Abstract

Diseases of the kidney contribute a significant morbidity and mortality burden on society. Localized delivery of therapeutics directly into the kidney, via its arterial blood supply, has the potential to enhance their therapeutic efficacy while limiting side effects associated with conventional systemic delivery. Targeted delivery in humans is feasible given that we can access the renal arterial blood supply using minimally invasive endovascular techniques and imaging guidance. However, there is currently no described way to reproduce or mimic this approach in a small animal model. Here, we develop in mice a reproducible microsurgical technique for the delivery of therapeutics directly into each kidney, via its arterial blood supply. Using our technique, intra-arterially (IA) injected tattoo dye homogenously stained both kidneys, without staining any other organ. Survival studies showed no resulting mortality or iatrogenic kidney injury. We demonstrate the therapeutic potential of our technique in a mouse model of cisplatin-induced acute kidney injury (AKI). IA injection of mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) successfully reversed AKI, with reduced physiological and molecular markers of kidney injury, attenuated inflammation, and restoration of proliferation and regeneration markers. This reproducible delivery technique will allow for further pre-clinical translational studies investigating other therapies for the treatment of renal pathologies.

Highlights

  • Kidney diseases contribute a significant morbidity and mortality burden on society: acute kidney injury (AKI) causes 9.5% of in-hospital mortality, and chronic kidney disease (CKD), most commonly due to hypertension and diabetes, has a staggering 14% prevalence in the United States [1]

  • Following exposure of the aorta, three sites were ligated with sutures: (1) the proximal aorta between the origins of the celiac trunk (CT) and superior mesenteric artery (SMA), (2) the SMA, and (3) the distal aorta (Figure 1B,C)

  • A metal clamp was placed temporarily on the left renal artery to first allow delivery to the right renal artery; after injection of 50% of the volume, the clamp was removed, which results in preferential delivery to the left kidney due to natural flow

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Summary

Introduction

Kidney diseases contribute a significant morbidity and mortality burden on society: acute kidney injury (AKI) causes 9.5% of in-hospital mortality, and chronic kidney disease (CKD), most commonly due to hypertension and diabetes, has a staggering 14% prevalence in the United States [1] Progression of both AKI and CKD can result in end stage renal disease, for which dialysis and kidney transplantation are the only treatment options. While intra-arterial (IA) delivery of therapeutics is already widely clinically utilized for the treatment of stroke [5], heart attacks [6], and liver cancer [7], there are comparatively few indications for IA delivery of therapeutics for pathologies of the kidney In part, this can be attributed to limited pre-clinical studies given that performing non-terminal IA injection into the kidneys in small animal models is technically challenging. To our knowledge, despite well-documented mice models of AKI, CKD, and orthotropic renal tumors, there is no published methodology to successfully deliver therapeutics into both kidneys in mice, via their arterial supply

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