Effect Of Uremic Toxins in Various Clinical Conditions

Kidney International (2001) 59, S266–S270; doi:10.1046/j.1523-1755.2001.59780266.x

Protein-bound uremic solutes: The forgotten toxins

RAYMOND VANHOLDER1, RITA DE SMET1 and NORBERT LAMEIRE1

1Nephrology Section, Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium

Correspondence: Dr Raymond Vanholder, Nephrology Section, Department of Internal Medicine, Ghent University Hospital, De Pinte-laan 185, B9000, Ghent, Belgium. E-mail: raymond.vanholder@rug.ac.be

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Abstract

Protein-bound uremic solutes: The forgotten toxins. The present concept of dialysis focuses mainly on the removal of small water-soluble compounds, and also, the currently applied kinetic parameters of dialysis adequacy are based on the behavior of water-soluble compounds. Nevertheless, many of the currently known biological effects in uremia are attributable to compounds with different physicochemical characteristics, and among these, protein-bound solutes play an important role. In this article, we review the characteristics and consequences of changes in protein binding in uremia, as well as the toxicity of the protein-bound uremic solutes 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), indoxyl sulfate, hippuric acid, homocysteine, and p-cresol. Starting from the example of p-cresol, we then summarize the impact of protein-binding on dialytic removal, whereby it is concluded that this removal is largely hampered by this protein-binding compared with that of classic markers such as urea and creatinine. Alternative removal strategies, such as strategies to modify intestinal generation or absorption, are considered.

Keywords:

uremic toxicity, dialysis, solute removal, p-cresol, CMPF, indoxyl sulfate, homocysteine, hippuric acid

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References

References

1. GANANSIA J, BIANCHETTI G & THÉNOT JP. Correlation between reversed-phase high-performance liquid chromatography and plasma protein binding. J Chromatogr 1987; 421: 83–90. | PubMed |
2. VANHOLDER R, VAN LANDSCHOOT N, DE SMET R, SCHOOTS A & RINGOIR S. Drug protein binding in chronic renal failure: Evaluation of nine drugs,. Kidney Int 1988; 33: 996–1004. | PubMed |
3. VANHOLDER R, HOEFFLIGER N, DE SMET R & RINGOIR S. Extraction of protein bound ligands from azotemic sera: Comparison of 12 deproteinization methods. Kidney Int 1992; 41: 1707–1712. | PubMed | ISI | ChemPort |
4. DE SMET R, VOGELEERE P, VAN KAER J, LAMEIRE N & VANHOLDER R. Study by means of high-performance liquid chromatography of solutes that decrease theophylline/protein binding in the serum of uremic patients. J Chromatogr A 1999; 847: 141–153. | Article | PubMed | ISI | ChemPort |
5. HSU CH, VANHOLDER R, PATEL S, DE SMET R, SANDRA P & RINGOIR SMG. Subfractions of uremic plasma ultrafiltrate inhibit calcitriol metabolism. Kidney Int 1991; 40: 868–873. | PubMed |
6. VANHOLDER R, DE SMET R, JACOBS V, VAN LANDSCHOOT N, WATERLOOS MA, VOGELEERE P & RINGOIR S. Uremic retention solutes depress polymorphonuclear response to phagocytosis. Nephrol Dial Transplant 1994; 9: 1271–1278. | PubMed | ISI | ChemPort |
7. HENDERSON SJ & LINDUP WE. Renal organic acid transport: Uptake by rat kidney slices of a furan dicarboxylic acid which inhibits plasma protein binding of acidic ligands in uremia. J Pharmacol Exp Ther 1992; 263: 54–60. | PubMed | ISI | ChemPort |
8. COSTIGAN MG & LINDUP WE. Plasma clearance in the rat of a furan dicarboxylic acid which accumulates in uremia. Kidney Int 1996; 49: 634–638. | PubMed | ISI | ChemPort |
9. MABUCHI H & NAKAHASHI H. Inhibition of hepatic glutathione S-transferases by a major endogenous ligand substance present in uremic serum. Nephron 1988; 49: 281–286. | PubMed |
10. LIM CF, BERNARD BF, DE JONG M, DOCTER R, KRENNING EP & HENNEMANN G. A furan fatty acid and indoxyl sulfate are the putative inhibitors of thyroxine hepatocyte transport in uremia. J Clin Endocrinol Metab 1993; 76: 318–324. | PubMed |
11. NIWA T, AIUCHI T, NAKAYA K, EMOTO Y, MIYAZAKI T & MAEDA K. Inhibition of mitochondrial respiration by furancarboxylic acid accumulated in uremic serum in its albumin-bound and non-dialyzable form. Clin Nephrol 1993; 39: 92–96. | PubMed |
12. COSTIGAN MG, O'CALLAGHAN CA & LINDUP WE. Hypothesis: is accumulation of a furan dicarboxylic acid (3-carboxy-4-methyl-5-propyl-2-furanpropionic acid) related to the neurological abnormalities in patients with renal failure?. Nephron 1996; 73: 169–173. | PubMed |
13. DEPNER TA. Suppression of tubular anion transport by an inhibitor of serum protein binding in uremia. Kidney Int 1981; 20: 511–518. | PubMed | ISI | ChemPort |
14. MOTOJIMA M, NISHIJIMA F, IKOMA M, KAWAMURA T, YOSHIOKA T, FOGO AB, SAKAI T & ICHIKAWA I. Role for "uremic toxin" in the progressive loss of intact nephrons in chronic renal failure. Kidney Int 1991; 40: 461–469. | PubMed | ISI | ChemPort |
15. NIWA T & ISE M. Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis. J Lab Clin Med 1994; 124: 96–104. | PubMed | ISI | ChemPort |
16. SPUSTOVA V, CERNAY P & GOLIER I. Inhibition of glucose utilization in uremia by hippurate: Liquid chromatographic isolation and mass spectrometric and nuclear magnetic resonance spectroscopic identification. J Chromatogr 1989; 490: 186–192. | PubMed |
17. PERNA AF, INGROSSO D, DE SANTO NG, GALLETTI P & ZAPPIA V. Mechanism of erythrocyte accumulation of methylation inhibitor S-adenosylhomocysteine in uremia. Kidney Int 1995; 47: 247–253. | PubMed | ISI | ChemPort |
18. CLARKE R, DALY L, ROBINSON K, NAUGHTEN E, CAHALANE S, FOWLER B & GRAHAM I. Hyperhomocysteinemia: An independent risk factor for vascular disease. N Engl J Med 1991; 324: 1149–1155. | PubMed | ISI | ChemPort |
19. BOSTOM AG, SHEMIN D, LAPANE KL, MILLER JW, SUTHERLAND P, NADEAU M, SEYOUM E, HARTMAN W, PRIOR R, WILSON PWF & SELHUB J. Hyperhomocysteinemia and traditional cardiovascular disease risk factors in end-stage renal disease patients on dialysis: A case-control study. Atherosclerosis 1995; 114: 93–103. | Article | PubMed | ISI | ChemPort |
20. MASSY ZA, CHADEFAUX-VEKEMANS B, CHEVALIER A, BADER CA, DRÜEKE TB, LEGENDRE C, LACOUR B, KAMOUN P & KREIS H. Hyperhomocysteinaemia: A significant risk factor for cardiovascular disease in renal transplant recipients. Nephrol Dial Transplant 1994; 9: 1103–1108. | PubMed | ISI | ChemPort |
21. TSAI C, PERRELLA MA, YOSHIZUMI M, HSIEN CM, HABE E, SCHLAGEL R & LEE ME. Promotion of vascular smooth muscle cell growth by homocysteine: A link to atherosclerosis. Proc Natl Acad Sci USA 1992; 91: 10193–10197.
22. MATTHIAS D, BECKER CH, RIEZLER R & KINDLING PH. Homocysteine induced arteriosclerosis-like alterations of the aorta in normotensive and hypertensive rats following application of high doses of methionine. Atherosclerosis 1996; 122: 201–216. | Article | PubMed | ISI | ChemPort |
23. HARPEL PC, ZHANG X & BORTH W. Homocysteine and hemostasis: Pathogenetic mechanisms predisposing to thrombosis. J Nutr 1996; 126: 1285S–1289S. | PubMed | ChemPort |
24. DE SMET R, GLORIEUX G & VANHOLDER R. P-cresol and uric acid: Two old uremic toxins revisited. Kidney Int 1997; 52 Suppl 62: S8–S11.
25. DE SMET R, DAVID F, SANDRA P, VAN KAER J, LESAFFER G, DHONDT A, LAMEIRE N & VANHOLDER R. A sensitive HPLC method for the quantification of free and total p-cresol in patients with chronic renal failure. Clin Chim Acta 1998; 278: 1–21. | Article | PubMed | ISI | ChemPort |
26. VANHOLDER R, DE SMET R, WATERLOOS MA, VAN LANDSCHOOT N, VOGELEERE P, HOSTE E & RINGOIR S. Mechanisms of the uremic inhibition of phagocyte reactive species production: Characterization of the role of p-cresol. Kidney Int 1995; 47: 510–517. | PubMed | ISI | ChemPort |
27. ABREO K, SELLA M, GAUTREAUX S, DE SMET R, VOGELEERE P, RINGOIR S & VANHOLDER R. P-cresol and phenol increase the uptake and toxicity of aluminum in cultured mouse hepatocytes. J Am Soc Nephrol 1997; 8: 935–942. | PubMed | ISI | ChemPort |
28. WRATTEN ML, TETTA C, DE SMET R, NERI R, SERENI L, CAMUSSI G & VANHOLDER R. Uremic ultrafiltrate inhibits platelet-activating factor synthesis. Blood Purif 1999; 17: 134–141. | Article | PubMed | ISI | ChemPort |
29. VANHOLDER R, DE SMET R & LESAFFER G. P-cresol: A toxin revealing many neglected but relevant aspects of uraemic toxicity. Nephrol Dial Transplant 1999; 14: 2813–2815. | PubMed | ISI | ChemPort |
30. LESAFFER G, DE SMET R, LAMEIRE N, DHONDT A, DUYM P & VANHOLDER R. Intra-dialytic removal of protein-bound uraemic toxins: Role of solute characteristics and of dialyzer membrane. Nephrol Dial Transplant 2000; 15: 50–57. | PubMed | ISI | ChemPort |
31. 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: 82–87. | PubMed | ISI | ChemPort |
32. GEYPENS B, CLAUS D, EVENEPOEL P, HIELE M, PEETERS M, RUTGEERTS P & GHOOS Y. Influence of dietary protein supplements on the formation of bacterial metabolites in the colon. Gut 1997; 41: 70–76. | PubMed |
33. YOKOYAMA MT, TABORI C, MIMMER ER & HOGBERG MG. The effect of antibiotics in the weanling pig diet on the growth and the excretion of volatile phenolic and aromatic bacterial metabolites. Am J Clin Nutr 1982; 35: 1417–1424. | PubMed | ISI | ChemPort |
34. LING WH & HÄNNINEN O. Shifting from a conventional diet to an uncooked vegan diet reversibly alters fecal hydrolytic activities in humans. J Nutr 1992; 122: 924–930. | PubMed |
35. VANHOLDER RC, DE SMET RV & RINGOIR SM. Assessment of urea and other uremic markers for quantification of dialysis adequacy. Clin Chem 1992; 38: 1429–1436. | PubMed | ISI | ChemPort |
36. VANHOLDER R, DE SMET R, HSU C, VOGELEERE P & RINGOIR S. Uremic toxins: The middle molecule hypothesis revisited. Semin Nephrol 1994; 14: 205–218. | PubMed | ISI | ChemPort |
37. LA GRECA G, BRENDOLAN A, GHEZZI PM, DE SMET R, TETTA C, GERVASIO R & RONCO C. The concept of sorbent in hemodialysis. Int J Artif Organs 1998; 21: 303–308. | PubMed | ISI | ChemPort |

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