Peripheral arterial disease (PAD) is three times as prevalent in patients with chronic kidney disease (CKD) compared with their non-CKD counterparts (1). This increased susceptibility has been attributed to the uremic milieu; however, specific mechanisms remain unknown. Recently, in the Journal of Clinical Investigation, Arinze and colleagues (2) shed new light on the detrimental impact of dietary and gut-converted, tryptophan-based uremic toxins (indoxyl sulfate and its metabolites) on neovascularization in PAD.
In a series of elegant studies, the investigators demonstrated that serum from patients with uremia, as well as indoxyl sulfate alone, induced a dose-dependent reduction in Wnt-β-catenin signaling in endothelial cells, which was exacerbated under hypoxic conditions. Interestingly, this effect was observed at levels of indoxyl sulfate consistent with that in patients with early-stage CKD. With the use of zebrafish and mouse models, the researchers demonstrated that this loss in Wnt-β-catenin signaling translated to decreased angiogenesis, capillary density, and vascular perfusion. The authors also identified that the reduction in active β-catenin was dependent on aryl hydrocarbon receptor activation. Importantly, in a mouse model of CKD and PAD, aryl hydrocarbon receptor inhibition restored Wnt-β-catenin signaling to that of non-uremic levels and restored neovascularization. The authors corroborated these findings in plasma from patients with CKD and PAD, where levels of indoxyl sulfate and its metabolites were predictive of subsequent adverse limb events in patients followed for up to 2 years.
Significant questions raised by these studies include the possibility of inhibiting aryl hydrocarbon receptor signaling as a therapeutic target in PAD, with or without CKD. Many of the same authors also previously demonstrated that aryl hydrocarbon receptor inhibition decreased the time to occlusion in a pro-thrombotic CKD murine model (3). Aryl hydrocarbon receptor inhibitors are currently in clinical trials for solid tumors and have been shown to reduce tumor growth when used in combination with immune checkpoint inhibition (4).
With the exceedingly high incidence of cardiovascular mortality in patients with CKD and kidney failure on dialysis, the role of aryl hydrocarbon receptor pathway antagonism in coronary circulation ischemia might also serve as another important avenue for future investigation. This study also resurfaces important questions that have been raised by nephrologists for decades: How can we optimize the dialysis prescription to enhance removal of these protein-bound tryptophan derivatives? Does modulating the dietary regimen to reduce the accumulation of indoxyl sulfate levels improve clinical outcomes? Taken together, Arinze et al. (2) highlight the critical need for randomized clinical trials to assess the therapeutic impact of targeting this pathway in patients with CKD and kidney failure on dialysis.
References
- 1.↑
Foley RN, et al. Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999. J Am Soc Nephrol 2005; 16:489–495. doi: 10.1681/ASN.2004030203
- 2.↑
Arinze NV, et al. Tryptophan metabolites suppress the Wnt pathway and promote adverse limb events in chronic kidney disease. J Clin Invest 2022; 132:e142260. doi: 10.1172/JCI142260
- 3.↑
Shashar M, et al. Targeting STUB1-tissue factor axis normalizes hyperthrombotic uremic phenotype without increasing bleeding risk. Sci Transl Med 2017; 9:eaam8475. doi: 10.1126/scitranslmed.aam8475
- 4.↑
Campesato LF, et al. Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-kynurenine. Nat Commun 2020; 11:4011. doi: 10.1038/s41467-020-17750-z
