Journal of Chinese Pharmaceutical Sciences ›› 2025, Vol. 34 ›› Issue (11): 979-988.DOI: 10.5246/jcps.2025.11.073
• Review •
Weiwei Xie, Ming Wang, Yuqian Zhang, Yiran Jin*(
)
Received:2025-07-20
Revised:2025-08-14
Accepted:2025-09-17
Online:2025-12-02
Published:2025-12-02
Contact:
Yiran Jin
Supporting:
Weiwei Xie, Ming Wang, Yuqian Zhang, Yiran Jin. Advancements in the therapeutic application of indoxyl sulfate for kidney injury management[J]. Journal of Chinese Pharmaceutical Sciences, 2025, 34(11): 979-988.
| [1] |
Schreiner, G.E.; Maher, J.F. Uremia: biochemistry, pathogenesis and treatment. Springfield, IL, USA: Charles C Thomas Publisher. 1961.
|
| [2] |
Meyer, T.W.; Hostetter, T.H. Uremic solutes from colon microbes. Kidney Int. 2012, 81, 949–954.
|
| [3] |
Zhang, L.S.; Davies, S.S. Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions. Genome Med. 2016, 8, 46.
|
| [4] |
Duranton, F.; Cohen, G.; De Smet, R.; Rodriguez, M.; Jankowski, J.; Vanholder, R.; Argiles, A. Normal and pathologic concentrations of uremic toxins. J. Am. Soc. Nephrol. 2012, 23, 1258–1270.
|
| [5] |
Meyer, T.W.; Hostetter, T.H. Uremia. N Engl. J. Med. 2007, 357, 1316–1325.
|
| [6] |
Vanholder, R.; De Smet, R.; Glorieux, G.; Argilés, A.; Baurmeister, U.; Brunet, P.; Clark, W.; Cohen, G.; De Deyn, P.P.; Deppisch, R.; Descamps-Latscha, B.; Henle, T.; Jörres, A.; Lemke, H.D.; Massy, Z.A.; Passlick-Deetjen, J.; Rodriguez, M.; Stegmayr, B.; Stenvinkel, P.; Tetta, C.; Wanner, C.; Zidek, W. Review on uremic toxins: Classification, concentration, and interindividual variability. Kidney Int. 2003, 63, 1934–1943.
|
| [7] |
Sakai, T.; Maruyama, T.; Imamura, H.; Shimada, H.; Otagiri, M. Mechanism of stereoselective serum binding of ketoprofen after hemodialysis. J. Pharmacol. Exp. Ther. 1996, 278, 786–792.
|
| [8] |
Bourlioux, P.; Koletzko, B.; Guarner, F.; Braesco, V. The intestine and its microflora are partners for the protection of the host: report on the Danone Symposium "The Intelligent Intestine," held in Paris, June 14, 2002. Am. J. Clin. Nutr. 2003, 78, 675–683.
|
| [9] |
Hooper, L.V.; Gordon, J.I. Commensal host-bacterial relationships in the gut. Science. 2001, 292, 1115–1118.
|
| [10] |
Savage, D.C. Gastrointestinal microflora in mammalian nutrition. Annu. Rev. Nutr. 1986, 6, 155–178.
|
| [11] |
Aronov, P.A.; Luo, F.J.; Plummer, N.S.; Quan, Z.; Holmes, S.; Hostetter, T.H.; Meyer, T.W. Colonic contribution to uremic solutes. J. Am. Soc. Nephrol. 2011, 22, 1769–1776.
|
| [12] |
Vaziri, N.D.; Yuan, J.; Norris, K. Role of urea in intestinal barrier dysfunction and disruption of epithelial tight junction in chronic kidney disease. Am. J. Nephrol. 2013, 37, 1–6.
|
| [13] |
Wang, L.; Sweet, D.H. Renal organic anion transporters (SLC22 family): expression, regulation, roles in toxicity, and impact on injury and disease. AAPS J. 2013, 15, 53–69.
|
| [14] |
Wu, W.; Bush, K.T.; Nigam, S.K. Key role for the organic anion transporters, OAT1 and OAT3, in the in vivo handling of uremic toxins and solutes. Sci. Rep. 2017, 7, 4939.
|
| [15] |
Poesen, R.; Viaene, L.; Verbeke, K.; Claes, K.; Bammens, B.; Sprangers, B.; Naesens, M.; Vanrenterghem, Y.; Kuypers, D.; Evenepoel, P.; Meijers, B. Renal clearance and intestinal generation of p-cresyl sulfate and indoxyl sulfate in CKD. Clin. J. Am. Soc. Nephrol. 2013, 8, 1508–1514.
|
| [16] |
Enomoto, A.; Takeda, M.; Tojo, A.; Sekine, T.; Cha, S.H.; Khamdang, S.; Takayama, F.; Aoyama, I.; Nakamura, S.; Endou, H.; Niwa, T. Role of organic anion transporters in the tubular transport of indoxyl sulfate and the induction of its nephrotoxicity. J. Am. Soc. Nephrol. 2002, 13, 1711–1720.
|
| [17] |
Motojima, M.; Hosokawa, A.; Yamato, H.; Muraki, T.; Yoshioka, T. Uremic toxins of organic anions up-regulate PAI-1 expression by induction of NF-κB and free radical in proximal tubular cells. Kidney Int. 2003, 63, 1671–1680.
|
| [18] |
Gelasco, A.K.; Raymond, J.R. Indoxyl sulfate induces complex redox alterations in mesangial cells. Am. J. Physiol. Ren. Physiol. 2006, 290, F1551–F1558.
|
| [19] |
Owada, S.; Goto, S.; Bannai, K.J.; Hayashi, H.; Nishijima, F.; Niwa, T. Indoxyl sulfate reduces superoxide scavenging activity in the kidneys of normal and uremic rats. Am. J. Nephrol. 2008, 28, 446–454.
|
| [20] |
Liu, Y.H. New insights into epithelial-mesenchymal transition in kidney fibrosis. J. Am. Soc. Nephrol. 2010, 21, 212–222.
|
| [21] |
Loeffler, I.; Wolf, G. Transforming growth factor-β and the progression of renal disease. Nephrol. Dial. Transplant. 2014, 29, i37–i45.
|
| [22] |
Menn-Josephy, H.; Lee, C.S.; Nolin, A.; Christov, M.; Rybin, D.V.; Weinberg, J.M.; Henderson, J.; Bonegio, R.; Havasi, A. Renal interstitial fibrosis: an imperfect predictor of kidney disease progression in some patient cohorts. Am. J. Nephrol. 2016, 44, 289–299.
|
| [23] |
Miyajima, A.; Chen, J.; Lawrence, C.; Ledbetter, S.; Soslow, R.A.; Stern, J.; Jha, S.; Pigato, J.; Lemer, M.L.; Poppas, D.P.; Vaughan, E.D. Jr, Felsen, D. Antibody to transforming growth factor-β ameliorates tubular apoptosis in unilateral ureteral obstruction. Kidney Int. 2000, 58, 2301–2313.
|
| [24] |
Isaka, Y. Targeting TGF-β signaling in kidney fibrosis. Int. J. Mol. Sci. 2018, 19, 2532.
|
| [25] |
Miyazaki, T.; Ise, M.; Seo, H.; Niwa, T. Indoxyl sulfate increases the gene expressions of TGF-beta 1, TIMP-1 and pro-alpha 1(I) collagen in uremic rat kidneys. Kidney Int. Suppl. 1997, 62, S15–S22.
|
| [26] |
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.
|
| [27] |
Sancho-Martínez, S.M.; López-Novoa, J.M.; López-Hernández, F.J. Pathophysiological role of different tubular epithelial cell death modes in acute kidney injury. Clin. Kidney J. 2015, 8, 548–559.
|
| [28] |
Ferenbach, D.A.; Bonventre, J.V. Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD. Nat. Rev. Nephrol. 2015, 11, 264–276.
|
| [29] |
Ellis, R.J.; Small, D.M.; Ng, K.L.; Vesey, D.A.; Vitetta, L.; Francis, R.S.; Gobe, G.C.; Morais, C. Indoxyl sulfate induces apoptosis and hypertrophy in human kidney proximal tubular cells. Toxicol. Pathol. 2018, 46, 449–459.
|
| [30] |
Kim, S.H.; Yu, M.-A.; Ryu, E.S.; Jang, Y.H.; Kang, D.H. Indoxyl sulfate-induced epithelial-to-mesenchymal transition and apoptosis of renal tubular cells as novel mechanisms of progression of renal disease. Lab. Investig. 2012, 92, 488–498.
|
| [31] |
Bolati, D.; Shimizu, H.; Yisireyili, M.; Nishijima, F.; Niwa, T. Indoxyl sulfate, a uremic toxin, downregulates renal expression of Nrf2 through activation of NF-κB. BMC Nephrol. 2013, 14, 56.
|
| [32] |
Schulman, G.; Agarwal, R.; Acharya, M.; Berl, T.; Blumenthal, S.; Kopyt, N. A multicenter, randomized, double-blind, placebo-controlled, dose-ranging study of AST-120 (kremezin) in patients with moderate to severe CKD. Am. J. Kidney Dis. 2006, 47, 565–577.
|
| [33] |
Aoyama, I.; Shimokata, K.; Niwa, T. An oral adsorbent downregulates renal expression of genes that promote interstitial inflammation and fibrosis in diabetic rats. Nephron. 2002, 92, 635–651.
|
| [34] |
Aoyama, I.; Shimokata, K.; Niwa, T. Oral adsorbent AST-120 ameliorates interstitial fibrosis and transforming growth factor-β1 expression in spontaneously diabetic (OLETF) rats. Am. J. Nephrol. 2000, 20, 232–241.
|
| [35] |
Zou, C.; Lu, F.H.; Wu, Y.C.; Lin, Q.Z.; Liu, X.S. Indoxyl sulfate serum level in chronic renal failure patients detected using fluorescence-HPLC. Kidney Res. Clin. Pract. 2012, 31, A26.
|
| [36] |
Al Za’abi, M.; Ali, B.; Al Toubi, M. HPLC-fluorescence method for measurement of the uremic toxin indoxyl sulfate in plasma. J. Chromatogr. Sci. 2013, 51, 40–43.
|
| [37] |
Lin, C.N.; Wu, I.W.; Huang, Y.F.; Peng, S.Y.; Huang, Y.C.; Ning, H.C. Measuring serum total and free indoxyl sulfate and p-cresyl sulfate in chronic kidney disease using UPLC-MS/MS. J. Food Drug Anal. 2019, 27, 502–509.
|
| [38] |
Torii, T.; Kanemitsu, K.; Wada, T.; Itoh, S.; Kinugawa, K.; Hagiwara, A. Measurement of short-chain fatty acids in human faeces using high-performance liquid chromatography: specimen stability. Ann. Clin. Biochem. 2010, 47, 447–452.
|
| [39] |
Ali, I.; Gupta, V.K.; Aboul-Enein, H.Y.; Hussain, A. Hyphenation in sample preparation: Advancement from the micro to the nano world. J. Sep. Sci. 2008, 31, 2040–2053.
|
| [40] |
ALOthman, Z.A.; ALanazi, A.G.; Ali, I. A comparative and simultaneous analysis of indoxyl sulfate and sodium butyrate in human plasma by SPE and HPLC methods for kidney patients. J. Chromatogr. B. 2020, 1159, 122356.
|
| [41] |
Fushimi, Y.; Tatebe, J.; Okuda, Y.; Ishii, T.; Ujiie, S.; Morita, T. Performance evaluation of an indoxyl sulfate assay kit "NIPRO". Clin. Chem. Lab. Med. 2019, 57, 1770–1776.
|
| [42] |
Pretorius, C.J.; McWhinney, B.C.; Sipinkoski, B.; Johnson, L.A.; Rossi, M.; Campbell, K.L.; Ungerer, J.P.J. Reference ranges and biological variation of free and total serum indoxyl- and p-cresyl sulphate measured with a rapid UPLC fluorescence detection method. Clin. Chim. Acta. 2013, 419, 122–126.
|
| [43] |
Shu, C.; Chen, X.J.; Xia, T.Y.; Zhang, F.; Gao, S.H.; Chen, W.S. LC–MS/MS method for simultaneous determination of serum p-cresyl sulfate and indoxyl sulfate in patients undergoing peritoneal dialysis. Biomed. Chromatogr. 2016, 30, 1782–1788.
|
| [44] |
Vinge, E.; Lindergård, B.; Nilsson-Ehle, P.; Grubb, A. Relationships among serum cystatin C, serum creatinine, lean tissue mass and glomerular filtration rate in healthy adults. Scand. J. Clin. Lab. Investig. 1999, 59, 587–592.
|
| [45] |
Schwingshackl, L.; Hoffmann, G. Comparison of high vs. normal/low protein diets on renal function in subjects without chronic kidney disease: a systematic review and meta-analysis. PLoS One. 2014, 9, e97656.
|
| [46] |
Wu, I.W.; Hsu, K.H.; Lee, C.C.; Sun, C.Y.; Hsu, H.J.; Tsai, C.J.; Tzen, C.Y.; Wang, Y.C.; Lin, C.Y.; Wu, M.S. P-Cresyl sulphate and indoxyl sulphate predict progression of chronic kidney disease. Nephrol. Dial. Transplant. 2011, 26, 938–947.
|
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