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

Abstract

Related Article, p. 891Failure of the kidneys results in retention of solutes that in some part have a role in uremic syndrome.1Meyer T.W. Hostetter T.H. Uremia.N Engl J Med. 2007; 357: 1316-1325Crossref PubMed Scopus (370) Google Scholar 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 al2Meijers B.K.I. Van kerckhoven S. Verbeke K. et al.The uremic retention solute p-cresyl sulfate and markers of endothelial damage.Am J Kidney Dis. 2009; 54: 891-901Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar 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.3Meijers B.K. Bammens B. De Moor B. et al.Free p-cresol is associated with cardiovascular disease in hemodialysis patients.Kidney Int. 2008; 73: 1174-1180Crossref PubMed Scopus (237) Google Scholar 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.4Chironi G.N. Boulanger C.M. Simon A. et al.Endothelial microparticles in diseases.Cell Tissue Res. 2009; 335: 143-151Crossref PubMed Scopus (336) Google Scholar In the present report, Meijers et al2Meijers B.K.I. Van kerckhoven S. Verbeke K. et al.The uremic retention solute p-cresyl sulfate and markers of endothelial damage.Am J Kidney Dis. 2009; 54: 891-901Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar 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 al2Meijers B.K.I. Van kerckhoven S. Verbeke K. et al.The uremic retention solute p-cresyl sulfate and markers of endothelial damage.Am J Kidney Dis. 2009; 54: 891-901Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar 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 al2Meijers B.K.I. Van kerckhoven S. Verbeke K. et al.The uremic retention solute p-cresyl sulfate and markers of endothelial damage.Am J Kidney Dis. 2009; 54: 891-901Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar 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 al5Lesaffer G. De Smet R. Belpaire F.M. et al.Urinary excretion of the uraemic toxin p-cresol in the rat: Contribution of glucuronidation to its metabolization.Nephrol Dial Transplant. 2003; 18: 1299-1306Crossref PubMed Scopus (33) Google Scholar 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.6Leypoldt J.K. Cheung A. Carroll C. et al.Effect of dialysis membranes and middle molecule removal on chronic hemodialysis patient survival.Am J Kidney Dis. 1999; 33: 349-355Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, 7Koda Y. Nishi S. Miyazaki S. et al.Switch from conventional to high-flux membrane reduces the risk of carpal tunnel syndrome and mortality of hemodialysis patients.Kidney Int. 1997; 52: 1096-1101Crossref PubMed Scopus (226) Google Scholar, 8Woods H.F. Nandakumar M. Improved outcome for haemodialysis patients treated with high-flux membranes.Nephrol Dial Transplant. 2000; 15: S36-S42Crossref PubMed Scopus (91) Google Scholar, 9Port F.K. Wolfe R.A. Hulbert-Shearon T.E. et al.Mortality risk by hemodialyzer reuse practice and dialyzer membrane characteristics: Results from the USRDS Dialysis Morbidity and Mortality Study.Am J Kidney Dis. 2001; 37: 276-286Abstract Full Text PDF PubMed Scopus (134) Google Scholar 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,10Eknoyan G. Beck G.J. Cheung A.K. et al.HEMO Study GroupEffect of dialysis dose and membrane flux in maintenance hemodialysis.N Engl J Med. 2002; 347: 2010-2019Crossref PubMed Scopus (1559) Google Scholar subanalysis showed a better outcome in those with lower β2-microglobulin concentrations achieved by using high-flux dialyzers.11Cheung A.K. Rocco M.V. Yan G. et al.Serum beta-2 microglobulin levels predict mortality in dialysis patients: Results of the HEMO Study.J Am Soc Nephrol. 2006; 17: 546-555Crossref PubMed Scopus (357) Google Scholar 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.12Meijers B.K.I. Weber V. Bammens B. et al.Removal of the uremic retention solute p-cresol using fractionated plasma separation and adsorption.Artif Organs. 2007; 32: 214-219Crossref Scopus (53) Google Scholar, 13Meijers B.K.I. Verhamme P. Nevens F. et al.Major coagulation disturbances during fractionated plasma separation and adsorption.Am J Transplant. 2007; 7: 2195-2199Crossref PubMed Scopus (52) Google ScholarTreatments 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.14Bammens B. Evenepoel P. Verbeke K. Vanrenterghem Y. Removal of the protein-bound solute p-cresol by convective transport: A randomized crossover study.Am J Kidney Dis. 2004; 44: 278-285Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 15Luo F.J. Patel K.P. Marquez I.O. et al.Effect of increasing dialyzer mass transfer area coefficient and dialysate flow on clearance of protein-bound solutes: A pilot crossover trial.Am J Kidney Dis. 2009 Apr 24; ([Epub ahead of print])Google Scholar 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.16Kobayashi T. Takeda K. Ohashi A. et al.Selective removal of bisphenol A from serum using molecular imprinted polymer membranes.Ther Apher Dial. 2009; 13: 19-26Crossref PubMed Scopus (15) Google Scholar, 17Chang Y.S. Ko T.H. Hsu T.J. Syu M.J. Synthesis of an imprinted hybrid organic-inorganic polymeric sol-gel matrix toward the specific binding and isotherm kinetics investigation of creatinine.Anal Chem. 2009; 81: 2098-2105Crossref PubMed Scopus (68) Google ScholarProgress 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.7Koda Y. Nishi S. Miyazaki S. et al.Switch from conventional to high-flux membrane reduces the risk of carpal tunnel syndrome and mortality of hemodialysis patients.Kidney Int. 1997; 52: 1096-1101Crossref PubMed Scopus (226) Google Scholar, 8Woods H.F. Nandakumar M. Improved outcome for haemodialysis patients treated with high-flux membranes.Nephrol Dial Transplant. 2000; 15: S36-S42Crossref PubMed Scopus (91) Google Scholar Related Article, p. 891 Related Article, p. 891 Related Article, p. 891 Failure of the kidneys results in retention of solutes that in some part have a role in uremic syndrome.1Meyer T.W. Hostetter T.H. Uremia.N Engl J Med. 2007; 357: 1316-1325Crossref PubMed Scopus (370) Google Scholar 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 al2Meijers B.K.I. Van kerckhoven S. Verbeke K. et al.The uremic retention solute p-cresyl sulfate and markers of endothelial damage.Am J Kidney Dis. 2009; 54: 891-901Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar 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.3Meijers B.K. Bammens B. De Moor B. et al.Free p-cresol is associated with cardiovascular disease in hemodialysis patients.Kidney Int. 2008; 73: 1174-1180Crossref PubMed Scopus (237) Google Scholar 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.4Chironi G.N. Boulanger C.M. Simon A. et al.Endothelial microparticles in diseases.Cell Tissue Res. 2009; 335: 143-151Crossref PubMed Scopus (336) Google Scholar In the present report, Meijers et al2Meijers B.K.I. Van kerckhoven S. Verbeke K. et al.The uremic retention solute p-cresyl sulfate and markers of endothelial damage.Am J Kidney Dis. 2009; 54: 891-901Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar 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 al2Meijers B.K.I. Van kerckhoven S. Verbeke K. et al.The uremic retention solute p-cresyl sulfate and markers of endothelial damage.Am J Kidney Dis. 2009; 54: 891-901Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar 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 al2Meijers B.K.I. Van kerckhoven S. Verbeke K. et al.The uremic retention solute p-cresyl sulfate and markers of endothelial damage.Am J Kidney Dis. 2009; 54: 891-901Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar 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 al5Lesaffer G. De Smet R. Belpaire F.M. et al.Urinary excretion of the uraemic toxin p-cresol in the rat: Contribution of glucuronidation to its metabolization.Nephrol Dial Transplant. 2003; 18: 1299-1306Crossref PubMed Scopus (33) Google Scholar 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.6Leypoldt J.K. Cheung A. Carroll C. et al.Effect of dialysis membranes and middle molecule removal on chronic hemodialysis patient survival.Am J Kidney Dis. 1999; 33: 349-355Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, 7Koda Y. Nishi S. Miyazaki S. et al.Switch from conventional to high-flux membrane reduces the risk of carpal tunnel syndrome and mortality of hemodialysis patients.Kidney Int. 1997; 52: 1096-1101Crossref PubMed Scopus (226) Google Scholar, 8Woods H.F. Nandakumar M. Improved outcome for haemodialysis patients treated with high-flux membranes.Nephrol Dial Transplant. 2000; 15: S36-S42Crossref PubMed Scopus (91) Google Scholar, 9Port F.K. Wolfe R.A. Hulbert-Shearon T.E. et al.Mortality risk by hemodialyzer reuse practice and dialyzer membrane characteristics: Results from the USRDS Dialysis Morbidity and Mortality Study.Am J Kidney Dis. 2001; 37: 276-286Abstract Full Text PDF PubMed Scopus (134) Google Scholar 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,10Eknoyan G. Beck G.J. Cheung A.K. et al.HEMO Study GroupEffect of dialysis dose and membrane flux in maintenance hemodialysis.N Engl J Med. 2002; 347: 2010-2019Crossref PubMed Scopus (1559) Google Scholar subanalysis showed a better outcome in those with lower β2-microglobulin concentrations achieved by using high-flux dialyzers.11Cheung A.K. Rocco M.V. Yan G. et al.Serum beta-2 microglobulin levels predict mortality in dialysis patients: Results of the HEMO Study.J Am Soc Nephrol. 2006; 17: 546-555Crossref PubMed Scopus (357) Google Scholar 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.12Meijers B.K.I. Weber V. Bammens B. et al.Removal of the uremic retention solute p-cresol using fractionated plasma separation and adsorption.Artif Organs. 2007; 32: 214-219Crossref Scopus (53) Google Scholar, 13Meijers B.K.I. Verhamme P. Nevens F. et al.Major coagulation disturbances during fractionated plasma separation and adsorption.Am J Transplant. 2007; 7: 2195-2199Crossref PubMed Scopus (52) Google Scholar 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.14Bammens B. Evenepoel P. Verbeke K. Vanrenterghem Y. Removal of the protein-bound solute p-cresol by convective transport: A randomized crossover study.Am J Kidney Dis. 2004; 44: 278-285Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 15Luo F.J. Patel K.P. Marquez I.O. et al.Effect of increasing dialyzer mass transfer area coefficient and dialysate flow on clearance of protein-bound solutes: A pilot crossover trial.Am J Kidney Dis. 2009 Apr 24; ([Epub ahead of print])Google Scholar 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.16Kobayashi T. Takeda K. Ohashi A. et al.Selective removal of bisphenol A from serum using molecular imprinted polymer membranes.Ther Apher Dial. 2009; 13: 19-26Crossref PubMed Scopus (15) Google Scholar, 17Chang Y.S. Ko T.H. Hsu T.J. Syu M.J. Synthesis of an imprinted hybrid organic-inorganic polymeric sol-gel matrix toward the specific binding and isotherm kinetics investigation of creatinine.Anal Chem. 2009; 81: 2098-2105Crossref PubMed Scopus (68) Google Scholar 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.7Koda Y. Nishi S. Miyazaki S. et al.Switch from conventional to high-flux membrane reduces the risk of carpal tunnel syndrome and mortality of hemodialysis patients.Kidney Int. 1997; 52: 1096-1101Crossref PubMed Scopus (226) Google Scholar, 8Woods H.F. Nandakumar M. Improved outcome for haemodialysis patients treated with high-flux membranes.Nephrol Dial Transplant. 2000; 15: S36-S42Crossref PubMed Scopus (91) Google Scholar Financial Disclosure: None. The Uremic Retention Solute p-Cresyl Sulfate and Markers of Endothelial DamageAmerican Journal of Kidney DiseasesVol. 54Issue 5PreviewCardiovascular disease is highly prevalent in patients with chronic kidney disease. In hemodialysis patients, the protein-bound uremic retention solute p-cresol is independently associated with cardiovascular disease. The underlying mechanisms have not been elucidated. Full-Text PDF