Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original article
  • Published:
Clinical and Experimental Nephrology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. El Nahas AM, Bello AK. Chronic kidney disease: the global challenge. Lancet. 2005;365(9456):331e40.

    Article  Google Scholar 

  2. Kaysen GA. The microinflammatory state in uremia: causes and potential consequences. J Am Soc Nephrol. 2001;12:1549–57.

    PubMed  CAS  Google Scholar 

  3. Cozzolino M, Brancaccio D, Gallieni M, Slatopolsky E. Pathogenesis of vascular calcification in chronic kidney disease. Kidney Int. 2005;68:429–36.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  6. Cummings JH. Fermentation in the human large intestine: evidence and implications for health. Lancet. 1983;1:1206–9.

    Article  PubMed  CAS  Google Scholar 

  7. Evenepoel P, Meijers BKI, Bammens BRM, Verbeke K. Uremic toxins originating from colonic microbial metabolism. Kidney Int. 2009;76(Suppl 114):S12–9.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  9. Ramezani A, Raj DS. The gut microbiome, kidney disease, and target interventions. J Am Soc Nephrol. 2014;25:657–70.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  17. Davenport A. Role of dialysis technology in the removal of uremic toxins. Hemodial Int. 2011;15:S49–53.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  19. Goto S, Yoshiya K, Kita T, Fujii H, Fukagawa M. Uremic toxins and oral adsorbents. Ther Apher Dial. 2011;15:132–4.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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. 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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. 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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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. Ritz E. Intestinal-renal syndrome: mirage or reality? Blood Purif. 2011;31:70–6.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  36. Vaziri ND, Wong J, Pahl M, et al. Chronic kidney disease alters intestinal microbial flora. Kidney Int. 2013;83(2):308–15.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  40. American Diabetes Association. Executive summary: standards of medical care in diabetes. Diabetes Care. 2009;32:S13–61.

    Article  PubMed Central  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  44. Sun W, Liu D, Gong P, et al. Predicting cardiovascular mortality in chronic kidney disease (CKD) patients. Ann Transplant. 2014;19:513–8.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  55. Kalaitzidis RG, Elisaf MS. Hyperphosphatemia and phosphate binders: effectiveness and safety. Curr Med Res Opin. 2014;30(1):109–12.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Nephrology, Second University of Naples, Naples, Italy

    Eleonora Riccio

  2. Chair of Nephrology, Department of Public Health, Federico II University of Naples, Naples, Italy

    Massimo Sabbatini, Cristina Marchetiello, Maria Amicone & Antonio Pisani

  3. Chair of Statistics, Department of Public Health, Federico II University of Naples, Naples, Italy

    Dario Bruzzese

  4. Department of Pharmacy, School of Medicine and Surgery, Federico II University of Naples, Naples, Italy

    Lucia Grumetto & Giacomo Russo

  5. Unit of Nephrology, Department of Health Sciences, “Magna Graecia” University, Catanzaro, Italy

    Michele Andreucci

  6. Division of Physiology, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy

    Bruna Guida

  7. Department of Economics and Law, University of Cassino and Southern Lazio, Cassino, Italy

    Davide Passaretti

Authors
  1. Eleonora Riccio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Massimo Sabbatini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dario Bruzzese
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lucia Grumetto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cristina Marchetiello
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maria Amicone
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michele Andreucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bruna Guida
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Davide Passaretti
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Giacomo Russo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Antonio Pisani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eleonora Riccio.

Ethics declarations

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.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Riccio, E., Sabbatini, M., Bruzzese, D. et al. Plasma p-cresol lowering effect of sevelamer in non-dialysis CKD patients: evidence from a randomized controlled trial. Clin Exp Nephrol 22, 529–538 (2018). https://doi.org/10.1007/s10157-017-1504-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10157-017-1504-8

Keywords

Search

Navigation