It Comes As a Shock: Kidney Repair Using Shockwave Therapy

Abstract

Chronic kidney disease is a global health care burden, yet clinically-proven treatments are limited. Low-intensity shockwave, which utilizes ≈10% of the energy levels used in clinically indicated shockwave lithotripsy, is a promising technique to ameliorate ischemia and regenerate tissues. It has been demonstrated to improve healing in tissues such as bone, muscle, myocardium, and kidney via several mechanisms, particularly through promoting neovascularization. Low-intensity shockwave stimulates mechanoreceptors located primarily in endothelial and proximal tubular cells and subsequently upregulates vascular endothelial growth factors. This, in turn, promotes angiogenesis and ameliorates renal hypoxia, inflammation, and fibrosis, and ultimately preserves renal function. Furthermore, low-intensity shockwave can stimulate release of homing factors to attract endothelial progenitor or stem cells into injured kidneys for tissue repair. These effects may be beneficial in several kidney disease models, including renal artery stenosis, diabetic kidney disease, and various chronic kidney diseases, although most studies reported to date have been performed in animal models. Because of its low energy intensity, the procedure is relatively tolerable and safe, yet, more clinical studies are needed to establish its efficacy beyond currently existing strategies. Therefore, low-intensity shockwave therapy emerges as an alternative therapeutic approach that may offer a promising noninvasive intervention for treating renal diseases. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02515461; NCT03602807; and NCT03445247.

Keywords: extracorporeal shockwave therapy; myocardial ischemia; renal insufficiency; renal insufficiency, chronic; ultrasonography, interventional.

Figures

Figure 1.. Mechanisms of SW in repairing kidney injury

LiSW affects several kidneys cell types, particularly proximal tubules and endothelium, via mechanoreceptors such as β1-integrin, FAK and Piezo-1. Subsequently, angiogenic factors (VEGF, Angiopoietin-1, and eNOS) and receptors (e.g., Flk-1) are upregulated, thus promoting renal angiogenesis. LiSW also suppresses inflammation (macrophages, MCP-1, TNF-α, TGF-β, and NF-ƙB), and increases anti-inflammatory markers (IMP-2), thereby reducing inflammation, tubular injury and fibrosis. The numbers of podocytes are also preserved. Furthermore, LiSW enhances stem cell homing into kidneys by upregulating SDF-1 and SCF. Collectively, these effects translate into improvement in renal function, mitigating oxidative stress, and ameliorating renal hypoxia. eNOS: endothelial nitric oxide synthase, FAK: focal adhesion kinase, Flk-1: VEGF receptor, HIF-1α: hypoxia-inducible factor-1α, IMP-2: integral membrane protein-2, M1: M1 macrophage, M2: M2 macrophage, MCP-1: monocyte chemoattractant-1, NF-ƙB: nuclear factor-ƙB, NOX: nicotinamide adenine dinucleotide phosphate hydrogen oxidase, PCT: proximal convoluted tubule, SCF: stem-cell factor, SDF-1: stromal-derived factor-1, TNF-α: tumor necrosis factor-α, TGF-β: transformation growth factor-β, VEGF: vascular endothelial growth factor, ZO-1; zonula occluden-1

Figure 2.. Low-intensity shockwave application

Schematic demonstrating low-intensity shockwave (LiSW) administration in pigs (adapted with permission from Zhang et al). A: Experimental setting. Green arrows indicate elements in the ultrasound probes, LiSW applicator, and the systems. B: Diagram indicating specific zones of LiSW delivery in the kidney. C: An ultrasound image illustrating LiSW treatment-zones along the short axis of the kidney