Is 3-Carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) a Clinically Relevant Uremic Toxin in Haemodialysis Patients?
ABSTRACT: 3-Carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) is a metabolite of furan fatty acid and a marker of fish oil intake. CMPF is described as a protein-bound uremic toxin and interacts with free oxygen radicals, which can induce cell damages. However, the clinical consequences of CMPF accumulation in haemodialysis patients remain poorly documented. The aims of this study are to investigate potential association between CMPF levels and (i) biochemical and nutritional parameters; (ii) cardiovascular events and (iii) mortality. Two hundred and fifty-two patients undergoing maintenance haemodialysis were included. Routine clinical biochemistry tests and assay for CMPF by HPLC technique were performed at the inclusion. Body composition parameters were measured using a bioimpedance spectroscopy method. The enrolled patients were prospectively monitored for cardiovascular events and mortality. CMPF level was positively correlated with nutritional parameters and lean mass and is significantly higher in patients without protein-energy wasting. However, the multivariate linear regression analysis indicated that CMPF level was not independently associated with albumin, prealbumin, creatinemia and body mass index. Elevated serum CMPF was not associated with mortality and cardiovascular morbidity. Our results indicate that CMPF is not a relevant uremic toxin in haemodialysis and in contrast could be a marker of healthy diet and omega 3 intakes.
Project description:OBJECTIVE:3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) is a metabolite produced endogenously from dietary sources of furan fatty acids. The richest source of furan fatty acids in human diet is fish. CMPF was recently shown to be elevated in fasting plasma in individuals with gestational diabetes and type 2 diabetes, and mechanistically high level of CMPF was linked to ? cell dysfunction. Here we aimed to study the association between plasma CMPF level and glucose metabolism in persons with impaired glucose metabolism. METHODS:Plasma CMPF concentration was measured from plasma samples of the study participants in an earlier controlled dietary intervention. All of them had impaired glucose metabolism and two other characteristics of the metabolic syndrome. Altogether 106 men and women were randomized into three groups for 12 weeks with different fish consumption (either three fatty fish meals per week, habitual fish consumption or maximum of one fish meal per week). Associations between concentration of CMPF and various glucose metabolism parameters at an oral glucose tolerance test at baseline and at the end of the study were studied. RESULTS:Fasting plasma CMPF concentration was significantly increased after a 12-week consumption of fatty fish three times per week, but the concentration remained much lower compared to concentrations reported in diabetic patients. Increases of plasma CMPF concentrations mostly due to increased fish consumption were not associated with impaired glucose metabolism in this study. Instead, elevated plasma CMPF concentration was associated with decreased 2-hour insulin concentration in OGTT. CONCLUSIONS:Moderately elevated concentration of CMPF in plasma resulting from increased intake of fish is not harmful to glucose metabolism. Further studies are needed to fully explore the role of CMPF in the pathogenesis of impaired glucose metabolism. TRIAL REGISTRATION:ClinicalTrials.gov NCT00573781.
Project description:Previous studies have found that 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) was associated with diabetes. This study aimed to investigate the relationship between abnormal increased CMPF levels and gestational diabetes mellitus (GDM).We recruited 828 pregnant women, and all of them underwent an oral glucose tolerance test (OGTT). We screened out 141 GDM patients and 230 pregnant women with normal glucose tolerance as controls. The serum CMPF concentration in participants was measured, and the relationship between the serum CMPF concentration and various parameters and biochemical indices was analyzed.Compared with the serum levels in pregnant women with normal glucose tolerance, GDM patients exhibited markedly higher serum CMPF levels. The serum CMPF concentration showed an independent positive correlation with the blood glucose levels, glycated hemoglobin A1c(HbA1c), and the area under the glucose-time curve from the 2-h OGTT (AUC for glucose). Moreover, the CMPF concentration was independently negatively correlated with insulin secretion. However, CMPF was not significantly associated with lipid metabolism.Elevated serum CMPF levels are detrimental to the development of hyperglycemia and islet ?-cell functional failure in patients with GDM, which may promote the development of GDM.
Project description:Examining the effect of CMPF treatment in the livers of mice. This study examines both the prevention and reversal of steatosis. We used arrays to determine the pathways through which CMPF prevents and reverses steatosis Overall design: In the prevention model, mice were treated for one week prior to being changed to a HFD for 4-5 weeks. The reversal model, mice were fed a HFD for 6 weeks followed by 2 weeks of CMPF treatment.
Project description:Prescription ?-3 fatty acid ethyl ester supplements are commonly used for the treatment of hypertriglyceridemia. However, the metabolic profile and effect of the metabolites formed by these treatments remain unknown. Here we utilized unbiased metabolomics to identify 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) as a significant metabolite of the ?-3-acid ethyl ester prescription Lovaza™ in humans. Administration of CMPF to mice before or after high-fat diet feeding at exposures equivalent to those observed in humans increased whole-body lipid metabolism, improved insulin sensitivity, increased beta-oxidation, reduced lipogenic gene expression, and ameliorated steatosis. Mechanistically, we find that CMPF acutely inhibits ACC activity, and induces long-term loss of SREBP1c and ACC1/2 expression. This corresponds to an induction of FGF21, which is required for long-term steatosis protection, as FGF21KO mice are refractory to the improved metabolic effects. Thus, CMPF treatment in mice parallels the effects of human Lovaza™ supplementation, revealing that CMPF may contribute to the improved metabolic effects observed with ?-3 fatty acid prescriptions.
Project description:BACKGROUND:Thrice-weekly haemodialysis is the usual dose when starting renal replacement therapy; however, this schedule is no longer appropriate since it does not consider residual renal function. Several reports have suggested the potential benefit of beginning haemodialysis less frequently and incrementally increasing the dose as the residual renal function decreases. However, all the data published so far are from observational studies. Thus, this clinical trial avoids any potential selection bias and will assess the possible benefits that have been observed in observational studies. METHODS/DESIGN:This report describes the study protocol of a randomized prospective multi-centre open-label clinical trial to evaluate whether starting renal replacement therapy with twice-weekly haemodialysis sessions preserves residual renal function better than the standard thrice-weekly regimen. We also explore other clinical parameters, such as concentrations of uremic toxins, dialysis doses, control of anaemia, removal of medium-weight uremic toxins, nutritional status, quality of life, hospital admissions and mortality. Only incident haemodialysis patients who can maintain a urea clearance rate KrU ? 2.5?mL/min/1.73?m2 are eligible. Patient recruitment began on 1 January 2017 and will last for 2 years or until the required sample size has been recruited to ensure the established statistical power has been reached. The minimum follow-up period will be 1 year. Anuric patients with acute renal failure and patients who return to haemodialysis after a kidney transplant failure are excluded. It has been calculated that 44 patients should be recruited into each group to achieve a power of 80% in a two-sided comparison of means with a usual significance level of 0.05. A time-to-event analysis will estimate the probability of kidney function survival in both groups using the Kaplan-Meier method. Survival curves will be compared with log-rank tests. This survival analysis will be complemented with a proportional hazard model to estimate the hazard ratio of kidney function survival adjusted for any confounding factors. Analyses will be carried out in accordance with the intention-to-treat principle. DISCUSSION:The incremental initiation of dialysis may preserve residual renal function better than the conventional treatment, with similar or higher survival rates, as reported by observational studies. To our knowledge, this is the first clinical trial to evaluate whether initiating renal replacement therapy with twice-weekly haemodialysis sessions preserves residual renal function better than beginning with the standard thrice-weekly regimen. TRIAL REGISTRATION:ClinicalTrials.gov, NCT03302546. Registered on 5 October 2017.
Project description:OBJECTIVES:While maintenance of both phosphorus concentration and nutritional status is a major concern in managing haemodialysis patients, the interaction between these parameters is not well understood. The aim of this study was to assess whether or not nutritional index influences the association between phosphorus concentration and all-cause mortality. DESIGN:A cohort study. SETTING:The Dialysis Outcomes and Practice Pattern Study, which included 99 representative dialysis facilities in Japan between 1997 and 2010. PARTICIPANTS:A total of 6230 adult haemodialysis patients who had spent at least 6?months on haemodialysis. MAIN PREDICTORS:Six categories based on time-averaged factors of the geriatric nutritional risk index (GNRI; the lowest two and highest tertiles) and phosphorus concentration (<3.5, 3.5 to <6 and ?6?mg/dL). PRIMARY OUTCOME MEASURE:All-cause mortality rate. ANALYSIS:Time-dependent Cox regression adjusting for potential confounders. RESULTS:During the follow-up period (12?294 person-years), we noted 561 deaths (4.6 per 100 person-years), and both high phosphorus concentrations and low-middle GNRI were separately associated with all-cause mortality. The harmful effect of high phosphorus concentrations on all-cause mortality was stronger in patients with high GNRI than in those with low-middle GNRI. On the other hand, the harmful effect of low phosphorus concentrations was stronger in those with low-middle GNRI than in those with high GNRI. Relative excess risk due to interaction (RERI) between high phosphorus concentrations and low-middle GNRI was -0.57, indicating an antagonistic interaction. We also observed a significant statistical multiplicative interaction between phosphorus concentrations and GNRI (p=0.05 by likelihood ratio test). CONCLUSIONS:The association between time-averaged serum phosphorus concentration and all-cause mortality differs across the nutritional index. Accordingly, nutritional index should be considered when the impact of phosphorus concentration on mortality in haemodialysis patients is evaluated.
Project description:CMPF is elevated in diabetes and is associated with impaired insulin secretion. We used microarrays to determine the effect of CMPF on gene expression in isolated islets. Isolated islets from male CD1 mice were treated for 24h with vehicle control or 200uM CMPF.
Project description:Cardiovascular mortality is high in ESRD, partly driven by sudden cardiac death and recurrent heart failure due to uremic cardiomyopathy. We investigated whether speckle-tracking echocardiography is superior to routine echocardiography in early detection of uremic cardiomyopathy in animal models and whether it predicts cardiovascular mortality in patients undergoing dialysis. Using speckle-tracking echocardiography in two rat models of uremic cardiomyopathy soon (4-6 weeks) after induction of kidney disease, we observed that global radial and circumferential strain parameters decreased significantly in both models compared with controls, whereas standard echocardiographic readouts, including fractional shortening and cardiac output, remained unchanged. Furthermore, strain parameters showed better correlations with histologic hallmarks of uremic cardiomyopathy. We then assessed echocardiographic and clinical characteristics in 171 dialysis patients. During the 2.5-year follow-up period, ejection fraction and various strain parameters were significant risk factors for cardiovascular mortality (primary end point) in a multivariate Cox model (ejection fraction hazard ratio [HR], 0.97 [95% confidence interval (95% CI), 0.95 to 0.99; P=0.012]; peak global longitudinal strain HR, 1.17 [95% CI, 1.07 to 1.28; P<0.001]; peak systolic and late diastolic longitudinal strain rates HRs, 4.7 [95% CI, 1.23 to 17.64; P=0.023] and 0.25 [95% CI, 0.08 to 0.79; P=0.02], respectively). Multivariate Cox regression analysis revealed circumferential early diastolic strain rate, among others, as an independent risk factor for all-cause mortality (secondary end point; HR, 0.43; 95% CI, 0.25 to 0.74; P=0.002). Together, these data support speckle tracking as a postprocessing echocardiographic technique to detect uremic cardiomyopathy and predict cardiovascular mortality in ESRD.
Project description:Background/aim:Malnutrition is an important and commonly seen prognostic factor in patients with cirrhosis. The diagnosis of malnutrition in cirrhosis patients may be challenging, and an easily measured and widely usable marker is lacking. Prealbumin, however, is an easily measured marker. In the current study we measured prealbumin levels in cirrhotic patients with no clinically apparent malnutrition and used it as a malnutrition marker. Another aim of this study was to evaluate the effect of nutritional support on patient with low prealbumin levels. Materials and methods:Fifty-two patients with Child A and Child B cirrhosis were selected for the study. Prealbumin levels were studied, and Child and MELD scores were calculated. Patients with prealbumin levels ?180 mg/L were considered to have malnutrition, and two different types of nutritional products were given to these patients. The patients given nutritional support were investigated a month later, and parameters were compared. Results:According to the prealbumin threshold of 180 mg/L, malnutrition frequencies were 59.3% for Child A and 95% for Child B cirrhosis. After the provision of nutritional support statistically significant improvements in albumin and INR levels were detected. In addition, the MELD score decreased; however, it was not statistically significant (P: 0.088). A statistically significant decrease in the MELD score was only obtained in patients with Child B cirrhosis (P: 0.033). When the oral replacement therapies were investigated separately, a statistically significant decrease in MELD scores was detected with product 1 (P: 0.043). Conclusion:Prealbumin can be used as an easily measured parameter for earlier detection of malnutrition in patients with cirrhosis and without clinically apparent malnutrition. Oral nutritional support, especially with products containing relatively high carbohydrate levels and low protein, may have a favorable effect on MELD scores.
Project description:In vitro data indicates that the kidney proximal tubule (PT) transporters of uremic toxins and solutes (e.g., indoxyl sulfate, p-cresol sulfate, kynurenine, creatinine, urate) include two "drug" transporters of the organic anion transporter (OAT) family: OAT1 (SLC22A6, originally NKT) and OAT3 (SLC22A8). Here, we have examined new and prior metabolomics data from the Oat1KO and Oat3KO, as well as newly obtained metabolomics data from a "chemical double" knockout (Oat3KO plus probenecid). This gives a picture of the in vivo roles of OAT1 and OAT3 in the regulation of the uremic solutes and supports the centrality of these "drug" transporters in independently and synergistically regulating uremic metabolism. We demonstrate a key in vivo role for OAT1 and/or OAT3 in the handling of over 35 uremic toxins and solutes, including those derived from the gut microbiome (e.g., CMPF, phenylsulfate, indole-3-acetic acid). Although it is not clear whether trimethylamine-N-oxide (TMAO) is directly transported, the Oat3KO had elevated plasma levels of TMAO, which is associated with cardiovascular morbidity in chronic kidney disease (CKD). As described in the Remote Sensing and Signaling (RSS) Hypothesis, many of these molecules are involved in interorgan and interorganismal communication, suggesting that uremia is, at least in part, a disorder of RSS.