Indoxyl Sulphate Retention Is Associated with Microvascular Endothelial Dysfunction after Kidney Transplantation

Int J Mol Sci. 2023 Feb 11;24(4):3640. doi: 10.3390/ijms24043640.

Abstract

Kidney transplantation (KTx) is the preferred form of renal replacement therapy in chronic kidney disease (CKD) patients, owing to increased quality of life and reduced mortality when compared to chronic dialysis. Risk of cardiovascular disease is reduced after KTx; however, it is still a leading cause of death in this patient population. Thus, we aimed to investigate whether functional properties of the vasculature differed two years post-KTx (postKTx) compared to baseline (time of KTx). Using the EndoPAT device in 27 CKD patients undergoing living-donor KTx, we found that vessel stiffness significantly improved while endothelial function worsened postKTx vs. baseline. Furthermore, baseline serum indoxyl sulphate (IS), but not p-cresyl sulphate, was independently negatively associated with reactive hyperemia index, a marker of endothelial function, and independently positively associated with P-selectin postKTx. Finally, to better understand the functional effects of IS in vessels, we incubated human resistance arteries with IS overnight and performed wire myography experiments ex vivo. IS-incubated arteries showed reduced bradykinin-mediated endothelium-dependent relaxation compared to controls via reduced nitric oxide (NO) contribution. Endothelium-independent relaxation in response to NO donor sodium nitroprusside was similar between IS and control groups. Together, our data suggest that IS promotes worsened endothelial dysfunction postKTx, which may contribute to the sustained CVD risk.

Keywords: EndoPAT; chronic kidney disease; endothelial dysfunction; indoxyl sulphate; kidney transplantation; nitric oxide; p-cresyl sulphate; vessel stiffness.

MeSH terms

  • Cardiovascular Diseases
  • Endothelium, Vascular / metabolism
  • Humans
  • Indican* / metabolism
  • Kidney Transplantation* / adverse effects
  • Nitroprusside / pharmacology
  • Quality of Life
  • Renal Insufficiency, Chronic* / therapy
  • Vascular Diseases* / metabolism
  • Vascular Diseases* / pathology

Substances

  • Indican
  • Nitroprusside

Grants and funding

This research was funded by EU RESEARCH FRAMEWORK PROGRAMME: Innovative Training Network “CaReSyAn” (H2020-MSCA-ITN-764474), Heart and Lung Foundation (20160384), Njurfonden, Swedish Medical Research Council (Vetenskapsrådet 2018-00932 GOING-FWD; 2021-01102) and CIMED.