p-Cresyl sulfate

The p-Cresol is a protein-bound uremic retention solute ¹.

Free p-Cresol was found to be a cardiovascular risk factor in non-diabetic hemodialysis patients. In patients with diabetes, the level of both free p-cresol and total p-cresol were markedly higher. In patients treated by hemodialysis, the levels of these two forms of p-cresol were also significantly higher than that of patients treated by hemodiafiltration. The univariate cox proportional hazard analysis showed that the concentration of free p-cresol was obviously associated with cardiovascular disease (CVD). Quite many patients with high free p-cresol concentrations had new fatal or non-fatal cardiovascular events. Besides that, p-cresol was also found to inhibit cell proliferation. It inhibited the proliferation of cultured endothelial cells by 26% without affecting cell viability. Moreover, p-cresol treatment reduced endothelial wound repair by 19%, 28% and 40% at concentrations of 10, 25 and 50 μg/ml, respectively ^1,2.

References:
1. Meijers B K I, Bammens B, De Moor B, et al. Free p-cresol is associated with cardiovascular disease in hemodialysis patients. Kidney international, 2008, 73(10): 1174-1180.
2. Dou L, Bertrand E, Cerini C, et al. The uremic solutes p-cresol and indoxyl sulfate inhibit endothelial proliferation and wound repair. Kidney international, 2004, 65(2): 442-451.

p-Cresyl sulfate affects the oxidative burst, phagocytosis process, and antigen presentation of monocyte-derived macrophages.[Pubmed:27760375]

Toxicol Lett. 2016 Nov 30;263:1-5.

Immune system dysfunction is a common condition in chronic kidney disease (CKD). The present study investigated the effect of p-Cresyl sulfate (pCS) on human cell line U937 monocyte-derived macrophages (MDM) activity. MDM (1x10(6) cells/mL) were incubated with pCS (10, 25, or 50mug/mL), with or without lipopolysaccharide (LPS; 25ng/mL) and then evaluated NO production, phagocytosis and antigen-presenting molecules expression (HLA-ABC, HLA-DR, CD80 and CD86). All analyses were performed by flow cytometry. All pCS concentrations were able to increase NO production (49+/-12.1%, 39.8+/-7.75%, 43.7+/-11.9%, respectively) compared to untreated cells (4.35+/-3.34%) after 6h incubation but only the lowest concentration increased this production after 12h (82.9+/-8.6%, 61+/-7.2%, 40.8+/-11.7%). Combined with LPS, the same results were observed. Regarding to phagocytosis, all concentrations were able to induce bead engulfment (35.4+/-2.71%, 30+/-3.04%, 23.28+/-4.58%). In addition, pCS (50mug/mL) was able to increase HLA-ABC and CD80 expression, showed a slight effect on HLA-DR expression and, no difference in basal CD86 levels. pCS can induce an increased oxidative burst and phagocytosis by human macrophages while no modulation of HLA-DR or CD86 expression was induced. Together, these results suggest that pCS induces macrophage activation but interfere in antigen processing, leading to a failure in adaptive immune response in CKD.

Beta-Glucans Supplementation Associates with Reduction in P-Cresyl Sulfate Levels and Improved Endothelial Vascular Reactivity in Healthy Individuals.[Pubmed:28107445]

PLoS One. 2017 Jan 20;12(1):e0169635.

BACKGROUND: Oat and barley beta-glucans are prebiotic fibers known for their cholesterol-lowering activity, but their action on the human gut microbiota metabolism is still under research. Although the induction of short-chain fatty acids (SCFA) following their ingestion has previously been reported, no study has investigated their effects on proteolytic uremic toxins p-Cresyl sulfate (pCS) and indoxyl sulfate (IS) levels, while others have failed to demonstrate an effect on the endothelial function measured through flow-mediated dilation (FMD). OBJECTIVE: The aim of our study was to evaluate whether a nutritional intervention with a functional pasta enriched with beta-glucans could promote a saccharolytic shift on the gut microbial metabolism and improve FMD. METHODS: We carried out a pilot study on 26 healthy volunteers who underwent a 2-month dietary treatment including a daily administration of Granoro "Cuore Mio" pasta enriched with barley beta-glucans (3g/100g). Blood and urine routine parameters, serum pCS/IS and FMD were evaluated before and after the dietary treatment. RESULTS: The nutritional treatment significantly reduced LDL and total cholesterol, as expected. Moreover, following beta-glucans supplementation we observed a reduction of serum pCS levels and an increase of FMD, while IS serum levels remained unchanged. CONCLUSIONS: We demonstrated that a beta-glucans dietary intervention in healthy volunteers correlates with a saccharolytic shift on the gut microbiota metabolism, as suggested by the decrease of pCS and the increase of SCFA, and associates with an improved endothelial reactivity. Our pilot study suggests, in addition to cholesterol, novel pCS-lowering properties of beta-glucans, worthy to be confirmed in large-scale trials and particularly in contexts where the reduction of the microbial-derived uremic toxin pCS is of critical importance, such as in chronic kidney disease.

p-Cresyl Sulfate.[Pubmed:28146081]

Toxins (Basel). 2017 Jan 29;9(2). pii: toxins9020052.

If chronic kidney disease (CKD) is associated with an impairment of kidney function, several uremic solutes are retained. Some of these exert toxic effects, which are called uremic toxins. p-Cresyl sulfate (pCS) is a prototype protein-bound uremic toxin to which many biological and biochemical (toxic) effects have been attributed. In addition, increased levels of pCS have been associated with worsening outcomes in CKD patients. pCS finds its origin in the intestine where gut bacteria metabolize aromatic amino acids, such as tyrosine and phenylalanine, leading to phenolic end products, of which pCS is one of the components. In this review we summarize the biological effects of pCS and its metabolic origin in the intestine. It appears that, according to in vitro studies, the intestinal bacteria generating phenolic compounds mainly belong to the families Bacteroidaceae, Bifidobacteriaceae, Clostridiaceae, Enterobacteriaceae, Enterococcaceae, Eubacteriaceae, Fusobacteriaceae, Lachnospiraceae, Lactobacillaceae, Porphyromonadaceae, Staphylococcaceae, Ruminococcaceae, and Veillonellaceae. Since pCS remains difficult to remove by dialysis, the gut microbiota could be a future target to decrease pCS levels and its toxicity, even at earlier stages of CKD, aiming at slowing down the progression of the disease and decreasing the cardiovascular burden.

p-Cresyl sulfate promotes the formation of atherosclerotic lesions and induces plaque instability by targeting vascular smooth muscle cells.[Pubmed:27527366]

Front Med. 2016 Sep;10(3):320-9.

Coronary atherosclerosis is a major complication of chronic kidney disease. This condition contributes to the increased mortality in dialysis patients. p-Cresyl sulfate (PCS) is a prototype of protein-bound uremic toxins that cannot be efficiently removed through routine dialysis procedures. In the present study, ApoE(-/-) mice that underwent 5/6 nephrectomy were randomly divided into two groups, namely, vehicle-treated group (n = 20) and PCS-treated group (n = 20). Mice were sacrificed for en face and immunohistological analyses after 8 or 24 weeks of high-fat diet. Rat aortic vascular smooth muscle cells (VSMCs) were treated with phosphate buffer solution or 500 mumol/L PCS for in vitro evaluation. PCS-treated mice were observed to suffer increased atherosclerotic lesions after eight weeks of PCS administration. Moreover, 24 weeks of PCS administration also markedly increased the vulnerability index of aortic plaques. PCS was also observed to facilitate the migration and proliferation of VSMCs during the progression of the disease. Moreover, PCS disturbed the balance between matrix metalloproteinases and tissue inhibitor of metalloproteinases within the plaques. Thus, PCS played a vital role in promoting atherogenesis and disturbing the stability of formed plaques probably by targeting VSMCs.