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Abstract: FR-PO110

The Roles of Uremic Toxin Early Elimination on AKI to CKD Transition

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Chen, Jia-Huang, National Taiwan University, College of medicine, Taipei, TAIWAN, Taiwan
  • Chiang, Chih-Kang, National Taiwan University, College of medicine, Taipei, TAIWAN, Taiwan
Background

The post-AKI fibrosis is emerging as a major driver of progressive CKD. However, the cause of abnormal renal recovery after AKI is multifactorial and still poorly understood. Indoxyl sulfate (IS) is a protein-bound uremic toxin produced by bacterial metabolism of the amino acid tryptophan, which excreted through organic anion transporter on renal tubular epithelial cells into urinary and generally accumulates in patients with CKD. Although the adverse effects of IS on CKD progression have been well documented, its impacts on post-AKI fibrosis are still unknown. Accordingly, we investigated whether AKI induces an increased level of serum IS and its role in AKI to CKD transition. Also, the therapeutic potency of early elimination of uremic toxins by absorbent Kremezin (AST-120) was tested.

Methods

In animal study, the two-step unilateral ischemia reperfusion injury with contralateral nephrectomy (hereafter abbreviated as UIRI) was used as a post-AKI fibrosis model. Briefly, C57BL/6 mice were subjected to 30 minutes unilateral ischemia reperfusion injury and contralateral nephrectomy were conducted at day10, and then sacrificed at day 15. All mice are randomly divided into: (1) Sham, (2) UIRI, (3) UIRI + indole, (4) UIRI + indole+ AST-120, and (5) UIRI + AST-120. For in vitro investigation, HK-2 cells were treated with 1mM IS for 48 h, followed by 12 hours of hypoxia and 24 hours of reperfusion (H/R) to explore the underlying mechanism.

Results

In our animal studies, we observed an increased serum IS levels without simutaneous accumulation of small uremic toxin molecules following 10 days of UIRI. Furthermore, AST-120 administration actually reduced deterioration of renal function caused by UIRI combined with high protein intake. We also revealed the possible mechanisms underlying the IS-enhanced proximal tubule damage after AKI. IS exposure potentiated H/R-induced G2/M cell cycle arrest, which also aggravated ER stress-mediated epithelial mesenchymal transition (EMT) as demonstrated by 4-PBA-treated rescue experiments.

Conclusion

Our results support the pathological role of uremic toxins in post-ischemic AKI fibrosis, and low protein diets would be recommended to prevent advanced kidney disease progression. Furthermore, elimination of IS by AST-120 is likely to prove useful for the prevention/treatment of post-AKI renal impairment.

Funding

  • Government Support - Non-U.S.