p-Cresol Sulfate: Further Understanding of Its Cardiovascular Disease Potential in CKD

Failure of the kidneys results in retention of solutes that in some part have a role in uremic syndrome.1 However, we know remarkably little about which of the many retained solutes are toxic. One such solute is p-cresol sulfate, a metabolite of tyrosine, which is bound to albumin and hence poorly removed by conventional hemodialysis. The study by Meijers et al2 in this issue of the American Journal of Kidney Diseases strengthens the case for the toxicity of p-cresol sulfate and exemplifies the type of work required to advance our understanding of uremic toxicity. The point of departure for Meijers et al was their own prior finding in a population of 175 prevalent hemodialysis patients that high baseline p-cresol sulfate levels, measured as p-cresol, were associated with increased risk of cardiovascular events.3 In the present study, they show that high plasma p-cresol sulfate levels also are associated with high concentrations of endothelial microparticles (EMPs). These microparticles are submicron membrane vesicles derived from platelets, leukocytes, and endothelial cells in certain disease states. EMPs are associated with increased arterial stiffness and act as prothrombotic stimulants and proinflammatory mediators. In endothelial injury and prothrombotic states (acute coronary syndromes, severe hypertension with end organ damage, and thrombotic thrombocytopenic purpura), EMP levels are increased. In end-stage renal disease, endothelial microparticle release has been observed; however, the mechanisms for their release have been largely unknown.4 In the present report, Meijers et al2 report a strong positive correlation between EMP and p-cresol sulfate levels in 100 hemodialysis patients.

Association between 2 factors does not necessarily indicate causation, even when the association is statistically significant after correction for multiple potentially confounding variables. We face a particularly difficult problem in studying uremia, in which concentrations of numerous unmeasured organic solutes likely correlate with concentrations of the few we measure, and high solute concentrations in general may correlate with known risk factors for illness, including inadequate dialysis and poor adherence to dietary and medical prescriptions. A notable value of the work of Meijers et al2 is that the investigators went beyond examining the association of p-cresol sulfate and microparticle number and examined the effect of p-cresol sulfate on endothelial cells in vitro. Meijers et al2 showed that EMP shedding from human umbilical vascular endothelial cells in vitro can be induced by p-cresol sulfate. The importance of this study is that it extends this group's earlier epidemiological association of p-cresol sulfate with mortality and provides a plausible biological role in the development of cardiovascular disease in uremia.

What should be the next step? It is remarkable that infusion studies in animals are almost never performed to test the effects of putative uremic toxins in vivo. Meijers et al5 argue against taking this step with p-cresol sulfate on the grounds that p-cresol may be excreted more as the glucuronate conjugate than the sulfate conjugate in rats. However, demonstration of injury in an in vivo model would greatly strengthen the case that p-cresol sulfate is toxic. The ultimate step would be a clinical trial testing whether a renal replacement treatment that decreases p-cresol sulfate levels prevents vascular disease in dialysis patients.

Some non–protein-bound uremic toxins may be amenable to dialytic removal. In patients treated with high-permeability dialyzer membranes, there appears to be a correlation between middle-molecule removal and improved outcome.6, 7, 8, 9 Although the Hemodialysis (HEMO) Study, which examined the role of urea kinetics as the primary end point, did not show a benefit in patients treated with high-flux dialyzers or those treated with high-efficiency dialyzers versus low-flux dialysis,10 subanalysis showed a better outcome in those with lower β2-microglobulin concentrations achieved by using high-flux dialyzers.11 Fractionated plasma separation and adsorption of p-cresol sulfate has been shown in a study of the Prometh01 and Prometh02 adsorbers (Fresenius Medical Care, Bad Homburg, Germany), resulting in decreases in p-cresol sulfate levels exceeding that of conventional hemodialysis. However, coagulation problems associated with the device precluded continuation of the clinical study.12, 13

Treatments also are available that improve the clearance of p-cresol sulfate and other bound solutes, including hemodiafiltration with high replacement volumes and hemodialysis with a larger dialyzer size and dialysate flow rate than used for current standard treatment.14, 15 It is presumed, but not yet shown, that regular application of such treatments would decrease p-cresol sulfate levels. It is doubtful that resources will soon be available to support the use of these experimental treatments in a large enough number of patients during a long enough period to test their effect on cardiovascular outcomes. A more readily achievable goal may be to test the shorter term effect of decreasing p-cresol sulfate levels by using EMP concentrations as one such short-term or surrogate end point.

The difficulty teasing out the effects of a specific uremic toxin is hampered by the lack of targeted removal methods, be it dialysis or nonselective sorbents. One method, albeit likely costly to produce, could be the construction of specific adsorbents that remove only 1 toxin. This technique would use resins or membranes manufactured to create pores that accept only a pure candidate molecular species, which is introduced during the polymerization process, but later removed, leaving behind a molecularly imprinted, but vacant, pore.16, 17

Progress in the study of uremia has been slow, in part because we fear to fail and have too little idea of where to start. Evidence for the toxicity of individual uremic solutes is limited. Investigators and funding agencies are reluctant to study substances that may turn out to be insignificant. Means to decrease levels of specific solutes therefore are not devised, and the toxicity of the solutes cannot be assessed more definitively. These linked disincentives to investigation, as shown in Fig 1, have slowed the study of uremic toxins, even as the number of patients with end-stage renal disease has increased dramatically. Hopefully, the future will bring us more studies like that of Meijers et al and renewed progress in this important area.7, 8

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Figure 1. Potential disincentives to research in uremia. Abbreviation: ESRD, end-stage renal disease.