Pharmacological Actions of Indoxyl Sulfate and AST-120 That Should Be Recognized for the Strategic Treatment of Patients with Chronic Kidney Disease

Figures & data

Figure 1 Structure of indoxyl sulfate: C₈H₈NO₄S.

Figure 2 Metabolism of indoxyl sulfate and the beneficial effect of AST-120.

Table 1 Summary of Results of Similar Studies Conducted to Investigate the Association Between Indoxyl Sulfate, CKD, and CVD

Study	Methods	Results
Niwa et al^Citation19	Oral administration of indole to 5/6-nephrectomized rats	The oral administration of indole to 5/6-nephrectomized uremic rats increased the serum levels of creatinine and blood urea nitrogen.After oral administration, indole could not be detected in the urine, but a large amount of its metabolite, indoxyl sulfate (IS) was. The glomerular sclerosis index in the indole-treated rats was higher than that in the control uremic rats.
Enomoto et al^Citation20	Oral and IP administration of IS to 5/6-nephrectomized rats	The administration of IS to 5/6-nephrectomized rats caused a faster progression to chronic renal failure, and immunohistochemistry revealed that IS was detected in the proximal and distal tubules
Miyazaki et al^Citation21	(in vivo) Oral administration of IS to 5/6-nephrectomized rats (in vitro) IS administration to cultured proximal tubular cells	(in vivo) Indoxyl sulfate administration was observed to enhance the mRNA levels of ICAM-1, TGF-beta 1, TIMP-1 and pro alpha 1 collagen in the renal cortex of 5/6-nephrectomized uremic rats. (in vitro) The addition of IS increased the synthesis of TGF-beta 1 in the cultured proximal tubular cells.
Bolati et al^Citation22	(in vivo) Oral administration of IS to Dahl salt-sensitive hypertensive (DH) rats (in vitro) IS administration to the cultured human proximal tubular cells (HK-2)	(in vivo) DH+IS rats showed increased Masson’s trichrome-positive fibrosis areas compared to DH rats. (in vitro) IS-treated HK-2 cells showed a reduced expression of E-cadherin and ZO-1 and enhanced expression of alpha-SMA.
Dou et al^Citation23	IS administration to the cultured human umbilical vein endothelial cells (HUVEC)	IS inhibited the proliferation of endothelial cells and decreased endothelial wound repair.
Yamamoto et al^Citation24	IS administration to the cultured rat vascular smooth muscle cells	IS directly stimulated the proliferation of rat vascular smooth muscle cells via MAP kinase activation.
Yamamoto et al^Citation25	Apolipoprotein E-deficient mice underwent uninephrectomy, 5/6-nephrectomy, or sham operation at 8 weeks of age and were treated with AST-120 after renal ablation	AST-120 reduced the extent of atherosclerosis induced by kidney injury and altered the lesion characteristics in apolipoprotein E-deficient mice.
Shimazu et al^Citation26	Serum IS and plasma brain natriuretic peptide (BNP) levels were measured in 76 patients with dilated cardiomyopathy (DCM) who also underwent echocardiographic examination.	Cardiac dysfunction was associated with an increased serum IS level, which might serve as a new prognostic marker in DCM patients with either normal renal function or mild to moderate CKD.
Barreto et al^Citation27	Investigation of the association among serum IS, vascular calcification, vascular stiffness, and mortality in a cohort of CKD patients	The highest IS tertile was a powerful predictor of overall and cardiovascular mortality. IS may play a significant role in the vascular disease and higher mortality observed in CKD patients.
Liu et al^Citation28	Investigation of serum IS, p-cresol, and other variables on clinical outcomes in HD patients during a 20-month follow-up	Serum IS and p-cresol levels were related to cardiovascular events.
Shafi et al^Citation29	Association of baseline free levels of IS, p-cresol sulfate, indoxyl, hippurate and phenylacetylglutamine, with outcomes in hemodialysis patients.	Free levels of IS were associated with a higher risk of cardiovascular morbidity and mortality in incidental hemodialysis patients.
Cao et al^Citation30	Association of IS with heart failure among patients on hemodialysis	Plasma IS was associated with the first event of heart failure in patients on hemodialysis.

Abbreviations: IS, indoxyl sulfate; IP, intraperitoneal; CKD, chronic kidney disease; HD, hemodialysis.

Table 2 The Primary Endpoint (Renal Outcome) Was Not Statistically Positive in the AST-120-Treated Group, but the Secondary Endpoint (eGFR) Was Significantly Suppressed. Adherence Data in CAP-KD Trial Was Not Available in the Original Document

Trial	Period (Year)	Dose of AST-120 (g/Day)	Primary Endpoint (Renal Outcomes)	Secondary Endpoint (eGFR Decline)	Adherence
CAP-KD	1	6	Negative	Positive	N.A.
EPPIC	3.5	9	Negative	Positive	>90%
K-STAR	3	6	Negative	Positive (post hoc)	90%

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