participants with diabetes had more unfavourable levels of metabolic risk factors and biochemical markers already 15-20 years before diagnosis and worse subsequent trajectories than others. Our results highlight the need, in particular, for maintenance of a healthy weight from young adulthood onwards for diabetes prevention.

Potassium supplementation and heart rate: A meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Increasing the intake of potassium has been shown to lower blood pressure, but whether it also affects heart rate (HR) is largely unknown. We therefore assessed the effect of potassium supplementation on HR in a meta-analysis of randomized controlled trials. METHODS AND RESULTS: We searched PubMed (1966-October 2014) for randomized, placebo-controlled trials in healthy adults with a minimum duration of two weeks in which the effect of increased potassium intake on HR was assessed. In addition, reference lists from meta-analysis papers on potassium and blood pressure were hand-searched for publications. Two investigators independently extracted the data. We performed random effects meta-analyses, subgroup and meta-regression analyses for characteristics of the study (e.g. design, intervention duration, potassium dose and salt type, change in potassium excretion, sodium excretion during intervention) and study population (e.g. gender, age, hypertensive status, pre-study HR, pre-study potassium excretion). A total of 22 trials (1086 subjects), with a median potassium dose of 2.5 g/day (range: 0.9-4.7 g/day), and median intervention duration of 4 weeks (range: 2-24 weeks) were included. The meta-analysis showed no overall effect of increased potassium intake on HR (0.19 bpm, 95% CI: -0.44, 0.82). Stratified analyses yielded no significant effects of potassium intake on HR in subgroups, and there was no evidence for a dose-response relationship in meta-regression analyses. CONCLUSION: A chronic increase in potassium intake with supplemental doses of 2-3 g/day is unlikely to affect HR in apparently healthy adults.

Concordance of dietary sodium intake and concomitant phosphate load: Implications for sodium interventions.

BACKGROUND AND AIMS: Both a high dietary sodium and high phosphate load are associated with an increased cardiovascular risk in patients with chronic kidney disease (CKD), and possibly also in non-CKD populations. Sodium and phosphate are abundantly present in processed food. We hypothesized that (modulation of) dietary sodium is accompanied by changes in phosphate load across populations with normal and impaired renal function. METHODS AND RESULTS: We first investigated the association between sodium and phosphate load in 24-h urine samples from healthy controls (n = 252), patients with type 2 diabetes mellitus (DM, n = 255) and renal transplant recipients (RTR, n = 705). Secondly, we assessed the effect of sodium restriction on phosphate excretion in a nondiabetic CKD cohort (ND-CKD: n = 43) and a diabetic CKD cohort (D-CKD: n = 39). Sodium excretion correlated with phosphate excretion in healthy controls (R = 0.386, P < 0.001), DM (R = 0.490, P < 0.001), and RTR (R = 0.519, P < 0.001). This correlation was also present during regular sodium intake in the intervention studies (ND-CKD: R = 0.491, P < 0.001; D-CKD: R = 0.729, P < 0.001). In multivariable regression analysis, sodium excretion remained significantly correlated with phosphate excretion after adjustment for age, gender, BMI, and eGFR in all observational cohorts. In ND-CKD and D-CKD moderate sodium restriction reduced phosphate excretion (31 ± 10 to 28 ± 10 mmol/d; P = 0.04 and 26 ± 11 to 23 ± 9 mmol/d; P = 0.02 respectively). CONCLUSIONS: Dietary exposure to sodium and phosphate are correlated across the spectrum of renal function impairment. The concomitant reduction in phosphate intake accompanying sodium restriction underlines the off-target effects on other nutritional components, which may contribute to the beneficial cardiovascular effects of sodium restriction. (f) Registration numbers: Dutch Trial Register NTR675, NTR2366.

Effects of sodium and potassium supplementation on blood pressure and arterial stiffness: a fully controlled dietary intervention study.

We performed a randomised, placebo-controlled, crossover study to examine the effects of sodium and potassium supplementation on blood pressure (BP) and arterial stiffness in untreated (pre)hypertensive individuals. During the study, subjects were on a fully controlled diet that was relatively low in sodium and potassium. After a 1-week run-in period, subjects received capsules with supplemental sodium (3 g d(-1), equals 7.6 g d(-1) of salt), supplemental potassium (3 g d(-1)) or placebo, for 4 weeks each, in random order. Fasting office BP, 24-h ambulatory BP and measures of arterial stiffness were assessed at baseline and every 4 weeks. Of 37 randomized subjects, 36 completed the study. They had a mean pre-treatment BP of 145/81 mm Hg and 69% had systolic BP ⩾140 mm Hg. Sodium excretion was increased by 98 mmol per 24 h and potassium excretion by 63 mmol per 24 h during active interventions, compared with placebo. During sodium supplementation, office BP was significantly increased by 7.5/3.3 mm Hg, 24-h BP by 7.5/2.7 mm Hg and central BP by 8.5/3.6 mm Hg. During potassium supplementation, 24-h BP was significantly reduced by 3.9/1.6 mm Hg and central pulse pressure by 2.9 mm Hg. Pulse wave velocity and augmentation index were not significantly affected by sodium or potassium supplementation. In conclusion, increasing the intake of sodium caused a substantial increase in BP in subjects with untreated elevated BP. Increased potassium intake, on top of a relatively low-sodium diet, had a beneficial effect on BP. Arterial stiffness did not materially change during 4-week interventions with sodium or potassium.

Sex specific association between carnosinase gene CNDP1 and cardiovascular mortality in patients with type 2 diabetes (ZODIAC-22).

INTRODUCTION: Homozygosity for a 5-leucine repeat (5L-5L) in the carnosinase gene (CNDP1) has been associated with a reduced prevalence of diabetic nephropathy in cross-sectional studies in patients with type 2 diabetes, particularly in women. Prospective studies on mortality are not available. This study investigated whether 5L-5L was associated with mortality and progression of renal function loss and to what extent this effect is modified by sex. METHODS: In a prospective cohort of patients with type 2 diabetes, a Cox proportional hazard model was used to compare 5L-5L with other genotypes regarding (cardiovascular) mortality. Renal function slopes were obtained by within-individual linear regression of the estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) equation, and were compared between 5L-5L and other genotypes. RESULTS: 871 patients were included (38% with 5L-5L). After 9.5 years of follow-up, hazards ratios (HR) for all-cause and cardiovascular mortality in 5L-5L versus other genotypes were 1.09 [95% confidence interval (CI) 0.88-1.36] and 1.12 (95% CI 0.79-1.58), respectively. There was a significant interaction between CNDP1 and sex for the association with cardiovascular mortality (p = 0.01), not for all-cause mortality (p = 0.32). Adjusted HR in 5L-5L for cardiovascular mortality was 0.69 (95% CI 0.39-1.23) in men and 1.77 (95% CI 1.12-2.81) in women. The slopes of eGFR-MDRD did not significantly differ between 5L-5L and other genotypes. CONCLUSIONS: The association between CNDP1 and cardiovascular mortality was sex-specific, with a higher risk in women with 5L-5L genotype. CNDP1 was not associated with all-cause mortality or change in eGFR.

Effect of a high-protein diet on maintenance of blood pressure levels achieved after initial weight loss: the DiOGenes randomized study.

Randomized trials have shown significant blood pressure (BP) reductions after increased protein compared with carbohydrate intake, but the effect on BP maintenance after initial weight loss is unclear. We examined the effect of a high-protein diet on the maintenance of reduced BP after weight loss in 420 overweight adults from the Diet, Obesity and Genes study. After an 8-week weight-loss period (>8% BW), subjects (42±6 years) were randomized to either a high-protein diet (23-28 en% protein) or a lower-protein control diet (10-15 en% protein) for 26 weeks. BMI after weight loss was 30.3±4.3 kg m(-2), BP was 118/73 mm Hg and 28 subjects (6.5%) used antihypertensive agents. Systolic BP during 26 weeks of weight maintenance dietary intervention increased in both treatment groups, but it was 2.2 mm Hg less (95% CI: -4.6 to 0.2 mm Hg, P=0.08) in the high-protein group than in the lower-protein control group. In 191 (pre)hypertensive subjects (baseline systolic BP⩾120 mm Hg), a larger difference was observed (-4.2 mm Hg (-7.7, -0.7), P=0.02). The effect was attenuated after adjustment for initial BP (-3.4 mm Hg (-6.9, -0.03), P=0.048), and after additional adjustment for weight change (-2.7 mm Hg (-6.1, 0.4), P=0.11). Adjustment for 24-h urinary excretion of sodium and potassium did not change the results. Diastolic BP yielded similar results. These findings suggest that a BP reduction after weight loss is better maintained when the intake of protein is increased at the expense of carbohydrates. This effect is partly mediated by body weight.

Effects of adverse life events on heart rate variability, cortisol, and C-reactive protein.

OBJECTIVE: Our objective was to assess whether self-reported adverse life events during childhood or over the lifespan are associated with altered activity of the autonomic nervous system (ANS), the hypothalamic-pituitary-adrenal axis (HPA axis), and the immune system. METHOD: This study was performed in a population-based cohort of 1094 adults aged 33-79 years, 46.3% male, average age 53 (SD 11.4). Two waves of data were collected at a 2-year interval, enabling replication of the analyses. Cumulative exposure to adverse life events was assessed by means of the List of Threatening Experiences. ANS function was assessed by spectral analysis of heart rate variability in the high-frequency band (HRV-HF). HPA axis function was assessed by 24-h urinary free cortisol (24-h UFC) excretion. Inflammation was assessed by high-sensitive C-reactive protein (hsCRP). RESULTS: Multiple linear regression analyses did not reveal any significant associations, with the exception of one significant negative association between the lifetime score of adverse life events and HRV-HF ß = -0.028; P = 0.037 at baseline, but not at follow up 2 years later. CONCLUSION: In a large population-based cohort, adverse life events were not consistently associated with HRV-HF, 24-h UFC or (hsCRP).

Proceedings from an international consensus meeting on posttransplantation diabetes mellitus: recommendations and future directions.

A consensus meeting was held in Vienna on September 8-9, 2013, to discuss diagnostic and therapeutic challenges surrounding development of diabetes mellitus after transplantation. The International Expert Panel comprised 24 transplant nephrologists, surgeons, diabetologists and clinical scientists, which met with the aim to review previous guidelines in light of emerging clinical data and research. Recommendations from the consensus discussions are provided in this article. Although the meeting was kidney-centric, reflecting the expertise present, these recommendations are likely to be relevant to other solid organ transplant recipients. Our recommendations include: terminology revision from new-onset diabetes after transplantation to posttransplantation diabetes mellitus (PTDM), exclusion of transient posttransplant hyperglycemia from PTDM diagnosis, expansion of screening strategies (incorporating postprandial glucose and HbA1c) and opinion-based guidance regarding pharmacological therapy in light of recent clinical evidence. Future research in the field was discussed with the aim of establishing collaborative working groups to address unresolved questions. These recommendations are opinion-based and intended to serve as a template for planned guidelines update, based on systematic and graded literature review, on the diagnosis and management of PTDM.

Hepatic syndecan-1 changes associate with dyslipidemia after renal transplantation.

Syndecan-1 is a transmembrane heparan sulfate (HS) proteoglycan present on hepatocytes and involved in uptake of triglyceride-rich lipoproteins via its HS polysaccharide side chains. We hypothesized that altered hepatic syndecan-1 metabolism could be involved in dyslipidemia related to renal transplantation. In a rat renal transplantation model elevated plasma triglycerides were associated with fivefold increased expression of hepatic syndecan-1 mRNA (p < 0.01), but not protein. Expression of syndecan-1 sheddases (ADAM17, MMP9) and heparanase was significantly up-regulated after renal transplantation (all p < 0.05). Profiling of HS side chains revealed loss of hepatic HS upon renal transplantation accompanied by significant decreased functional capacity for VLDL binding (p = 0.02). In a human renal transplantation cohort (n = 510), plasma levels of shed syndecan-1 were measured. Multivariate analysis showed plasma syndecan-1 to be independently associated with triglycerides (p < 0.0001) and inversely with HDL cholesterol (p < 0.0001). Last, we show a physical association of syndecan-1 to HDL from renal transplant recipients (RTRs), but not to HDL from healthy controls. Our data suggest that after renal transplantation loss of hepatic HS together with increased syndecan-1 shedding hampers lipoprotein binding and uptake by the liver contributing to dyslipidemia. Our data open perspectives toward improvement of lipid profiles by targeted inhibition of syndecan-1 catabolism in renal transplantation.

Fish and omega-3 fatty acid intake in relation to circulating fibroblast growth factor 23 levels in renal transplant recipients.

BACKGROUND AND AIMS: A high circulating fibroblast growth factor 23 (FGF23) level is an independent risk factor for cardiovascular mortality in renal transplant recipients and the general population. N-3 fatty acids eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) may contribute to cardiovascular risk reduction. We investigated whether fish and EPA-DHA intake are related to FGF23 levels in renal transplant recipients. METHODS AND RESULTS: We performed a cross-sectional analysis in 619 stable renal transplant recipients (mean age 53 years, 57% male, estimated glomerular filtration rate [eGFR] 53 ± 20 mL/min/1.73 m(2)). Dietary intake was assessed by a 177-item food frequency questionnaire. Serum intact FGF23 was measured by ELISA. We examined differences in FGF23 levels across categories of fish and EPA-DHA intake using analysis of variance models adjusted for age, sex, dietary and lifestyle factors and key determinants of FGF23. Patients consumed on average 15 g of fish and 139 mg EPA-DHA/day. Median FGF23 was 62 pg/mL (IQR 43-98 pg/mL). Higher dietary EPA-DHA and fish intake were associated with lower serum FGF23 levels. Subgroup analyses revealed that particularly in patients with reduced renal function (eGFR <60 mL/min/1.73 m(2)), adjusted FGF23 levels (114, 79, 75 pg/mL, P = 0.0001) were inversely associated with tertiles of EPA-DHA intake. Similarly, we observed an inverse association between fish consumption and serum FGF23 levels in adjusted analyses. CONCLUSION: A higher intake of fish and dietary n-3 fatty acids (EPA-DHA) is related to lower circulating FGF23 levels in renal transplant recipients. Further research is needed to assess the causality of this association and the clinical implications.

Longitudinal measurement of physical activity following kidney transplantation.

The purpose of this longitudinal observational study was to (i) examine the change of daily physical activity in 28 adult kidney transplant recipients over the first 12 months following transplantation; and (ii) to examine the change in metabolic characteristics and renal function. Accelerometer-based daily physical activity and metabolic- and clinical characteristics were measured at six wk (T1), three months (T2), six months (T3) and 12 months (T4) following transplantation. Linear mixed effect analyses showed an increase in steps/d (T1 = 6326 ± 2906; T4 = 7562 ± 3785; F = 3.52; p = 0.02), but one yr after transplantation only 25% achieved the recommended 10 000 steps/d. There was no significant increase in minutes per day spent on moderate-to-vigorous intensity physical activity (T1 = 80.4 ± 63.6; T4 = 93.2 ± 55.1; F = 1.71; p = 0.17). Body mass index increased over time (T1 = 25.4 ± 3.2; T4 = 27.2 ± 3.8; F = 12.62; p < 0.001), mainly due to an increase in fat percentage (T1 = 30.3 ± 8.0; T4 = 34.0 ± 7.9; F = 14.63; p < 0.001). There was no significant change in renal function (F = 0.17; p = 0.92). Although the recipients increased physical activity, the majority did not meet the recommended levels of physical activity after one yr. In addition to the weight gain, this may result in negative health consequences. Therefore, it is important to develop strategies to support kidney transplant recipients to comply with healthy lifestyle recommendations, including regular physical activity.

Urine and plasma metabolites predict the development of diabetic nephropathy in individuals with Type 2 diabetes mellitus.

AIMS: Early detection of individuals with Type 2 diabetes mellitus or hypertension at risk for micro- or macroalbuminuria may facilitate prevention and treatment of renal disease. We aimed to discover plasma and urine metabolites that predict the development of micro- or macroalbuminuria. METHODS: Patients with Type 2 diabetes (n = 90) and hypertension (n = 150) were selected from the community-cohort 'Prevention of REnal and Vascular End-stage Disease' (PREVEND) and the Steno Diabetes Center for this case-control study. Cases transitioned in albuminuria stage (from normo- to microalbuminuria or micro- to macroalbuminuria). Controls, matched for age, gender, and baseline albuminuria stage, remained in normo- or microalbuminuria stage during follow-up. Median follow-up was 2.9 years. Metabolomics were performed on plasma and urine. The predictive performance of a metabolite for albuminuria transition was assessed by the integrated discrimination index. RESULTS: In patients with Type 2 diabetes with normoalbuminuria, no metabolites discriminated cases from controls. In patients with Type 2 diabetes with microalbuminuria, plasma histidine was lower (fold change = 0.87, P = 0.02) and butenoylcarnitine was higher (fold change = 1.17, P = 0.007) in cases vs. controls. In urine, hexose, glutamine and tyrosine were lower in cases vs. controls (fold change = 0.20, P < 0.001; 0.32, P < 0.001; 0.51, P = 0.006, respectively). Adding the metabolites to a model of baseline albuminuria and estimated glomerular filtration rate metabolites improved risk prediction for macroalbuminuria transition (plasma integrated discrimination index = 0.28, P < 0.001; urine integrated discrimination index = 0.43, P < 0.001). These metabolites did not differ between hypertensive cases and controls without Type 2 diabetes. CONCLUSIONS: Type 2 diabetes-specific plasma and urine metabolites were discovered that predict the development of macroalbuminuria beyond established renal risk markers. These results should be confirmed in a large, prospective cohort.

The importance of short-term off-target effects in estimating the long-term renal and cardiovascular protection of angiotensin receptor blockers.

Angiotensin receptor blockers (ARBs) have multiple effects that may contribute to their efficacy on renal/cardiovascular outcomes. We developed and validated a risk score that incorporated short-term changes in multiple risk markers to predict the ARB effect on renal/cardiovascular outcomes. The score was used to predict renal/cardiovascular risk at baseline and at month 6 in the ARB treatment arm of the Reduction of Endpoints in NIDDM (noninsulin-dependent diabetes mellitus) with the Angiotensin II Antagonist Losartan (RENAAL) trial. The net risk difference at these time points indicated the estimated long-term renal/cardiovascular treatment effect. Predicted relative risk reductions (RRRs) based on multiple markers were close to observed RRRs for renal (RRR(predicted): 30.1% vs. RRR(observed): 21.8%; P = 0.44) and cardiovascular outcomes (RRR(predicted): 9.4% vs. RRR(observed): 9.2%; P = 0.98), in addition to being markedly more accurate than predicted RRRs based on changes in single markers. The score was validated in an independent ARB trial. Predictions of long-term renal/cardiovascular ARB effects are more accurate when considering short-term changes in multiple risk markers, challenging the use of single markers to establish drug efficacy.