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Please note that you are viewing an archived section from 2019 and some content may be unavailable. To unlock all content for 2019, please visit the archives.

Abstract: SA-PO340

Indoleamine 2,3-Dioxygenase-1, a Novel Therapeutic Target in Thrombotic Uremic Toxicity

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • Walker, Joshua A., Boston University, Boston, Massachusetts, United States
  • Richards, Sean, Boston University Medical Center, Boston, Massachusetts, United States
  • Belghasem, Mostafa, Boston University, Boston, Massachusetts, United States
  • Yoo, Sung bok, Boston University, Boston, Massachusetts, United States
  • Arinze, Nkiruka, Boston Medical Center, Boston, Massachusetts, United States
  • Whelan, Stephen A., Boston Univeristy, Boston, Massachusetts, United States
  • Lee, Norman, Boston University, Boston, Massachusetts, United States
  • Chitalia, Vipul C., Boston University School of Medicine, Boston, Massachusetts, United States
Background

Metabolites associated with chronic kidney disease (CKD) are highly thrombogenic. Emerging evidence validated CKD-specific mediators and definined the uremic solute-aryl hydrocarbon receptor (AHR)-tissue factor (TF) axis resulting in increased thrombosis. Given the importance of tryptophan metabolites in inducing thrombosis in CKD, we examined the role of Indoleamine 2,3-dioxygenase-1 (IDO), the rate limiting enzyme of the kynurenine pathway in CKD-mediated thrombosis.

Methods

Global IDO knock-out and wild type mice treated with 1-methyltryptophan (1-MT), a specific inhibitor of IDO, were used in an adenine-induced model of CKD. Plasma uremic solutes were measured by LC/MS. IDO protein and mRNA were examined in vascular smooth muscle cells (vSMCs) and in flow-loops. Prothrombic effects of IDO were further confirmed in clinical, Dialysis Access consortium (DAC)-fistual and Thrombolysis in Myocardial Infacrction (TIMI)-II.

Results

Compared to IDO+/+mice, IDO-/-mice showed a significantly increased time to occlusion (TTO) in both non-CKD and CKD mice models (p<0.05). IDO+/+mice administered 1-MT in a CKD model had increased TTO compared to controls, supporting the role of IDO in thrombosis. (p<0.05). Indoxyl sulfate (IS), a prothrombotic uremic solute, increased IDO expression in a dose-dependent manner in vSMCs in vitroand 3D flow loops. IDO protein and mRNA was upregulated by IS at concentrations observed in CKD patients. Polyubiquitination and proteasomal degradation of IDO was substantially inhibited by IS. IDO activity of sera samples was significantly higher in those patients who subseqently developed AVF thrombosis (DAC-fistula trial, p=0.001) and post-angioplasty thrombois (TIMI-II trial, p=0.008) compared to subjects without a thrombotic event.

Conclusion

We demonstrate a novel role for IDO as a contributor to CKD-mediated thrombosis and as a potential therapeutic target in post-interventional thrombosis in CKD patients. The current study further underscores a complex interplay of unique mediators triggered in the uremic milieu that impart thrombotic risk to CKD patients.

Funding

  • Other NIH Support