Impacts of Indoxyl Sulfate and p-Cresol Sulfate on Chronic Kidney Disease and Mitigating Effects of AST-120

Wen-Chih Liu, Yasuhiko Tomino, Kuo-Cheng Lu, Wen-Chih Liu, Yasuhiko Tomino, Kuo-Cheng Lu

Abstract

Uremic toxins, such as indoxyl sulfate (IS) and p-cresol, or p-cresyl sulfate (PCS), are markedly accumulated in the organs of chronic kidney disease (CKD) patients. These toxins can induce inflammatory reactions and enhance oxidative stress, prompting glomerular sclerosis and interstitial fibrosis, to aggravate the decline of renal function. Consequently, uremic toxins play an important role in the worsening of renal and cardiovascular functions. Furthermore, they destroy the quantity and quality of bone. Oral sorbent AST-120 reduces serum levels of uremic toxins in CKD patients by adsorbing the precursors of IS and PCS generated by amino acid metabolism in the intestine. Accordingly, AST-120 decreases the serum IS levels and reduces the production of reactive oxygen species by endothelial cells, to impede the subsequent oxidative stress. This slows the progression of cardiovascular and renal diseases and improves bone metabolism in CKD patients. Although large-scale studies showed no obvious benefits from adding AST-120 to the standard therapy for CKD patients, subsequent sporadic studies may support its use. This article summarizes the mechanisms of the uremic toxins, IS, and PCS, and discusses the multiple effects of AST-120 in CKD patients.

Keywords: chronic kidney disease-mineral bone disease; indoxyl sulfate; reactive oxygen species; uremic toxin; uremic toxin adsorbent.

Conflict of interest statement

The authors declare that there is no conflict of interest regarding the publication of this paper.

Figures

Figure 1
Figure 1
Mechanisms of IS pathology. IS enters renal tubular cells or VSMCs through OAT1 and OAT3. It induces free radical production, reduces nitric oxide levels, and activates AHR to produce ROS that damage cells. In the cardiovascular system, damaged endothelial cells and VSMCs secrete elevated amounts of NADPH and Nox4, while secreting less KLOTHO, a protective role in the kidney. This causes dysfunction of endothelial cells and osteoblastic phenotyped-VSMCs, which ultimately lead to atherosclerosis and arteriosclerosis. In the kidney, injured tubular cells and mesangial cells secrete various cytokines to promote EMT transition, which results in tubular and interstitial cell fibrosis. In the bone, at early-stage CKD, hyperphosphatemia, hypocalcemia, vitamin D deficiency, FGF23 elevation, and parathyroid hormone (PTH) elevation lead to bone fragility and fracture. IS potentiates this condition. Upon further worsening of the renal function, the viability and function of osteoblasts and osteoclasts are impaired and PTH is secreted, leading to reduced bone quantity. This is called CKD-MBD, or renal osteodystrophy. IS causes deterioration of some material properties of the bone. Changes in these material properties perturb bone elasticity, leading to a decline in bone quality. This disease concept is called “uremic osteoporosis”. AHR, aryl hydrocarbon receptor; CBF-1, core binding factor 1; CKD-MBD, chronic kidney disease-mineral bone disease; CYP1A1, cytochrome P450 family 1 subfamily A member 1; EMT, epithelial-to-mesenchymal transition; FGF23, fibroblast growth factor 23; ICAM-1, intercellular adhesion molecule 1; IS, indoxyl sulfate; NADPH, nicotinamide adenine dinucleotide phosphate hydrogen; NF-κB, nuclear factor kappa B; NO, nitric oxide; Nox4, NADPH Oxidase 4; OAT, organic anion transporters; ROS, reactive oxygen species; PAI-1, plasminogen activation inhibitor -1; PTH, parathyroid hormone; TGF-β1, transforming growth factor β-1; VSMCs, vascular smooth muscle cells.

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