Uremic toxins. Back to the future

Main Article Content

I.L. Kuchma


In the review, the author returns to the topic of uremia and uremic toxins, their importance for practitioners in the treatment using renal replacement therapies, gives a modern look at their classification, place during the onset and development of pathological processes in the progression of chronic kidney disease. However, current guidelines and studies for the treatment of chro­nic kidney disease indicate a lack of attention to the role and importance of uremic toxins in the predialysis stages of uremia treatment, in particular to the possible damaging effects of substances retained in the body with reduced glomerular filtration, directly to the renal function. The tables with the list of uremic toxins according to their classification are presented. References are made to the results of clinical and laboratory studies of uremic toxins, their impact on the general clinical picture of uremia and ways of their influence on the progression of chronic kidney disease and the further progression of the clinical picture of uremia. Attention is drawn to the fact that substances recognized as uremic toxins are present in healthy individuals without manifestations of their negative effects, and therefore the opinion is expressed about the need to study the physiological significance of these solvents under normal glomerular filtration. The question arises about the consideration of the factors of uremic toxins impact as a point of application in terms of the progression of chronic kidney disease and the use of this knowledge in renoprotective therapy in the predialysis stages of chronic kidney disease.

Article Details

How to Cite
Kuchma, I. “Uremic Toxins. Back to the Future”. KIDNEYS, vol. 10, no. 2, July 2021, pp. 78-87, doi:10.22141/2307-1257.10.2.2021.234323.
Looking at the problem


When to start dialysis. In: European Best Practice Guidelines for Haemodialysis (Part 1). Nephrology Dialysis Transplantation. 2002;17(Suppl 7):10-11. doi: 10.1093/ndt/17.suppl_7.10.

Lisowska-Myjak B. Uremic toxins and their effects on multiple organ systems. Nephron Clin Pract. 2014;128(3-4):303-11. doi: 10.1159/000369817.

Bergström J, Fürst P. Uremic toxins. Kidney Int Suppl. 1978 Jun;(8):S9-12. PMID: 211307.

Vanholder R, De Smet R, Glorieux G, et al; European Uremic Toxin Work Group (EUTox). Review on uremic toxins: classification, concentration, and interindividual variability. Kidney Int. 2003 May;63(5):1934-43. doi: 10.1046/j.1523-1755.2003.00924.x.

Duranton F, Cohen G, De Smet R, et al; European Uremic Toxin Work Group. Normal and pathologic concentrations of uremic toxins. J Am Soc Nephrol. 2012 Jul;23(7):1258-70. doi: 10.1681/ASN.2011121175.

Vanholder R, Pletinck A, Schepers E, Glorieux G. Biochemical and Clinical Impact of Organic Uremic Retention Solutes: A Comprehensive Update. Toxins (Basel). 2018 Jan 8;10(1):33. doi: 10.3390/toxins10010033.

Meert N, Schepers E, De Smet R, et al. Inconsistency of reported uremic toxin concentrations. Artif Organs. 2007 Aug;31(8):600-11. doi: 10.1111/j.1525-1594.2007.00434.x.

Almeras C, Argilés A. The general picture of uremia. Semin Dial. 2009 Jul-Aug;22(4):329-33. doi: 10.1111/j.1525-139X.2009.00575.x.

Sindhu KK. Uremic toxins: some thoughts on acrolein and spermine. Ren Fail. 2016 Nov;38(10):1755-1758. doi: 10.1080/0886022X.2016.1229990.

Hai X, Landeras V, Dobre MA, DeOreo P, Meyer TW, Hostetter TH. Mechanism of Prominent Trimethylamine Oxide (TMAO) Accumulation in Hemodialysis Patients. PLoS One. 2015 Dec 9;10(12):e0143731. doi: 10.1371/journal.pone.0143731.

Vanholder RC, Eloot S, Glorieux GL. Future Avenues to Decrease Uremic Toxin Concentration. Am J Kidney Dis. 2016 Apr;67(4):664-76. doi: 10.1053/j.ajkd.2015.08.029.

Schulman G, Berl T, Beck GJ, et al. Randomized Placebo-Controlled EPPIC Trials of AST-120 in CKD. J Am Soc Nephrol. 2015 Jul;26(7):1732-46. doi: 10.1681/ASN.2014010042.

Cha RH, Kang SW, Park CW, et al. A Randomized, Controlled Trial of Oral Intestinal Sorbent AST-120 on Renal Function Deterioration in Patients with Advanced Renal Dysfunction. Clin J Am Soc Nephrol. 2016 Apr 7;11(4):559-67. doi: 10.2215/CJN.12011214.

Jourde-Chiche N, Dou L, Cerini C, Dignat-George F, Vanholder R, Brunet P. Protein-bound toxins--update 2009. Semin Dial. 2009 Jul-Aug;22(4):334-9. doi: 10.1111/j.1525-139X.2009.00576.x.

Vanholder R, Schepers E, Pletinck A, Nagler EV, Glorieux G. The uremic toxicity of indoxyl sulfate and p-cresyl sulfate: a systematic review. J Am Soc Nephrol. 2014 Sep;25(9):1897-907. doi: 10.1681/ASN.2013101062.

Gryp T, Vanholder R, Vaneechoutte M, Glorieux G. p-Cresyl Sulfate. Toxins (Basel). 2017 Jan 29;9(2):52. doi: 10.3390/toxins9020052.

Kawakami T, Inagi R, Wada T, Tanaka T, Fujita T, Nangaku M. Indoxyl sulfate inhibits proliferation of human proximal tubular cells via endoplasmic reticulum stress. Am J Physiol Renal Physiol. 2010 Sep;299(3):F568-76. doi: 10.1152/ajprenal.00659.2009.

Niwa T. Indoxyl sulfate is a nephro-vascular toxin. J Ren Nutr. 2010 Sep;20(5 Suppl):S2-6. doi: 10.1053/j.jrn.2010.05.002.

Ellis RJ, Small DM, Ng KL, et al. Indoxyl Sulfate Induces Apoptosis and Hypertrophy in Human Kidney Proximal Tubular Cells. Toxicol Pathol. 2018 Jun;46(4):449-459. doi: 10.1177/0192623318768171.

Fantuzzi G. Adiponectin in inflammatory and immune-mediated diseases. Cytokine. 2013 Oct;64(1):1-10. doi: 10.1016/j.cyto.2013.06.317.

Jia T, Carrero JJ, Lindholm B, Stenvinkel P. The complex role of adiponectin in chronic kidney disease. Biochimie. 2012 Oct;94(10):2150-6. doi: 10.1016/j.biochi.2012.02.024.

Cui J, Panse S, Falkner B. The role of adiponectin in metabolic and vascular disease: a review. Clin Nephrol. 2011 Jan;75(1):26-33.

Lim YJ, Sidor NA, Tonial NC, Che A, Urquhart BL. Uremic Toxins in the Progression of Chronic Kidney Disease and Cardiovascular Disease: Mechanisms and Therapeutic Targets. Toxins (Basel). 2021 Feb 13;13(2):142. doi: 10.3390/toxins13020142.

Schepers E, Glorieux G, Vanholder R. The gut: the forgotten organ in uremia? Blood Purif. 2010;29(2):130-6. doi: 10.1159/000245639.

Vanholder R, Bammens B, de Loor H, et al. Warning: the unfortunate end of p-cresol as a uraemic toxin. Nephrol Dial Transplant. 2011 May;26(5):1464-7. doi: 10.1093/ndt/gfr056.

de Loor H, Bammens B, Evenepoel P, De Preter V, Verbeke K. Gas chromatographic-mass spectrometric analysis for measurement of p-cresol and its conjugated metabolites in uremic and normal serum. Clin Chem. 2005 Aug;51(8):1535-8. doi: 10.1373/clinchem.2005.050781.

Martinez AW, Recht NS, Hostetter TH, Meyer TW. Removal of P-cresol sulfate by hemodialysis. J Am Soc Nephrol. 2005 Nov;16(11):3430-6. doi: 10.1681/ASN.2005030310.

Leong SC, Sirich TL. Indoxyl Sulfate-Review of Toxicity and Therapeutic Strategies. Toxins (Basel). 2016 Nov 30;8(12):358. doi: 10.3390/toxins8120358.

Sirich T, Meyer TW. Indoxyl sulfate: long suspected but not yet proven guilty. Clin J Am Soc Nephrol. 2011 Jan;6(1):3-4. doi: 10.2215/CJN.10141110.

Barreto FC, Barreto DV, Stinghen AEM, Massy ZA. Comment on Indoxyl Sulfate-Review of Toxicity and Therapeutic Strategies. Toxins 2016, 8, 358. Toxins (Basel). 2017 Apr 17;9(4):142. doi: 10.3390/toxins9040142.

Hsu WL, Li SY, Liu JS, et al. High Uric Acid Ameliorates Indoxyl Sulfate-Induced Endothelial Dysfunction and Is Associated with Lower Mortality among Hemodialysis Patients. Toxins (Basel). 2017 Jan 6;9(1):20. doi: 10.3390/toxins9010020.

Wu CC, Hung SC, Kuo KL, Tarng DC. Impact of Indoxyl Sulfate on Progenitor Cell-Related Neovascularization of Peripheral Arterial Disease and Post-Angioplasty Thrombosis of Dialysis Vascular Access. Toxins (Basel). 2017 Jan 7;9(1):25. doi: 10.3390/toxins9010025.

Grooteman MP, van den Dorpel MA, Bots ML, et al; CONTRAST Investigators. Effect of online hemodiafiltration on all-cause mortality and cardiovascular outcomes. J Am Soc Nephrol. 2012 Jun;23(6):1087-96. doi: 10.1681/ASN.2011121140.

Ok E, Asci G, Toz H, et al; Turkish Online Haemodiafiltration Study. Mortality and cardiovascular events in online haemodiafiltration (OL-HDF) compared with high-flux dialysis: results from the Turkish OL-HDF Study. Nephrol Dial Transplant. 2013 Jan;28(1):192-202. doi: 10.1093/ndt/gfs407.

Morena M, Jaussent A, Chalabi L, et al; FRENCHIE Study Investigators. Treatment tolerance and patient-reported outcomes favor online hemodiafiltration compared to high-flux hemodialysis in the elderly. Kidney Int. 2017 Jun;91(6):1495-1509. doi: 10.1016/j.kint.2017.01.013.

Locatelli F, Karaboyas A, Pisoni RL, et al. Mortality risk in patients on hemodiafiltration versus hemodialysis: a 'real-world' comparison from the DOPPS. Nephrol Dial Transplant. 2018 Apr 1;33(4):683-689. doi: 10.1093/ndt/gfx277.

Maduell F, Moreso F, Pons M, et al; ESHOL Study Group. High-efficiency postdilution online hemodiafiltration reduces all-cause mortality in hemodialysis patients. J Am Soc Nephrol. 2013 Feb;24(3):487-97. doi: 10.1681/ASN.2012080875.