Microbiota-Derived Phenylacetylglutamine Associates with Overall Mortality and Cardiovascular Disease in Patients with CKD

Abstract

Colonic microbial metabolism substantially contributes to uremic solute production. p-Cresyl sulfate and indoxyl sulfate are the main representatives of solutes of microbial origin and also, protein-bound solutes, exhibiting high protein-binding affinity and dependence on tubular secretion. Phenylacetylglutamine is another microbial metabolite with high dependence on tubular secretion but low protein-binding affinity. The relevance of such solutes is unknown. Therefore, we prospectively followed 488 patients with CKD stages 1-5 and a measurement of serum phenylacetylglutamine by liquid chromatography-mass spectrometry. In a subgroup, we determined 24-hour urinary excretion as a surrogate of intestinal uptake as well as renal clearance of phenylacetylglutamine. We performed outcome analysis for mortality (51 events) and cardiovascular disease (75 events). Serum phenylacetylglutamine level correlated with 24-hour urinary excretion (rho=0.55; P,0.001) and clearance of phenylacetylglutamine (rho=20.76; P,0.001). Phenylacetylglutamine clearance also correlated with eGFR (rho=0.84; P,0.001). Furthermore, serum phenylacetylglutamine level associated with mortality (hazard ratio per 1-SD increase, 1.77; 95% confidence interval, 1.22 to 2.57; P=0.003) and cardiovascular disease (hazard ratio, 1.79; 95% confidence interval, 1.32 to 2.41; P,0.001) after adjustment for age, sex, presence of diabetes mellitus, prior cardiovascular disease, and eGFR. Thus, serum phenylacetylglutamine level is elevated in patients with more advanced CKD and determined by intestinal uptake and renal clearance, and it is not fully accounted for by differences in eGFR. High serum phenylacetylglutamine level is a strong and independent risk factor for mortality and cardiovascular disease, suggesting the relevance of microbial metabolism and/or tubular dysfunction in CKD, irrespective of protein binding.

Altered microbiome in chronic kidney disease: systemic effects of gut-derived uremic toxins

“…These molecules have been shown to interact with insulin and lipoproteins, thus promoting acceleration of atherosclerosis [88]. Another water-soluble uremic toxin, phenylacetylglutamine, has also been demonstrated to correlate independently with mortality and cardiovascular disease in a prospective study of 448 CKD patients [89].…”

Results of the HEMO Study suggest that p-cresol sulfate and indoxyl sulfate are not associated with cardiovascular outcomes

“…Prior studies, including our work, also suggest that phenylacetylglutamine retention may also contribute to cardiovascular events in patients on hemodialysis 5 and also in patients with earlier stages of chronic kidney disease. 6 All these solutes share the property that they are cleared largely by secretion in the normal kidney. Because dialysis does not replicate secretory processes, their concentrations rise much higher relative to normal than concentrations of urea and creatinine in patients maintained on dialysis.…”

The role of intestinal microbiota in cardiovascular disease

“…PCS levels have been shown to predict cardiovascular events and all‐cause mortality in elderly haemodialysis patients . Likewise, PAG is one of the colonic microbial metabolites produced by glutamine conjugation of phenylacetic acid, high levels of which were known as a strong and independent risk factor for CVD and mortality in patients with chronic kidney disease …”