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Experimental studies have shown that urinary dipeptidyl peptidase 4 (uDPP4), unlike serum DPP4 (sDPP4) activity, correlates with proteinuria, serum creatinine, and left ventricular (LV) hypertrophy in chronic kidney disease (CKD) models, suggesting a potential role for uDPP4 in CKD progression. This study examined the relationship of uDPP4 and sDPP4 activities with renal, cardiovascular, and metabolic markers, along with mortality and initiation of kidney replacement therapy (KRT) events in individuals with CKD. DPP4 activity was measured in the urine and serum of 426 participants from the Brazilian CKD cohort, PROGREDIR. Participants were stratified into tertiles based on uDPP4 and sDPP4 activities. Multivariable linear regression, Kaplan–Meier analysis, Cox hazards, and competing risk models (cause-specific and Fine–Gray) were used. uDPP4 activity was positively associated with albuminuria, urinary retinol-binding protein 4, LV mass, and type 2 diabetes but inversely associated with body mass index and use of renin-angiotensin system blockers. In contrast, sDPP4 activity correlated only with age and biological sex. Higher uDPP4 activity was associated with a higher incidence rate of all-cause mortality (p < 0.0001). Participants in the second and third uDPP4 activity tertiles had greater mortality risk compared to the lowest tertile (HR 2.03, 95% CI 1.36–3.04 and HR 2.48, 95% CI 1.67–3.67, respectively), even after controlling for potential confounders. No independent association was found between sDPP4 activity and mortality or initiation of KRT. These findings support uDPP4’s involvement in CKD progression and its association with increased mortality risk in individuals with CKD.

IntroductionMetabolomics allows exploration of novel biomarkers and provides insights on metabolic pathways associated with disease. To date, metabolomics studies on CKD have been largely limited to Caucasian populations and have mostly examined surrogate end points.ObjectiveIn this study, we evaluated the role of metabolites in predicting a primary outcome defined as dialysis need, doubling of serum creatinine or death in Brazilian macroalbuminuric DKD patients.MethodsNon-targeted metabolomics was performed on plasma from 56 DKD patients. Technical triplicates were done. Metabolites were identified using Agilent Fiehn GC/MS Metabolomics and NIST libraries (Agilent MassHunter Work-station Quantitative Analysis, version B.06.00). After data cleaning, 186 metabolites were left for analyses.ResultsDuring a median follow-up time of 2.5 years, the PO occurred in 17 patients (30.3%). In non-parametric testing, 13 metabolites were associated with the PO. In univariate Cox regression, only 1,5-anhydroglucitol (HR 0.10; 95% CI 0.01–0.63, p = .01), norvaline and l-aspartic acid were associated with the PO. After adjustment for baseline renal function, 1,5-anhydroglucitol (HR 0.10; 95% CI 0.02–0.63, p = .01), norvaline (HR 0.01; 95% CI 0.001–0.4, p = .01) and aspartic acid (HR 0.12; 95% CI 0.02–0.64, p = .01) remained significantly and inversely associated with the PO.ConclusionOur results show that lower levels of 1,5-anhydroglucitol, norvaline and l-aspartic acid are associated with progression of macroalbuminuric DKD. While norvaline and l-aspartic acid point to interesting metabolic pathways, 1,5-anhydroglucitol is of particular interest since it has been previously shown to be associated with incident CKD. This inverse biomarker of hyperglycemia should be further explored as a new tool in DKD.

Abstract Objectives: To examine the relation between self reported eating frequency and serum lipid concentrations in a free living population. Design: Cross sectional population based study. Setting: Norfolk, England. Participants: 14 666 men and women aged 45–75 years from the Norfolk cohort of the European prospective investigation into cancer (EPIC-Norfolk). Main outcome measures: Concentrations of blood lipids. Results: Mean concentrations of total cholesterol and low density lipoprotein cholesterol decreased in a continuous relation with increasing daily frequency of eating in men and women. No consistent relation was observed for high density lipoprotein cholesterol, body mass index, waist to hip ratio, or blood pressure. Mean cholesterol concentrations differed by about 0.25 mmol/l between people eating more than six times a day and those eating once or twice daily; this difference was reduced to 0.15 mmol/l after adjustment for possible confounding variables, including age, obesity, cigarette smoking, physical activity, and intake of energy and nutrients (alcohol, fat, fatty acids, protein, and carbohydrate). Conclusions: Concentrations of total cholesterol and low density lipoprotein cholesterol are negatively and consistently associated with frequency of eating in a general population. The effects of eating frequency on lipid concentrations induced in short term trials in animals and human volunteers under controlled laboratory conditions can be observed in a free living general population. We need to consider not just what we eat but how often we eat. What is already known on this topic Studies in animals and small human trials indicate that eating frequency is inversely related to serum lipid concentrations Few studies have examined this in a free living population under no dietary restrictions What this study adds In a free living population increased eating frequency was negatively and significantly associated with concentrations of total cholesterol and low density lipoprotein cholesterol This association was still present after adjustment for body mass index, physical activity, cigarette smoking, and dietary intake Mean age adjusted cholesterol concentrations differed by 0.25 mmol/l between people eating more than six times a day and those eating less than twice daily

Glycemic control in patients with chronic kidney disease (CKD) is particularly hard to achieve because of a slower insulin degradation by the kidney. It might modify the long-acting insulin analogue pharmacokinetics, increasing its time–action and the risk of hypoglycemia. However, because this insulin has no peak action, it might be a more tolerable approach to patients with CKD. This hypothesis remains to be tested, because no study has thus far examined the efficacy and safety profile of long-acting basal analogues in patients with significant loss of renal function. The purpose of this study was to compare the glycemic response to treatment with glargine U100 or neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes mellitus (T2DM) and CKD stages 3 and 4. Thirty-four patients were randomly assigned to glargine U100 or NPH insulin after a 2-way crossover open-label design. The primary end point was the difference in glycosylated hemoglobin (HbA1c) and in the number of hypoglycemic events between weeks 1 and 24, whereas secondary end points included changes in glycemic patterns, weight and body mass index, and total daily dose of insulin. HbA1c was determined by ion-exchange HPLC, and hypoglycemia was defined as glucose concentration of 54 mg/dL (3.0 mmol/L) detected by self-monitoring of plasma glucose or continuous glucose monitoring. After 24 weeks, mean HbA1c decreased on glargine U100 treatment (−0.91%; P < 0.001), but this benefit was not observed for NPH (0.23%; P = 0.93). Moreover, incidence of nocturnal hypoglycemia was 3 times lower with glargine than with NPH insulin (P = 0.047). Our results found that insulin glargine U100 could be effective, once it improved glycemic control, reducing HbA1c with fewer nocturnal hypoglycemia episodes compared with NPH insulin in this population. These clinical benefits justify the use of basal insulin analogues, despite their high cost to treat patients with T2DM and CKD stages 3 and 4. Clinical Trials identifier: NCT02451917.

Chronic effect of parathyroid hormone on NHE3 expression in rat renal proximal tubules. The most abundant Na+/H+ exchanger in the apical membrane of proximal tubules is the type 3 isoform (NHE3), and its activity is acutely inhibited by parathyroid hormone (PTH). In the present study, we investigate whether changes in protein abundance as well as in mRNA levels play a significant role in the long-term modulation of NHE3 by PTH. Three groups of animals were compared: (1) HP: animals submitted to hyperparathyroidism by subcutaneous implantation of PTH pellets, providing threefold basal levels of this hormone (2.1 U · h-1); (2) control: sham-operated rats in which placebo pellets were implanted; (3) PTX: animals submitted to hypoparathyroidism by thyroparathyroidectomy followed by subcutaneous implantation of thyroxin pellets, which provided basal levels of thyroid hormone. After eight days, we measured bicarbonate reabsorption in renal proximal tubules by in vivo microperfusion. NHE3 activity was also measured in brush border membrane (BBM) vesicles by proton dependent uptake of 22Na. NHE3 expression was evaluated by Northern blot, Western blot and immunohistochemistry. Bicarbonate reabsorption in renal proximal tubules was significantly decreased in HP rats. Na+/H+ exchange activity in isolated BBM vesicles was 6400 ± 840, 9225 ± 505, and 12205 ± 690 cpm · mg-1· 15 s-1 in HP, sham, and PTX groups, respectively. BBM NHE3 protein abundance decreased 39.3 ± 8.2% in HP rats and increased 54.6 ± 7.8% in PTX rats. Immunohistochemistry showed that expression of NHE3 protein in apical BBM was decreased in HP rats and was increased in PTX rats. Northern blot analysis of total kidney RNA showed that the abundance of NHE3 mRNA was 20.3 ± 1.3% decreased in HP rats and 27.7 ± 2.1% increased in PTX. Our results indicate that the chronic inhibitory effect of PTH on the renal proximal tubule NHE3 is associated with changes in the expression of NHE3 mRNA levels and protein abundance.

A case of a 66-year-old white man with recent onset of oedema, hypertension, metabolic alkalosis and profound hypokalaemia is described. The initial laboratorial workup showed that urinary chloride concentration and potassium excretion were increased, suggesting a state of hyperaldosteronism. Nonetheless, renin activity was low and aldosterone levels were normal. The metabolic alkalosis seen in this case was due to a rare cause, the ectopic adrenocorticotropic hormone syndrome. A literature review in the subject is presented.