Nutr Res Pract.  2022 Aug;16(4):464-475. 10.4162/nrp.2022.16.4.464.

Indoxyl sulfate, homocysteine, and antioxidant capacities in patients at different stages of chronic kidney disease

Affiliations
  • 1Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407219, Taiwan
  • 2Department of Life Science, Tunghai University, Taichung 407224, Taiwan
  • 3School of Medicine, China Medical University, Taichung 404333, Taiwan
  • 4College of Medicine, National Chung Hsing University, Taichung 402202, Taiwan
  • 5Department of Nutrition, Chung Shan Medical University, Taichung 402306, Taiwan
  • 6Department of Nutrition, Chung Shan Medical University Hospital, Taichung 402306, Taiwan
  • 7Department of Health Industry Technology Management, Chung Shan Medical University, Taichung 402306, Taiwan
  • 8Department of Nutrition, College of Medical and Health Care, Hung-Kuang University, Taichung 433304, Taiwan
  • 9School of Medicine, National Yang-Ming University, Taipei 112304, Taiwan

Abstract

BACKGROUND/OBJECTIVES
Increased levels of uremic toxins and decreased antioxidant capacity have a significant impact on the progression of chronic kidney disease (CKD). However, it remains unclear whether they interact with each other to mediate the damage of kidney function. The purpose of this study was to investigate whether uremic toxins (i.e., homocysteine and indoxyl sulfate [IS]), as well as glutathione-dependent antioxidant enzyme activities are dependently or independently associated with kidney function during different stages of CKD patients.
SUBJECTS/METHODS
One hundred thirty-two patients diagnosed with CKD at stages 1 to 5 participated in this cross-sectional study.
RESULTS
Patients who had reached an advanced CKD stage experienced an increase in plasma uremic toxin levels, along with decreased glutathione peroxidase (GSH-Px) activity. Plasma homocysteine, cysteine, and IS concentrations were all positively associated with each other, but negatively correlated to GSH-Px activity levels after adjusting for potential confounders in all CKD patients. Although plasma homocysteine, cysteine, IS, and GSHPx levels were significantly associated with kidney function, only plasma IS levels still had a significant association with kidney function after these parameters were simultaneously adjusted. In addition, plasma IS could interact with GSH-Px activity to be associated with kidney function.
CONCLUSIONS
IS plays a more dominant role than homocysteine and GSH-Px activity in relation to kidney function.

Keyword

Uremic toxins; homocysteine; indoxyl sulfate; glutathione peroxidase; chronic kidney disease

Reference

1. Vanholder R, De Smet R, Glorieux G, Argilés A, Baurmeister U, Brunet P, Clark W, Cohen G, De Deyn PP, Deppisch R, et al. Review on uremic toxins: classification, concentration, and interindividual variability. Kidney Int. 2003; 63:1934–1943. PMID: 12675874.
Article
2. Rossi M, Campbell KL, Johnson DW. Indoxyl sulphate and p-cresyl sulphate: therapeutically modifiable nephrovascular toxins. OA Nephrol. 2013; 1:13.
Article
3. Vanholder R, De Smet R, Lameire N. Protein-bound uremic solutes: the forgotten toxins. Kidney Int Suppl. 2001; 78:S266–S270. PMID: 11169024.
Article
4. Liu WC, Tomino Y, Lu KC. Impacts of indoxyl sulfate and p-cresol sulfate on chronic kidney disease and mitigating effects of AST-120. Toxins (Basel). 2018; 10:367.
Article
5. Niwa T. Uremic toxicity of indoxyl sulfate. Nagoya J Med Sci. 2010; 72:1–11. PMID: 20229698.
6. Lin CJ, Chen HH, Pan CF, Chuang CK, Wang TJ, Sun FJ, Wu CJ. p-Cresylsulfate and indoxyl sulfate level at different stages of chronic kidney disease. J Clin Lab Anal. 2011; 25:191–197. PMID: 21567467.
Article
7. Levi A, Cohen E, Levi M, Goldberg E, Garty M, Krause I. Elevated serum homocysteine is a predictor of accelerated decline in renal function and chronic kidney disease: a historical prospective study. Eur J Intern Med. 2014; 25:951–955. PMID: 25457436.
Article
8. Chen CH, Yang WC, Hsiao YH, Huang SC, Huang YC. High homocysteine, low vitamin B-6, and increased oxidative stress are independently associated with the risk of chronic kidney disease. Nutrition. 2016; 32:236–241. PMID: 26526964.
Article
9. Hoffman M. Hypothesis: hyperhomocysteinemia is an indicator of oxidant stress. Med Hypotheses. 2011; 77:1088–1093. PMID: 21963358.
Article
10. Long Y, Nie J. Homocysteine in renal injury. Kidney Dis (Basel). 2016; 2:80–87. PMID: 27536696.
Article
11. Sun CY, Hsu HH, Wu MS. p-Cresol sulfate and indoxyl sulfate induce similar cellular inflammatory gene expressions in cultured proximal renal tubular cells. Nephrol Dial Transplant. 2013; 28:70–78. PMID: 22610984.
Article
12. Gouroju S, Rao PVLNS, Bitla AR, Vinapamula KS, Manohar SM, Vishnubhotla S. Role of gut-derived uremic toxins on oxidative stress and inflammation in patients with chronic kidney disease. Indian J Nephrol. 2017; 27:359–364. PMID: 28904431.
Article
13. Stoyanova E, Sandoval SB, Zúñiga LA, El-Yamani N, Coll E, Pastor S, Reyes J, Andrés E, Ballarin J, Xamena N, et al. Oxidative DNA damage in chronic renal failure patients. Nephrol Dial Transplant. 2010; 25:879–885. PMID: 19889871.
Article
14. Sahni N, Gupta KL, Rana SV, Prasad R, Bhalla AK. Intake of antioxidants and their status in chronic kidney disease patients. J Ren Nutr. 2012; 22:389–399. PMID: 22227184.
Article
15. Sung CC, Hsu YC, Chen CC, Lin YF, Wu CC. Oxidative stress and nucleic acid oxidation in patients with chronic kidney disease. Oxid Med Cell Longev. 2013; 2013:301982. PMID: 24058721.
Article
16. Xu G, Luo K, Liu H, Huang T, Fang X, Tu W. The progress of inflammation and oxidative stress in patients with chronic kidney disease. Ren Fail. 2015; 37:45–49. PMID: 25375354.
Article
17. Avissar N, Ornt DB, Yagil Y, Horowitz S, Watkins RH, Kerl EA, Takahashi K, Palmer IS, Cohen HJ. Human kidney proximal tubules are the main source of plasma glutathione peroxidase. Am J Physiol. 1994; 266:C367–C375. PMID: 8141250.
Article
18. Brown KM, Arthur JR. Selenium, selenoproteins and human health: a review. Public Health Nutr. 2001; 4:593–599. PMID: 11683552.
Article
19. Zachara BA, Salak A, Koterska D, Manitius J, Wasowicz W. Selenium and glutathione peroxidases in blood of patients with different stages of chronic renal failure. J Trace Elem Med Biol. 2004; 17:291–299. PMID: 15139391.
Article
20. Johnson-Davis KL, Fernelius C, Eliason NB, Wilson A, Beddhu S, Roberts WL. Blood enzymes and oxidative stress in chronic kidney disease: a cross sectional study. Ann Clin Lab Sci. 2011; 41:331–339. PMID: 22166502.
21. Zargari M, Sedighi O. Influence of hemodialysis on lipid peroxidation, enzymatic and non-enzymatic antioxidant capacity n chronic renal failure patients. Nephrourol Mon. 2015; 7:e28526. PMID: 26539417.
Article
22. Himmelfarb J, Stenvinkel P, Ikizler TA, Hakim RM. The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney Int. 2002; 62:1524–1538. PMID: 12371953.
Article
23. Khazim K, Giustarini D, Rossi R, Verkaik D, Cornell JE, Cunningham SED, Mohammad M, Trochta K, Lorenzo C, Folli F, et al. Glutathione redox potential is low and glutathionylated and cysteinylated hemoglobin levels are elevated in maintenance hemodialysis patients. Transl Res. 2013; 162:16–25. PMID: 23333585.
Article
24. Tucker PS, Dalbo VJ, Han T, Kingsley MI. Clinical and research markers of oxidative stress in chronic kidney disease. Biomarkers. 2013; 18:103–115. PMID: 23339563.
Article
25. KDIGO CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013; 3:1–150.
26. Araki A, Sako Y. Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J Chromatogr A. 1987; 422:43–52.
Article
27. Cheng FP, Hsieh MJ, Chou CC, Hsu WL, Lee YJ. Detection of indoxyl sulfate levels in dogs and cats suffering from naturally occurring kidney diseases. Vet J. 2015; 205:399–403. PMID: 26118479.
Article
28. Lapenna D, Ciofani G, Pierdomenico SD, Giamberardino MA, Cuccurullo F. Reaction conditions affecting the relationship between thiobarbituric acid reactivity and lipid peroxides in human plasma. Free Radic Biol Med. 2001; 31:331–335. PMID: 11461770.
Article
29. Arnao MB, Cano A, Hernández-Ruiz J, García-Cánovas F, Acosta M. Inhibition by L-ascorbic acid and other antioxidants of the 2.2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) oxidation catalyzed by peroxidase: a new approach for determining total antioxidant status of foods. Anal Biochem. 1996; 236:255–261. PMID: 8660502.
Article
30. Zachara BA, Adamowicz A, Trafikowska U, Pilecki A, Manitius J. Decreased plasma glutathione peroxidase activity in uraemic patients. Nephron. 2000; 84:278–281. PMID: 10720902.
Article
31. Kuchta A, Pacanis A, Kortas-Stempak B, Cwiklińska A, Ziętkiewicz M, Renke M, Rutkowski B. Estimation of oxidative stress markers in chronic kidney disease. Kidney Blood Press Res. 2011; 34:12–19. PMID: 21071957.
Article
32. Zachara BA, Gromadzińska J, Wąsowicz W, Zbróg Z. Red blood cell and plasma glutathione peroxidase activities and selenium concentration in patients with chronic kidney disease: a review. Acta Biochim Pol. 2006; 53:663–677. PMID: 17160142.
Article
33. Ceballos-Picot I, Witko-Sarsat V, Merad-Boudia M, Nguyen AT, Thévenin M, Jaudon MC, Zingraff J, Verger C, Jungers P, Descamps-Latscha B. Glutathione antioxidant system as a marker of oxidative stress in chronic renal failure. Free Radic Biol Med. 1996; 21:845–853. PMID: 8902530.
Article
34. Lasseur C, Parrot F, Delmas Y, Level C, Ged C, Redonnet-Vernhet I, Montaudon D, Combe C, Chauveau P. Impact of high-flux/high-efficiency dialysis on folate and homocysteine metabolism. J Nephrol. 2001; 14:32–35. PMID: 11281342.
35. Wrone EM, Hornberger JM, Zehnder JL, McCann LM, Coplon NS, Fortmann SP. Randomized trial of folic acid for prevention of cardiovascular events in end-stage renal disease. J Am Soc Nephrol. 2004; 15:420–426. PMID: 14747389.
Article
36. Rossi M, Campbell K, Johnson D, Stanton T, Pascoe E, Hawley C, Dimeski G, McWhinney B, Ungerer J, Isbel N. Uraemic toxins and cardiovascular disease across the chronic kidney disease spectrum: an observational study. Nutr Metab Cardiovasc Dis. 2014; 24:1035–1042. PMID: 24880738.
Article
37. Xie T, Bao M, Zhang P, Jiao X, Zou J, Ding X, Cao X, Yu X. Serum concentration of indoxyl sulfate in peritoneal dialysis patients and low-flux hemodialysis patients. Blood Purif. 2019; 48:183–190. PMID: 31039561.
Article
38. 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; 25:1897–1907. PMID: 24812165.
Article
39. Milanesi S, Garibaldi S, Saio M, Ghigliotti G, Picciotto D, Ameri P, Garibotto G, Barisione C, Verzola D. Indoxyl sulfate induces renal fibroblast activation through a targetable heat shock protein 90-dependent pathway. Oxid Med Cell Longev. 2019; 2019:2050183. PMID: 31178953.
Article
40. Nakano T, Katsuki S, Chen M, Decano JL, Halu A, Lee LH, Pestana DVS, Kum AST, Kuromoto RK, Golden WS, et al. Uremic toxin indoxyl sulfate promotes proinflammatory macrophage activation via the interplay of OATP2B1 and DII4-Notch signaling. Circulation. 2019; 139:78–96. PMID: 30586693.
Article
41. Kamiński TW, Pawlak K, Karbowska M, Myśliwiec M, Pawlak D. Indoxyl sulfate - the uremic toxin linking hemostatic system disturbances with the prevalence of cardiovascular disease in patients with chronic kidney disease. BMC Nephrol. 2017; 18:35. PMID: 28122514.
Article
42. Hung SC, Kuo KL, Wu CC, Tarng DC. Indoxyl sulfate: a novel cardiovascular risk factor in chronic kidney disease. J Am Heart Assoc. 2017; 6:e005022. PMID: 28174171.
Article
43. Fan PC, Chang JC, Lin CN, Lee CC, Chen YT, Chu PH, Kou G, Lu YA, Yang CW, Chen YC. Serum indoxyl sulfate predicts adverse cardiovascular events in patients with chronic kidney disease. J Formos Med Assoc. 2019; 118:1099–1106. PMID: 30928187.
Article
44. Barisione C, Ghigliotti G, Canepa M, Balbi M, Brunelli C, Ameri P. Indoxyl sulfate: a candidate target for the prevention and treatment of cardiovascular disease in chronic kidney disease. Curr Drug Targets. 2015; 16:366–372. PMID: 25537654.
Article
45. Shimizu H, Bolati D, Adijiang A, Muteliefu G, Enomoto A, Nishijima F, Dateki M, Niwa T. NF-κB plays an important role in indoxyl sulfate-induced cellular senescence, fibrotic gene expression, and inhibition of proliferation in proximal tubular cells. Am J Physiol Cell Physiol. 2011; 301:C1201–C1212. PMID: 21832251.
Article
46. Yu M, Kim YJ, Kang DH. Indoxyl sulfate-induced endothelial dysfunction in patients with chronic kidney disease via an induction of oxidative stress. Clin J Am Soc Nephrol. 2011; 6:30–39. PMID: 20876676.
Article
47. Dou L, Jourde-Chiche N, Faure V, Cerini C, Berland Y, Dignat-George F, Brunet P. The uremic solute indoxyl sulfate induces oxidative stress in endothelial cells. J Thromb Haemost. 2007; 5:1302–1308. PMID: 17403109.
Article
48. Sirich TL, Plummer NS, Gardner CD, Hostetter TH, Meyer TW. Effect of increasing dietary fiber on plasma levels of colon-derived solutes in hemodialysis patients. Clin J Am Soc Nephrol. 2014; 9:1603–1610. PMID: 25147155.
Article
49. Rossi M, Johnson DW, Xu H, Carrero JJ, Pascoe E, French C, Campbell KL. Dietary protein-fiber ratio associates with circulating levels of indoxyl sulfate and p-cresyl sulfate in chronic kidney disease patients. Nutr Metab Cardiovasc Dis. 2015; 25:860–865. PMID: 26026209.
Article
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