Kidney and vascular function in adult patients with hereditary fructose intolerance

Objective: Previous studies have shown that patients with hereditary fructose intolerance (HFI) are characterized by a greater intrahepatic triglyceride content, despite a fructose-restricted diet. The present study aimed to examine the long-term consequences of HFI on other aldolase-B-expressing organs, i.e. the kidney and vascular endothelium. Methods: Fifteen adult HFI patients were compared to healthy control individuals matched for age, sex and body mass index. Aortic stiffness was assessed by carotid-femoral pulse wave velocity (cf-PWV) and endothelial function by peripheral arterial tonometry, skin laser doppler flowmetry and the endothelial function biomarkers soluble E-selectin [sE-selectin] and von Willebrand factor. Serum creatinine and cystatin C were measured to estimate the glomerular filtration rate (eGFR). Urinary glucose and amino acid excretion and the ratio of tubular maximum reabsorption of phosphate to GFR (TmP/GFR) were determined as measures of proximal tubular function. Results: Median systolic blood pressure was significantly higher in HFI patients (127 versus 122 mmHg, p = .045). Pulse pressure and cf-PWV did not differ between the groups (p = .37 and p = .49, respectively). Of all endothelial function markers, only sE-selectin was significantly higher in HFI patients (p = .004). eGFR was significantly higher in HFI patients than healthy controls (119 versus 104 ml/min/1.73m2, p = .001, respectively). All measurements of proximal tubular function did not differ significantly between the groups. Conclusions: Adult HFI patients treated with a fructose-restricted diet are characterized by a higher sE-selectin level and slightly higher systolic blood pressure, which in time could contribute to a greater cardiovascular risk. The exact cause and, hence, clinical consequences of the higher eGFR in HFI patients, deserves further study.</p

Association of common gene variants in glucokinase regulatory protein with cardiorenal disease: A systematic review and meta-analysis

<div><p>Background</p><p>Small-molecules that disrupt the binding between glucokinase and glucokinase regulatory protein (GKRP) in the liver represent a potential new class of glucose-lowering drugs. It will, however, take years before their effects on clinically relevant cardiovascular endpoints are known. The purpose of this study was to estimate the effects of these drugs on cardiorenal outcomes by studying variants in the GKRP gene (<i>GCKR</i>) that mimic glucokinase-GKRP disruptors.</p><p>Methods</p><p>The MEDLINE and EMBASE databases were searched for studies reporting on the association between <i>GCKR</i> variants (rs1260326, rs780094, and rs780093) and coronary artery disease (CAD), estimated glomerular filtration rate (eGFR), and chronic kidney disease (CKD).</p><p>Results</p><p>In total 5 CAD studies (n = 274,625 individuals), 7 eGFR studies (n = 195,195 individuals), and 4 CKD studies (n = 31,642 cases and n = 408,432 controls) were included. Meta-analysis revealed a significant association between <i>GCKR</i> variants and CAD (OR:1.02 per risk allele, 95%CI:1.00–1.04, p = 0.01). Sensitivity analyses showed that replacement of one large, influential CAD study by two other, partly overlapping studies resulted in similar point estimates, albeit less precise (OR:1.02; 95%CI:0.98–1.06 and OR: 1.02; 95%CI: 0.99–1.04). <i>GCKR</i> was associated with an improved eGFR (+0.49 ml/min, 95%CI:0.10–0.89, p = 0.01) and a trend towards protection from CKD (OR:0.98, 95%CI:0.95–1.01, p = 0.13).</p><p>Conclusion</p><p>This study suggests that increased glucokinase-GKRP disruption has beneficial effects on eGFR, but these may be offset by a disadvantageous effect on coronary artery disease risk. Further studies are warranted to elucidate the mechanistic link between hepatic glucose metabolism and eGFR.</p></div

Development of tools to facilitate the diagnosis of hereditary fructose intolerance

Although hereditary fructose intolerance (HFI) is an inborn error of fructose metabolism that classically presents at infancy, the diagnosis is often missed or delayed. In this study, we aimed to develop tools to facilitate the diagnosis of HFI. The intake of fructose-containing food products, that is, fruit, fruit juice and sugar-sweetened beverages, was assessed by a 3-day food diary in adult HFI patients ( ?=?15) and age, sex, and BMI-matched controls ( ?=?15). Furthermore, glycosylation of transferrin was examined using high-resolution mass spectrometry and abnormally glycosylated transferrin was expressed as ratio of normal glycosylated transferrin. We found that the sensitivity and specificity of the 3-day food diary for the intake of at least one fructose-containing food product were both 100%. Both mono-glyco:diglyco transferrin and a-glyco+mono-glyco:di-glyco transferrin were greater in HFI patients and had a high-discriminatory power (area under the receiver operating characteristic curve: 0.97 and 0.94, respectively). In this well-characterized cohort of adult HFI patients, the 3-day food questionnaire and the glycosylation pattern of transferrin are valuable tools to facilitate the recognition and diagnosis of HFI in adult patients

Development and validation of a UPLC-MS/MS method to quantify fructose in serum and urine

Background: The study of the involvement of fructose in the pathogenesis of cardiometabolic disease requires accurate and precise measurements of serum and urinary fructose. The aim of the present study was to develop and validate such a method by Ultra Performance Liquid Chromatography-tandem Mass Spectrometry (UPLCMS/MS). Methods: Fructose was quantified using hydrophilic interaction UPLC-MS/MS with a labelled internal standard. Serum fructose levels were determined in healthy individuals (n = 3) after a 15-gram oral fructose load. Twenty-four hours urinary fructose levels were determined in individuals consuming low (median: 1.4 g/day, interquartile range [IQR]: 0.9-2.0; n = 10), normal (31 g/day, 23-49; n = 15) and high (70 g/day, 55-84; n = 16) amounts of fructose. Results: The calibration curves showed perfect linearity in water, artificial, serum, and urine matrices (r(2) > 0.99). Infra- and inter-day assay variation of serum and urinary fructose ranged from 0.3 to 5.1% with an accuracy of similar to 98%. Fasting serum fructose levels (5.7 +/- 0.6 mu mol/L) increased 60 min after a 15-gram oral fructose load (to 150.3 +/- 41.7 mu mol/L) and returned to normal after 180 min (8.4 +/- 0.6 mu mol/L). Twenty-four hours urinary fructose levels were significantly lower in low fructose consumers when compared to normal and high fructose consumers (median: 36.1 mu mol/24 h, IQR: 26.4-64.2; 142.3 mu mol/24 h, 98.8-203.0; and 238.9 mu mol/24 h, 127.1-366.1; p = 0.004 and p <0.001, respectively). Conclusion: Fructose concentrations can be measured accurately and precisely with this newly-developed UPLC-MS/MS method. Its robustness makes it suitable for assessing the value of fructose in clinical studies

Developmental neurobiology as a guide for pharmacological management of pain in neonates

Pain in newborn children should be prevented due to negative short- and long-term consequences. A good understanding of the development of the nociceptive system in newborns is necessary to enable optimal pain assessment, and most importantly to treat and prevent pain adequately in neonates. So far, preclinical juvenile animal studies have led to a tremendous amount of information regarding the development of the nociceptive system. In addition, they have made clear that the developmental stage of the nociceptive system may influence the mechanism of action of different classes of analgesics. Age specific analgesic therapy, based on post-menstrual age, should therefore be considered by incorporating information on the developmental stages of the nociceptive system in combination with knowledge from pharmacokinetic and -dynamic studies in neonates.status: publishe

Effects of fructose restriction on liver steatosis (FRUITLESS); a double-blind randomized controlled trial

BACKGROUND: There is an ongoing debate on whether fructose plays a role in the development of nonalcoholic fatty liver disease. OBJECTIVES: The aim of this study was to investigate the effects of fructose restriction on intrahepatic lipid (IHL) content in a double-blind randomized controlled trial using an isocaloric comparator. METHODS: Between March 2017 and October 2019, 44 adult overweight individuals with a fatty liver index ≥ 60 consumed a 6-wk fructose-restricted diet (<7.5 g/meal and <10 g/d) and were randomly assigned to supplementation with sachets of glucose (= intervention group) or fructose (= control group) 3 times daily. Participants and assessors were blinded to the allocation. IHL content, assessed by proton magnetic resonance spectroscopy, was the primary outcome and glucose tolerance and serum lipids were the secondary outcomes. All measurements were conducted in Maastricht University Medical Center. RESULTS: Thirty-seven participants completed the study protocol. After 6 wk of fructose restriction, dietary fructose intake and urinary fructose excretion were significantly lower in the intervention group (difference: -57.0 g/d; 95% CI: -77.9, -39.5 g/d; and -38.8 μmol/d; 95% CI: -91.2, -10.7 μmol/d, respectively). Although IHL content decreased in both the intervention and control groups (P < 0.001 and P = 0.003, respectively), the change in IHL content was more pronounced in the intervention group (difference: -0.7% point, 95% CI: -2.0, -0.03% point). The changes in glucose tolerance and serum lipids were not significantly different between groups. CONCLUSIONS: Six weeks of fructose restriction per se led to a small, but statistically significant, decrease in IHL content in comparison with an isocaloric control group.This trial was registered at clinicaltrials.gov as NCT03067428

Developmental neurobiology as a guide for pharmacological management of pain in neonates

Pain in newborn children should be prevented due to negative short- and long-term consequences. A good understanding of the development of the nociceptive system in newborns is necessary to enable optimal pain assessment, and most importantly to treat and prevent pain adequately in neonates. So far, preclinical juvenile animal studies have led to a tremendous amount of information regarding the development of the nociceptive system. In addition, they have made clear that the developmental stage of the nociceptive system may influence the mechanism of action of different classes of analgesics. Age specific analgesic therapy, based on post-menstrual age, should therefore be considered by incorporating information on the developmental stages of the nociceptive system in combination with knowledge from pharmacokinetic and dynamic studies in neonates