AST-120 (kremezin; Kureha Chemical, Tokyo, Japan) is an oral spherical carbonaceous adsorbent, which was approved for clinical use in Japanese chronic kidney disease (CKD) patients in 1991. It adsorbs indole, the precursor of indoxyl sulfate, in the intestines and prevents indoxyl sulfate production. Indoxyl sulfate, initially identified as a major uremic toxin that causes uremic symptoms, contributes to CKD progression. Since AST-120 decreases serum indoxyl sulfate in a dose-dependent manner, multicenter prospective trials have been conducted in Japan in the 1980s; these trials were mostly in favor of the efficacy of AST-120 in delaying the initiation of dialysis in patients with advanced stage CKD. Many animal studies support the effects of AST-120 on renal outcomes as well as on cardiovascular complications. However, there are yet no reports that unequivocally demonstrate the improvement of hard renal endpoints and/or cardiovascular endpoints. This commentary briefly reviews the major outcomes of the recent clinical trials on AST-120.

1.
Niwa T, Ise M: Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis. J Lab Clin Med 1994;124:96-104.
2.
Barreto FC, Barreto DV, Liabeuf S, Meert N, Glorieux G, Temmar M, Choukroun G, Vanholder R, Massy ZA; European Uremic Toxin Work Group (EUTox): Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin J Am Soc Nephrol 2009;4:1551-1558.
3.
Niwa T: Role of indoxyl sulfate in the progression of chronic kidney disease and cardiovascular disease: experimental and clinical effects of oral sorbent AST-120. Ther Apher Dial 2011;15:120-124.
4.
Chiang CK, Tanaka T, Inagi R, Fujita T, Nangaku M: Indoxyl sulfate, a representative uremic toxin, suppresses erythropoietin production in a HIF-dependent manner. Lab Invest 2011;91:1564-1571.
5.
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;299:F568-F576.
6.
Palm F, Nangaku M, Fasching A, Tanaka T, Nordquist L, Hansell P, Kawakami T, Nishijima F, Fujita T: Uremia induces abnormal oxygen consumption in tubules and aggravates chronic hypoxia of the kidney via oxidative stress. Am J Physiol Renal Physiol 2010;299:F380-F386.
7.
Tanaka T, Yamaguchi J, Higashijima Y, Nangaku M: Indoxyl sulfate signals for rapid mRNA stabilization of Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2) and suppresses the expression of hypoxia-inducible genes in experimental CKD and uremia. FASEB J 2013;27:4059-4075.
8.
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.
9.
Velenosi TJ, Hennop A, Feere DA, Tieu A, Kucey AS, Kyriacou P, McCuaig LE, Nevison SE, Kerr MA, Urquhart BL: Untargeted plasma and tissue metabolomics in rats with chronic kidney disease given AST-120. Sci Rep 2016;6:22526.
10.
Okada K, Okawa E, Shibahara H, Maruyama T, Maruyama N, Matsumoto K, Takahashi S: Combination therapy with angiotensin-converting enzyme inhibitor and oral adsorbent of uremic toxins can delay the appearance of glomerular sclerosis and interstitial fibrosis in established renal failure. Kidney Blood Press Res 2004;27:218-225.
11.
Okada K, Matsumoto K, Takahashi S: Uremic toxins adsorbed by AST-120 promote tubular hypertrophy and interstitial fibrosis in nephrectomized rats. Kidney Blood Press Res 2005;28:8-13.
12.
Koshikawa S, et al: The effects of AST-120 on delaying initiation of dialysis therapy in end-stage renal disease. Kidney Dial 1992;32:783-794.
13.
Koide K, Koshikawa S, Yamane Y, et al: Clinical evaluation of AST-120 on suppression of progression of chronic renal failure - multi-center, double-blind study in comparison with placebo. Clin Eval 1987;15:527-564.
14.
Sanaka T, Sugino N, Teraoka S, Ota K: Therapeutic effects of oral sorbent in undialyzed uremia. Am J Kidney Dis 1988;12:97-103.
15.
Konishi K, Nakano S, Tsuda S, Nakagawa A, Kigoshi T, Koya D: AST-120 (Kremezin) initiated in early stage chronic kidney disease stunts the progression of renal dysfunction in type 2 diabetic subjects. Diabetes Res Clin Pract 2008;81:310-315.
16.
Owada A, Nakao M, Koike J, Ujiie K, Tomita K, Shiigai T: Effects of oral adsorbent AST-120 on the progression of chronic renal failure: a randomized controlled study. Kidney Int Suppl 1997;63:S188-S190.
17.
Shoji T, Wada A, Inoue K, Hayashi D, Tomida K, Furumatsu Y, Kaneko T, Okada N, Fukuhara Y, Imai E, Tsubakihara Y: Prospective randomized study evaluating the efficacy of the spherical adsorptive carbon AST-120 in chronic kidney disease patients with moderate decrease in renal function. Nephron Clin Pract 2007;105:c99-c107.
18.
Nakamura T, Kawagoe Y, Matsuda T, Ueda Y, Shimada N, Ebihara I, Koide H: Oral ADSORBENT AST-120 decreases carotid intima-media thickness and arterial stiffness in patients with chronic renal failure. Kidney Blood Press Res 2004;27:121-126.
19.
Akizawa T, Asano Y, Morita S, Wakita T, Onishi Y, Fukuhara S, Gejyo F, Matsuo S, Yorioka N, Kurokawa K; CAP-KD Study Group: Effect of a carbonaceous oral adsorbent on the progression of CKD: a multicenter, randomized, controlled trial. Am J Kidney Dis 2009;54:459-467.
20.
Schulman G, Berl T, Beck GJ, Remuzzi G, Ritz E, Arita K, Kato A, Shimizu M: Randomized placebo-controlled EPPIC trials of AST-120 in CKD. J Am Soc Nephrol 2015;26:1732-1746.
21.
Cha RH, Kang SW, Park CW, Cha DR, Na KY, Kim SG, Yoon SA, Han SY, Chang JH, Park SK, Lim CS, Kim YS: 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;11:559-567.
22.
Schulman G, Berl T, Beck G, Remuzzi G, Ritz E, Shimizu M, Shobu Y, Kikuchi M: Post hoc analyses of the EPPIC trials to assess the effect of AST-120 in chronic kidney disease patients. ASN Kidney Week 2015 San Diego, TH-PO654.
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