Clinical and Experimental Nephrology

, Volume 22, Issue 3, pp 529–538 | Cite as

Plasma p-cresol lowering effect of sevelamer in non-dialysis CKD patients: evidence from a randomized controlled trial

  • Eleonora Riccio
  • Massimo Sabbatini
  • Dario Bruzzese
  • Lucia Grumetto
  • Cristina Marchetiello
  • Maria Amicone
  • Michele Andreucci
  • Bruna Guida
  • Davide Passaretti
  • Giacomo Russo
  • Antonio Pisani
Original article
  • 178 Downloads

Abstract

Background

The accumulation of p-cresol, a metabolic product of aromatic amino acids generated by intestinal microbiome, increases the cardiovascular risk in chronic kidney disease (CKD) patients. Therefore, therapeutic strategies to reduce plasma p-cresol levels are highly demanded. It has been reported that the phosphate binder sevelamer (SEV) sequesters p-cresol in vitro, while in vivo studies on dialysis patients showed controversial results. Aim of our study was to evaluate the effect of SEV on p-cresol levels in non-dialysis CKD patients.

Methods

This was a single-blind, randomized placebo-controlled trial (Registration number NCT02199444) carried on 69 CKD patients (stage 3–5, not on dialysis), randomly assigned (1:1) to receive either SEV or placebo for 3 months. Total p-cresol serum levels were evaluated at baseline (T0), and 1 (T1) and 3 months (T3) after treatment start. The primary end-point was to evaluate the effect of SEV on p-cresol levels.

Results

Compared to baseline (T0, 7.4 ± 2.7 mg/mL), p-cresol mean concentration was significantly reduced in SEV patients after one (− 2.06 mg/mL, 95% CI − 2.62 to − 1.50 mg/mL; p < 0.001) and 3 months of treatment (− 3.97 mg/mL, 95% CI − 4.53 to − 3.41 mg/mL; p < 0.001); no change of plasma p-cresol concentration was recorded in placebo-treated patients. Moreover, P and LDL values were reduced after 3 months of treatment by SEV but not placebo.

Conclusions

In conclusion, our study represents the first evidence that SEV is effective in reducing p-cresol levels in CKD patients in conservative treatment, and confirms its beneficial effects on inflammation and lipid pattern.

Keywords

Chronic kidney disease p-Cresol Sevelamer Cardiovascular risk 

Notes

Compliance with ethical standards

Conflict of interest

All the authors have declared that no conflict of interest exists.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee at which the studies were conducted (IRB approval number 15/12) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Human and animal rights statement

This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    El Nahas AM, Bello AK. Chronic kidney disease: the global challenge. Lancet. 2005;365(9456):331e40.CrossRefGoogle Scholar
  2. 2.
    Kaysen GA. The microinflammatory state in uremia: causes and potential consequences. J Am Soc Nephrol. 2001;12:1549–57.PubMedGoogle Scholar
  3. 3.
    Cozzolino M, Brancaccio D, Gallieni M, Slatopolsky E. Pathogenesis of vascular calcification in chronic kidney disease. Kidney Int. 2005;68:429–36.CrossRefPubMedGoogle Scholar
  4. 4.
    Levin A. Anemia and left ventricular hypertrophy in chronic kidney disease populations: a review of the current state of knowledge. Kidney Int. 2002;61(Suppl. 80):S35–8.CrossRefGoogle Scholar
  5. 5.
    Lee JH, O’Keefe JH, Bell D, Hensrud DD, Holick MF. Vitamin D deficiency, an important, common, and easily treatable cardiovascular risk factor? J Am Coll Cardiol. 2008;52:1949–56.CrossRefPubMedGoogle Scholar
  6. 6.
    Cummings JH. Fermentation in the human large intestine: evidence and implications for health. Lancet. 1983;1:1206–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Evenepoel P, Meijers BKI, Bammens BRM, Verbeke K. Uremic toxins originating from colonic microbial metabolism. Kidney Int. 2009;76(Suppl 114):S12–9.CrossRefGoogle Scholar
  8. 8.
    Vanholder R, Bammens B, de Loor H, Glorieux G, Meijers B, et al. Warning: the unfortunate end of p-cresol as a uraemic toxin. Nephrol Dial Transplant. 2011;26:1464–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Ramezani A, Raj DS. The gut microbiome, kidney disease, and target interventions. J Am Soc Nephrol. 2014;25:657–70.CrossRefPubMedGoogle Scholar
  10. 10.
    Lin CJ, Wu CJ, Pan CF, Chen YC, Sun FJ, et al. Serum protein-bound uraemic toxins and clinical outcomes in haemodialysis patients. Nephrol Dial Transplant. 2010;25:3693–700.CrossRefPubMedGoogle Scholar
  11. 11.
    Meijers BK, Bammens B, De Moor B, Verbeke K, Vanrenterghem Y, et al. Free p-cresol is associated with cardiovascular disease in hemodialysis patients. Kidney Int. 2008;73:1174–80.CrossRefPubMedGoogle Scholar
  12. 12.
    Meijers BK, Claes K, Bammens B, de Loor H, Viaene L, et al. p-cresol and cardiovascular risk in mild-to-moderate kidney disease. Clin J Am Soc Nephrol. 2010;5:1182–9.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Liabeuf S, Barreto DV, Barreto FC, Meert N, Glorieux G, et al. Free pcresylsulphate is a predictor of mortality in patients at different stages of chronic kidney disease. Nephrol Dial Transplant. 2010;25:1183–91.CrossRefPubMedGoogle Scholar
  14. 14.
    Cerini C, Dou L, Anfosso F, Sabatier F, Moal V, et al. p-cresol, a uremic retention solute, alters the endothelial barrier function in vitro. Thromb Haemost. 2004;92:140–50.PubMedGoogle Scholar
  15. 15.
    Meijers BK, Van Kerckhoven S, Verbeke K, Dehaen W, Vanrenterghem Y, et al. The uremic retention solute p-cresyl sulfate and markers of endothelial damage. Am J Kidney Dis. 2009;54:891–901.CrossRefPubMedGoogle Scholar
  16. 16.
    Ying Y, Yang K, Liu Y, Chen QJ, Shen WF, et al. A uremic solute, Pcresol, inhibits the proliferation of endothelial progenitor cells via the p38 pathway. Circ J. 2011;75:2252–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Davenport A. Role of dialysis technology in the removal of uremic toxins. Hemodial Int. 2011;15:S49–53.CrossRefPubMedGoogle Scholar
  18. 18.
    Krieter DH, Hackl A, Rodriguez A, Chenine L, Moragues HL, et al. Protein-bound uraemic toxin removal in haemodialysis and post-dilution haemodiafiltration. Nephrol Dial Transplant. 2010;25:212–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Goto S, Yoshiya K, Kita T, Fujii H, Fukagawa M. Uremic toxins and oral adsorbents. Ther Apher Dial. 2011;15:132–4.CrossRefPubMedGoogle Scholar
  20. 20.
    Goldsmith DR, Scott LJ, Cvetković RS, Plosker GL. Sevelamer hydrochloride: a review of its use for hyperphosphataemia in patients with end-stage renal disease on haemodialysis. Drugs. 2008;68:85–104.CrossRefPubMedGoogle Scholar
  21. 21.
    Evenepoel P, Selgas R, Caputo F, Foggensteiner L, Heaf JG, et al. Efficacy and safety of sevelamer hydrochloride and calcium acetate in patients on peritoneal dialysis. Nephrol Dial Transplant. 2009;24:278–85.CrossRefPubMedGoogle Scholar
  22. 22.
    Riccio E, Cataldi M, Minco M, et al. Evidence that p-cresol and IL-6 are adsorbed by the HFR cartridge: towards a new strategy to decrease systemic inflammation in dialyzed patients? PLoS One. 2014;9(4):e95811.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Evenpoel P, Bammens B, Verbeke K, Vanrenterghem Y. Acarbose treatment lowers generation and serum concentration of protein-bound solute p-cresol: a pilot study. Kidney Int. 2006;70:192–8.CrossRefGoogle Scholar
  24. 24.
    Niwa T, Ise M, Miyazaki T, Meada K. Suppressive effect of an oral sorbent on the accumulation of p-cresol in the serum of experimental uremic rats. Nephron. 1993;65:82–7.CrossRefPubMedGoogle Scholar
  25. 25.
    De Smet R, Thermote F, Lameire N, Vanholder R. Sevelamer hydrochloride (Renagel) adsorbs the uremic compound indoxyl sulfate, indole and p-cresol. J Am Soc Nephrol. 2004;15:505A.Google Scholar
  26. 26.
    Brandenburg VM, Schlieper G, Heussen N, Holzmann S, Busch B, et al. Serological cardiovascular and mortality risk predictors in dialysis patients receiving sevelamer: a prospective study. Nephrol Dial Transplant. 2010;25:2672–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Guida B, Cataldi M, Riccio E, et al. Plasma p-cresol lowering effect of sevelamer in peritoneal dialysis patients: evidence from a cross-sectional observational study. PLoS One. 2013;8(8):e73558.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Vlassara H, Uribarri J, Cai W, et al. Effects of sevelamer on HbA1c, inflammation, and advanced glycation end products in diabetic kidney disease. Clin J Am Soc Nephrol. 2012;7(6):934–42.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Yuberro-Serrano EM, Woodward M, Poretsky L, et al. Effects of sevelamer carnonate on advanced glycation end products and antioxidant/pro-oxidant status in patients with diabetic kidney disease. Clin J Am Soc Nephrol. 2015;10(5):759–66.CrossRefGoogle Scholar
  30. 30.
    National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42(4, Suppl 3):S1–201.Google Scholar
  31. 31.
    Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Int Med. 1999;130:461–70.CrossRefPubMedGoogle Scholar
  32. 32.
    Maroni BJ, Steinman TI, Mitch WE. A method for estimating nitrogen intake in patients with chronic renal failure. Kidney Int. 1985;27:58–65.CrossRefPubMedGoogle Scholar
  33. 33.
    Lin CJ, Chen HH, Pan CF, Chuang CK, Wang TJ, et al. P-cresylsulfate and indoxyl sulfate level at different stages of chronic kidney disease. J Clin Lab Anal. 2011;25:191e7.Google Scholar
  34. 34.
    Ritz E. Intestinal-renal syndrome: mirage or reality? Blood Purif. 2011;31:70–6.CrossRefPubMedGoogle Scholar
  35. 35.
    Bammens B, Evenepoel P, Keuleers H, Verbeke K, Vanrenterghem Y. Free serum concentrations of the protein-bound retention solute p-cresol predict mortality in hemodialysis patients. Kidney Int. 2006;69:1081–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Vaziri ND, Wong J, Pahl M, et al. Chronic kidney disease alters intestinal microbial flora. Kidney Int. 2013;83(2):308–15.CrossRefPubMedGoogle Scholar
  37. 37.
    Anders HJ, Andersen K, Stecher B. The intestinal microbiota, a leaky gut, and abnormal immunity in kidney disease. Kidney Int. 2013;83(6):1010–6.CrossRefPubMedGoogle Scholar
  38. 38.
    Ohno I, Yamaguchi Y, Saikawa H, Uetake D, Hikita M, et al. Sevelamer decreases serum uric acid concentration through adsorption of uric acid in maintenance hemodialysis patients. Int Med. 2009;48:415–20.CrossRefGoogle Scholar
  39. 39.
    Phan O, Ivanovski O, Nguyen-Khoa T, Mothu N, Angulo J, et al. Sevelamer prevents uremia-enhanced atherosclerosis progression in apolipoprotein E-deficient mice. Circulation. 2005;112:2875–82.CrossRefPubMedGoogle Scholar
  40. 40.
    American Diabetes Association. Executive summary: standards of medical care in diabetes. Diabetes Care. 2009;32:S13–61.CrossRefPubMedCentralGoogle Scholar
  41. 41.
    Evenepoel P, Claus D, Geypens B, Hiele M, Geboes K, et al. Amount and fate of egg protein escaping assimilation in the small intestine of humans. Am J Physiol. 1999;277:G935–43.PubMedGoogle Scholar
  42. 42.
    Lin CJ, Wu CJ, Pan CF, Chen YC, Sun FJ, et al. Serum concentration of p-cresol and indoxyl sulfate in elderly hemodialysis patients. Int J Geront. 2011;5:80–3.CrossRefGoogle Scholar
  43. 43.
    Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C. Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int. 1999;55:648–58.CrossRefPubMedGoogle Scholar
  44. 44.
    Sun W, Liu D, Gong P, et al. Predicting cardiovascular mortality in chronic kidney disease (CKD) patients. Ann Transplant. 2014;19:513–8.CrossRefPubMedGoogle Scholar
  45. 45.
    Yamada K, Fujimoto S, Tokura T, et al. Effect of sevelamer on dyslipidemia and chronic inflammation in maintenance hemodialysis patients. Ren Fail. 2005;27(4):361–5.CrossRefPubMedGoogle Scholar
  46. 46.
    Chennasamudram SP, Noor T, Vasylyeva TL. Comparison of sevelamer and calcium carbonate on endothelial function and inflammation in patients on peritoneal dialysis. J Ren Care. 2013;39(2):82–9.CrossRefPubMedGoogle Scholar
  47. 47.
    Navarro-Gonzalez JF, Mora-Fernandez C, Muros de Fuentes M, Donate-Correa J, Cazaña-Pérez V, et al. Effect of phosphate binders on serum inflammatory profile, soluble CD14, and endotoxin levels in hemodialysis patients. Clin J Am Soc Nephrol. 2011;6:2272–9.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Ferramosca E, Burke S, Chasan-Taber S, Ratti C, Chertow GM, et al. Potential antiatherogenic and anti-inflammatory properties of sevelamer in maintenance hemodialysis patients. Am Heart J. 2005;149:820–5.CrossRefPubMedGoogle Scholar
  49. 49.
    Sun PP, Perianayagam MC, Jaber BL. Sevelamer hydrochloride use and endotoxin in hemodialysis patients: a pilot cross-sectional study. J Ren Nutr. 2009;19:432–8.CrossRefPubMedGoogle Scholar
  50. 50.
    Stinghen AE, Gonçalves SM, Bucharles S, Branco FS, Gruber B, et al. Sevelamer decreases systemic inflammation in parallel to a reduction in endotoxemia. Blood Purif. 2010;29:352–6.CrossRefPubMedGoogle Scholar
  51. 51.
    Levin A, Rigatto C, Barrett B, et al. CanPREDDICT Investigators. Biomarkers of inflammation, fibrosis, cardiac stretch and injury predict death but not renal replacement therapy at 1 year in a Canadian chronic kidney disease cohort. Nephrol Dial Transplant. 2014;29:1037–47.CrossRefPubMedGoogle Scholar
  52. 52.
    Burke SK, Dillon MA, Hemken DE, et al. Metaanalysis of the effect of sevelamer on phosphorus, calcium, PTH, and serum lipids in dialysis patients. Adv Ren Replace Ther. 2003;10:133–45.CrossRefPubMedGoogle Scholar
  53. 53.
    Imori S, Mori Y, Akita W, et al. Effects of sevelamer hydrochloride on mortality, lipid abnormality and arterial stiffness in hemodialyzed patients: a propensity matched observational study. Clin Exp Nephrol. 2012;16(6):930–7.CrossRefGoogle Scholar
  54. 54.
    Locatelli F, Del Vecchio L. Cardiovascular mortality in chronic kidney disease patients: potential mechanisms and possibilities of inhibition by resin-based phosphate binders. Expert Rev Cardiovasc Ther. 2015;13(5):489–99.CrossRefPubMedGoogle Scholar
  55. 55.
    Kalaitzidis RG, Elisaf MS. Hyperphosphatemia and phosphate binders: effectiveness and safety. Curr Med Res Opin. 2014;30(1):109–12.CrossRefPubMedGoogle Scholar
  56. 56.
    Frazão JM, Andragão T. Non-calcium-containing phosphate binders: comparing efficacy, safety and other clinical effects. Nephron Clin Pract. 2012;120(2):c108–19.CrossRefPubMedGoogle Scholar
  57. 57.
    Chertow GM, Burke SK, Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int. 2002;62:245–52.CrossRefPubMedGoogle Scholar
  58. 58.
    Block GA, Spiegel DM, Ehrlich J, et al. Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney Int. 2005;68:1815–24.CrossRefPubMedGoogle Scholar

Copyright information

© Japanese Society of Nephrology 2017

Authors and Affiliations

  • Eleonora Riccio
    • 1
  • Massimo Sabbatini
    • 2
  • Dario Bruzzese
    • 3
  • Lucia Grumetto
    • 4
  • Cristina Marchetiello
    • 2
  • Maria Amicone
    • 2
  • Michele Andreucci
    • 5
  • Bruna Guida
    • 6
  • Davide Passaretti
    • 7
  • Giacomo Russo
    • 4
  • Antonio Pisani
    • 2
  1. 1.Department of NephrologySecond University of NaplesNaplesItaly
  2. 2.Chair of Nephrology, Department of Public HealthFederico II University of NaplesNaplesItaly
  3. 3.Chair of Statistics, Department of Public HealthFederico II University of NaplesNaplesItaly
  4. 4.Department of Pharmacy, School of Medicine and SurgeryFederico II University of NaplesNaplesItaly
  5. 5.Unit of Nephrology, Department of Health Sciences“Magna Graecia” UniversityCatanzaroItaly
  6. 6.Division of Physiology, Department of Clinical Medicine and SurgeryFederico II University of NaplesNaplesItaly
  7. 7.Department of Economics and LawUniversity of Cassino and Southern LazioCassinoItaly

Personalised recommendations