Serum free p-cresyl sulfate levels predict cardiovascular and all-cause mortality in elderly hemodialysis patients--a prospective cohort study

254

225

In CKD, uremic solutes may induce endothelial dysfunction, inflammation, and oxidative stress, leading to increased cardiovascular risk. We investigated whether the uremic solute indole-3 acetic acid (IAA) predicts clinical outcomes in patients with CKD and has prooxidant and proinflammatory effects. We studied 120 patients with CKD. During the median study period of 966 days, 29 patients died and 35 experienced a major cardiovascular event. Kaplan-Meier analysis revealed that mortality and cardiovascular events were significantly higher in the higher IAA group (IAA.3.73 mM) than in the lower IAA group (IAA,3.73 mM). Multivariate Cox regression analysis demonstrated that serum IAA was a significant predictor of mortality and cardiovascular events after adjustments for age and sex; cholesterol, systolic BP, and smoking; C-reactive protein, phosphate, body mass index, and albumin; diastolic BP and history of cardiovascular disease; and uremic toxins p-cresyl sulfate and indoxyl sulfate. Notably, IAA level remained predictive of mortality when adjusted for CKD stage. IAA levels were positively correlated with markers of inflammation and oxidative stress: C-reactive protein and malondialdehyde, respectively. In cultured human endothelial cells, IAA activated an inflammatory nongenomic aryl hydrocarbon receptor (AhR)/p38MAPK/NF-kB pathway that induced the proinflammatory enzyme cyclooxygenase-2. Additionally, IAA increased production of endothelial reactive oxygen species. In conclusion, serum IAA may be an independent predictor of mortality and cardiovascular events in patients with CKD. In vitro, IAA induces endothelial inflammation and oxidative stress and activates an inflammatory AhR/p38MAPK/NF-kB pathway.

Section: Discussionmentioning

confidence: 75%

The Cardiovascular Effect of the Uremic Solute Indole-3 Acetic Acid

Dou

Sallée

Cérini

et al. 2015

254

225

“…26,27 Recent studies confirmed that free pCS levels were predictive for mortality at different stages of CKD 28 and cardiovascular and all-cause mortality in hemodialysis patients. 29 The relation between pCS and coronary artery disease in patients with no or only moderate degrees of CKD 30 extends the association of this compound with cardiovascular outcomes beyond the scope of pronounced uremia. 31 In clinical studies, it is difficult to determine whether a given uremic toxin intrinsically has deleterious effects or is merely an inert biomarker for the degree of renal dysfunction.…”

Section: Discussionmentioning

confidence: 89%

Protein-Bound Uremic Toxins Stimulate Crosstalk between Leukocytes and Vessel Wall

Pletinck

Glorieux

Schepers

et al. 2013

Leukocyte activation and endothelial damage both contribute to cardiovascular disease, a major cause of morbidity and mortality in CKD. Experimental in vitro data link several protein-bound uremic retention solutes to the modulation of inflammatory stimuli, including endothelium and leukocyte responses and cardiovascular damage, corroborating observational in vivo data. However, the impact of these uremic toxins on the crosstalk between endothelium and leukocytes has not been assessed. This study evaluated the effects of acute and continuous exposure to uremic levels of indoxylsulfate (IS), p-cresylsulfate (pCS), and p-cresylglucuronide (pCG) on the recruitment of circulating leukocytes in the rat peritoneal vascular bed using intravital microscopy. Superfusion with IS induced strong leukocyte adhesion, enhanced extravasation, and interrupted blood flow, whereas pCS caused a rapid increase in leukocyte rolling. Superfusion with pCS and pCG combined caused impaired blood flow and vascular leakage but did not further enhance leukocyte rolling over pCS alone. Intravenous infusion with IS confirmed the superfusion results and caused shedding of heparan sulfate, pointing to disruption of the glycocalyx as the mechanism likely mediating IS-induced flow stagnation. These results provide the first clear in vivo evidence that IS, pCS, and pCG exert proinflammatory effects that contribute to vascular damage by stimulating crosstalk between leukocytes and vessels.

“…57,58 Both indoxyl sulfate and p-cresyl sulfate per se have repeatedly been related to cardiovascular mortality. [10][11][12][13][14][15][16][17][18][19] Although strategies that more efficiently remove proteinbound solutes, such as frequent dialysis 59 and online hemodiafiltration, 60,61 in controlled studies are associated with improved outcomes, 62,63 it remains difficult to interpret these data because of the presence of confounding factors that affect the outcomes on their own and a lack of selectivity of removal, because dialysis strategies are usually not restricted to protein-bound solutes alone.…”

Section: Discussionmentioning

confidence: 99%

“…8,9 In the past decade, however, a growing number of publications documented the impact of protein-bound uremic toxins on vital processes and an association of their concentration with clinical outcome parameters. 6,[10][11][12][13][14][15][16][17][18][19] One factor blurring the interpretation of the biochemical effects of uremic toxins is the application of unrealistic concentrations compared with the concentrations observed in human CKD in in vitro testing or in vivo animal experiments. 4,20 Moreover, for protein-bound toxins, even with seemingly acceptable total concentrations, the quantities of albumin or protein present are often too low, resulting in unacceptably high and thus, irrelevant free concentrations.…”

mentioning

confidence: 99%

The Uremic Toxicity of Indoxyl Sulfate and p-Cresyl Sulfate

Vanholder

Schepers

Pletinck

et al. 2014

558

463

A growing number of publications supports a biologic effect of the protein-bound uremic retention solutes indoxyl sulfate and p-cresyl sulfate. However, the use of unrealistically high free concentrations of these compounds and/or inappropriately low albumin concentrations may blur the interpretation of these results. Here, we performed a systematic review, selecting only studies in which, depending on the albumin concentration, real or extrapolated free concentrations of indoxyl sulfate and p-cresyl sulfate remained in the uremic range. The 27 studies retrieved comprised in vitro and animal studies. A quality score was developed, giving 1 point for each of the following criteria: six or more experiments, confirmation by more than one experimental approach, neutralization of the biologic effect by counteractive reagents or antibodies, use of a real-life model, and use of dose-response analyses in vitro and/or animal studies. The overall average score was 3 of 5 points, with five studies scoring 5 of 5 points and six studies scoring 4 of 5 points, highlighting the superior quality of a substantial number of the retrieved studies. In the 11 highest scoring studies, most functional deteriorations were related to uremic cardiovascular disease and kidney damage. We conclude that our systematic approach allowed the retrieval of methodologically correct studies unbiased by erroneous conditions related to albumin binding. Our data seem to confirm the toxicity of indoxyl sulfate and p-cresyl sulfate and support their roles in vascular and renal disease progression.