Cell-based regenerative medicine for renovascular disease

Abstract

Renal artery stenosis (RAS) elicits the development of hypertension and post-stenotic kidney damage, which may become irresponsive to restoration of arterial patency. Rather than mere losses of blood flow or oxygen supply, irreversible intrarenal microvascular rarefaction, tubular injury, and interstitial fibrosis are now attributed to intrinsic pathways activated within the kidney, focusing attention on the kidney parenchyma as a therapeutic target. Several regenerative approaches involving the delivery of reparative cells or products have achieved kidney repair in experimental models of RAS and the delivery of mesenchymal stem/stromal cells (MSCs) has already been translated to human subjects with RAS with promising results. The ongoing development of innovative approaches in kidney disease awaits application, validation, and acceptance as routine clinical treatment to avert kidney damage in RAS.

Trial registration: ClinicalTrials.gov NCT00081731 NCT02266394.

Keywords: hypertension; mesenchymal stem/stromal cells; regeneration; renovascular disease.

Conflict of interest statement

Declaration of interests L.O.L. is an advisor to AstraZeneca, Janssen Pharmaceuticals, and Butterfly Biosciences. The author declares no conflict.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Figures

Figure 1.. Traditional paradigms underpinning kidney injury distal to large vessel disease.

Renal artery stenosis is purported to injure the post-stenotic kidney by inducing hypoperfusion that leads to hypoxia, and thereby chronic ischemic injury, which have traditionally been ascribed to the upstream occlusive lesion. Recent studies have implicated intrinsic renal mechanisms as perpetuating microvascular loss and interstitial fibrosis.

Figure 2.. Development and revascularization of renal artery stenosis (RAS).

A. Development of atherosclerotic (or other) lesions in the renal artery (seen in longitudinal and cross-sections) may lead to development of hypertension and to chronic kidney disease (CKD). B. During percutaneous transluminal renal angioplasty (PTRA), a balloon (often with a stent mounted on it) (top) is inflated in the stenotic renal artery (bottom) to dilate the obstruction. The balloon is subsequently deflated and disengaged, leaving the stent engrafted in the renal artery to keep it open. Created with BioRender.com.

Figure 3.. Nano-Engineered MSCs as Active Targeting Drug Delivery Vehicles.

The lack of specificity of therapeutic agents toward cells, and production of a plethora of undesirable side effects, led to development of novel strategies in drug delivery. Combining nanotechnology and cell-based therapy enables generation of “nano-engineered” mesenchymal stem cells (MSCs), or alternatively extracellular vesicles derived from them, which would be able to both actively target the disease site and protect the drug-loaded nanoparticle (NP) from vascular filtration and macrophage clearance. Adapted from “Nano-Engineered MSCs as Active Targeting Drug Delivery Vehicles”, by BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates