4-cresol-sulfate and Heart-Failure

The clearance of protein-bound solutes by the proximal tubules is an innate kidney mechanism for removing putative uremic toxins that could exert cardiovascular toxicity in humans. However, potential associations between impaired kidney clearances of secretory solutes and cardiovascular events among patients with chronic kidney disease (CKD) remains uncertain.. A multicenter, prospective, cohort study.. We evaluated 3,407 participants from the Chronic Renal Insufficiency Cohort (CRIC) study.. Baseline kidney clearances of 8 secretory solutes. We measured concentrations of secretory solutes in plasma and paired 24-hour urine specimens using liquid chromatography-tandem mass spectrometry (LC-MS/MS).. Incident heart failure, myocardial infarction, and stroke events.. We used Cox regression to evaluate associations of baseline secretory solute clearances with incident study outcomes adjusting for estimated GFR (eGFR) and other confounders.. Participants had a mean age of 56 years; 45% were women; 41% were Black; and the median estimated glomerular filtration rate (eGFR) was 43 mL/min/1.73 m. Exclusion of patients with severely reduced eGFR at baseline; measurement variability in secretory solutes clearances.. In a national cohort study of CKD, no clinically or statistically relevant associations were observed between the kidney clearances of endogenous secretory solutes and incident heart failure, myocardial infarction, or stroke after adjustment for eGFR. These findings suggest that tubular secretory clearance provides little additional information about the development of cardiovascular disease events beyond glomerular measures of GFR and albuminuria among patients with mild-to-moderate CKD.

Topics: Aged; Albuminuria; Chromatography, Liquid; Cohort Studies; Cresols; Female; Glomerular Filtration Rate; Glycine; Heart Failure; Humans; Incidence; Indican; Kidney Tubules; Kynurenic Acid; Male; Middle Aged; Myocardial Infarction; Organic Anion Transporters; Proportional Hazards Models; Prospective Studies; Pyridoxic Acid; Renal Insufficiency, Chronic; Ribonucleosides; Stroke; Sulfuric Acid Esters; Tandem Mass Spectrometry; Xanthines

Amino acid-derived metabolites, including protein-bound uremic toxins, may have prognostic value for patients with heart failure (HF). The aim of this study was to investigate whether p-cresyl sulfate (PCS), indoxyl sulfate (IS), and arginine metabolites provided prognostic values in addition to the traditional biomarker, B-type natriuretic peptide (BNP), in patients with HF. Chromatography mass spectrometry was performed to measure tyrosine, tryptophan, arginine, PCS, IS, and asymmetric (ADMA) and symmetric dimethylarginine (SDMA) in the plasma from 51 normal controls and 136 HF patients. Compared to the normal controls, PCS levels significantly increased in HF patients (p = 0.003). During the follow-up (2.3 ± 1.1 years), 35 (25.7 %) patients experienced a composite event of death or HF-related re-hospitalization. In univariable analysis, PCS, estimated glomerular filtration rate (eGFR), BNP, DMA/arginine ratio, and ADMA/arginine ratio were associated with a higher rate of composite events. In the multivariable analysis, PCS was the only independent predictor of composite events [hazard ratio (HR) 1.06 (per 10 μM), 95 % confidence interval (CI) 1.01-1.11, p = 0.02]. Kaplan-Meier curves showed that a PCS level of ≥50 μM was significantly associated with a higher composite event rate than those with a PCS level of <50 μM (Log rank = 5.11, p = 0.024; HR 2.13, 95 % CI 1.09-4.16, p = 0.02). In conclusion, among protein-bound uremic toxins, eGFR, and DMA metabolites, increased PCS is the only independent predictor of HF-related events in patients with HF. A combination of PCS and BNP should better risk-stratify patients with HF.

Topics: Adult; Aged; Aged, 80 and over; Arginine; Biomarkers; Case-Control Studies; Chi-Square Distribution; Chromatography, Liquid; Cresols; Female; Heart Failure; Humans; Indican; Kaplan-Meier Estimate; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Prospective Studies; Reproducibility of Results; Risk Factors; Spectrometry, Mass, Electrospray Ionization; Sulfuric Acid Esters; Time Factors; Up-Regulation; Young Adult

Global longitudinal strain (GLS) has emerged as a superior method for detecting left ventricular (LV) systolic dysfunction compared to ejection fraction (EF) on the basis that it is less operator dependent and more reproducible. The 2-dimensional strain (2DS) method is easily measured and integrated into a standard echocardiogram. This study aimed to determine the relationship between GLS and traditional and chronic kidney disease (CKD)-related risk factors of cardiovascular disease (CVD) in patients with CKD.. A cross sectional study of patients with moderate CKD stages 3 and 4 (n = 136). Clinical characteristics, anthropometric, biochemical data including markers of inflammation [C-reactive protein (CRP)], uremic toxins [indoxyl sulphate (IS), p-cresyl sulphate (PCS)], and arterial stiffness [pulse wave velocity (PWV)] were measured. Inducible ischemia was detected using exercise stress echocardiogram. GLS was determined from 3 standard apical views using 2-dimensional speckle tracking and EF was measured using Simpson's rule. Associations between GLS and traditional and CKD-related risk factors were explored using multivariate models.. The study population parameters included: age 59.4 ± 9.8 years, 58 % male, estimated glomerular filtration rate (eGFR) 44.4 ± 10.1 ml/min/1.73 m(2), GLS -18.3 ± 3.6 % and EF 65.8 % ± 7.8 %. This study demonstrated that GLS correlated with diabetes (r = 0.21, p = 0.01), history of heart failure (r = 0.20, p = 0.01), free IS (r = 0.24, p = 0.005) free PCS (r = 0.23, p = 0.007), body mass index (BMI) (r = 0.28, p < 0.001), and PWV (r = 0.24, p = 0.009). Following adjustment for demographic, baseline co-morbidities and laboratory parameters, GLS was independently associated with free IS, BMI and arterial stiffness (R(2) for model =  .30, p < 0.0001).. In the CKD cohort, LV systolic function assessed using GLS was associated with uremic toxins, obesity and arterial stiffness.

Topics: Aged; Body Mass Index; Cresols; Cross-Sectional Studies; Diabetes Mellitus; Exercise Test; Female; Glomerular Filtration Rate; Heart Failure; Humans; Indican; Male; Middle Aged; Renal Insufficiency, Chronic; Risk Factors; Sulfuric Acid Esters; Ultrasonography; Vascular Stiffness; Ventricular Dysfunction, Left