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Introduction and Aims: Serum p-cresyl sulfate associates with cardiovascular disease in patients at different stages of chronic kidney disease. p-Cresyl sulfate concentrations are determined by intestinal uptake of p-cresol, human metabolism to p-cresyl sulfate and renal clearance. Whether intestinal uptake of p-cresol itself is associated with cardiovascular disease in patients with renal disease has not been studied to date. Methods: We performed a prospective study in patients with chronic kidney disease stage 1-5 (clinicaltrials.gov NCT00441623). Intestinal uptake of p-cresol, under steady state conditions, was estimated from 24h urinary excretion of p-cresyl sulfate. Primary endpoint was time to first cardiovascular event, i.e. cardiac death, myocardial infarction/ischemia, ventricular arythmia, cardiovascular surgery, cerebrovascular accident or symptomatic peripheral arterial disease. Statistical analysis was done using Kaplan Meier estimates and Cox proportional hazard analyses. Results: In a cohort of 200 patients, median 24h urinary excretion of p-cresyl sulfate was 457.47 µmol (IQR 252.68-697.17). After a median follow-up of 52 months, 25 patients reached the primary endpoint (tertile 1/2/3: 5/6/14 events, log rank P 0.0368, see figure). Higher urinary excretion of p-cresyl sulfate was related with cardiovascular events (univariate hazard ratio per 100 µmol increase: 1.112, P 0.0015). In multivariate analysis, urinary excretion of p-cresyl sulfate remained a predictor of cardiovascular events, independent of markers of renal function (Hazard ratio 1.120, P 0.0022) and in different models with other cardiovascular risk factors (Framingham risk factors, cardiovascular history, diabetes mellitus and biochemical parameters). The independent association between urinary excretion of p-cresyl sulfate and outcome persisted after correction for serum p-cresyl sulfate. Conclusions: Intestinal uptake of p-cresol associates with cardiovascular disease independent of renal function. Insights into mechanisms governing intestinal generation and absorption of p-cresol may lead to identification of novel therapeutic targets to reduce cardiovascular disease risk in patients with chronic kidney disease.

Chronic kidney disease (CKD) carries an unequivocal high risk for cardiovascular disease (CVD) contributing to high morbimortality; however, the underlying reasons are not fully known. Among mechanisms involved in the pathophysiology of CVD, chronic overstimulation of the advanced glycation end-products (AGE)–receptor for AGE (RAGE) pathway is likely a major contributor in patients with CKD. This review describes briefly some of the components of this pathway, highlighting especially differences between circulating AGE and tissue AGE and how activation of the AGE–RAGE pathway may promote CVD in CKD.

Background Circulating advanced glycated end-products (AGEs) including pentosidine accumulating in chronic kidney disease (CKD) patients due to retention and increased formation are thought to contribute to cardiovascular disease (CVD). Here we evaluated factors linked to increased plasma pentosidine and its association with mortality in patients with different stages of CKD and undergoing different treatments. Methods Plasma pentosidine, biomarkers of inflammation, oxidative stress and nutritional status were investigated in CKD 1–2 (n = 37), CKD 3–4 (n = 54), CKD 5 non-dialyzed (CKD5-ND; n = 386), peritoneal dialysis (PD; n = 74) and hemodialysis (HD; n = 195) patients. Factors predicting plasma pentosidine were analysed by multivariate regression analysis and mortality risk was assessed by GENMOD procedure. Results Plasma pentosidine levels, which were higher in CKD5-ND, PD and HD groups than in CKD 1–2 group, were significantly lower in PD than in HD patients, and not different between PD patients and CKD5-ND patients. Pentosidine associated inversely with glomerular filtration rate (GFR), and additionally in PD with 8-hydroxy-2‘-deoxyguanosine (8-OHdG), and interleukin 6 (IL-6); in HD with age, IL-6 and body mass index (BMI); in CKD5-ND with age, 8-OHdG, IL-6, high-sensitive C-reactive protein (hsCRP), and soluble vascular cell adhesion protein-1 (sVCAM-1); in CKD 3–4 with 8-OHdG and sVCAM-1; and in CKD 1–2 with age and sVCAM-1. In multivariate analysis, age (one standard deviation, 1-SD higher), malnutrition (subjective global assessment, SGA), oxidative stress (8-OHdG, 1-SD higher), and belonging to CKD5-ND, HD and PD cohorts associated with 1-SD higher pentosidine. In GENMOD, 1-SD higher pentosidine independently predicted all-cause mortality (relative risk, RR = 1.04; 95% confidence interval, CI, 1.01–1.08, p = 0.01) and CVD mortality (RR = 1.03; 95% CI, 1.01–1.06, p = 0.03) after adjusting for all confounders. Conclusions Plasma pentosidine is markedly elevated in CKD and associates with low GFR, oxidative stress and inflammation, and is an independent predictor of mortality in CKD patients.

Background. Alterations in the advanced glycation end-products (AGE)—receptor of AGE (RAGE) system are linkedto several chronic diseases, which may result from vasculardamage. A high circulating level of the pro-inflammatoryRAGE-ligand S100A12, also known as EN-RAGE, is thoughtto promote while a high level of soluble RAGE (sRAGE) isthought to protect against development of atherosclerotic car-diovascular disease (CVD). We evaluated circulating S100A12and sRAGE in relation to clinical characteristics, nutritionalstatus, inflammation and mortality risk in chronic kidneydisease (CKD) Stage 5 patients starting on dialysis.Methods. Plasma S100A12 and sRAGE, biomarkers of inflam-mation and nutritional status, and comorbidities were investi-gated in 200 CKD Stage 5 patients [median age of 56 years,62% men and median glomerular filtration rate (GFR) of6.2 mL/min/1.73 m 2 ] in conjunction with initiation of dialysistherapy. Associations between mortality risk and S100A12 orsRAGE were assessed after a median follow-up period of23 months. In addition, for comparative analyses, S100A12and sRAGE levels were assessed also in 58 haemodialysis and78 peritoneal dialysis patients after 1 year of dialysis, 56 CKDStages 3–4 patients and 50 community-based control subjects.Results. The median level of S100A12 was 4-fold higher, mediansRAGE 2.4 higher and median ratio S100A12/sRAGE 2.27 timeshigher in CKD 5 patients than in controls. Similar alterationswere observed in CKD 3–4 patients; however, CKD 5 patientshad a higher median level of sRAGE than the CKD 3 –4patients.In the CKD 5 patients, S100A12 levels were higher in those withdiabetes or CVD than in those without these comorbidities. Fur-thermore, S100A12 correlated with high-sensitivity C-reactiveprotein (hsCRP) levels (ρ=0.53; P

OBJECTIVE—Impaired glucose tolerance (IGT) is believed to be a prediabetic phase that precedes the development of type 2 diabetes. In elderly subjects, IGT and diabetes are both independently associated with the occurrence of cardiovascular disease. Endothelial damage precedes atherosclerotic changes of the vascular wall. Therefore, several markers of endothelial dysfunction were examined in elderly subjects with IGT and elderly patients with type 2 diabetes. RESEARCH DESIGN AND METHODS—Von Willebrand factor (vWF), tissue plasminogen activator (t-PA), plasminogen activator inhibitor type-1 (PAI-1), and thrombomodulin were studied as markers of endothelial dysfunction in a population-based study of elderly subjects with normal glucose tolerance (NGT) or IGT and type 2 diabetes. In addition to these endothelium-dependent factors, we also investigated tissue factor pathway inhibitor (TFPI) activity in relation to metabolic parameters and cardiovascular risk factors. RESULTS—All data were adjusted for age. Increased levels of vWF antigen, t-PA antigen, and PAI-1 activity were seen in the IGT and diabetic group compared with the NGT group. TFPI activity and thrombomodulin levels were increased in all elderly subjects, and no differences were seen between the groups. There was a positive association between HbA1c and TFPI activity and vWF antigen. Fasting blood glucose levels correlated with vWF antigen, t-PA antigen, and PAI-1 activity, whereas urine albumin excretion correlated with TFPI activity, vWF antigen, and PAI-1 activity. Serum insulin levels correlated strongly not only with vWF antigen and t-PA antigen but also with PAI-1 activity. This correlation did not change after further adjustment for serum glucose and HbA1c, which may suggest that in the elderly subjects, impaired fibrinolysis is probably associated with insulin resistance. There were no associations between the endothelium-dependent hemostatic factors and lipids, except for a negative correlation between HDL cholesterol and thrombomodulin. CONCLUSIONS—In elderly subjects with IGT, several endothelium-dependent hemostatic factors are already consistently increased, indicating endothelial damage in this stage.