Ultrasound Therapy May Help Prevent and Treat Acute Kidney Injury

Acute kidney injury is one of the most common and serious complications of hospitalized patients. Yet there are no FDA-approved therapies for this disorder except dialysis, and potential drug therapies are associated with a number of adverse effects.

“There is an important gap in our ability to address this problem,” said Mark Okusa, MD, of the University of Virginia. Okusa and his colleagues may have stumbled upon a solution when they unexpectedly discovered that ultrasound exposure provides a simple, portable, noninvasive, and nonpharmacological approach to prevent acute kidney injury and long-term kidney fibrosis. Their findings were published recently in the Journal of the American Society of Nephrology.

Ultrasound alone

Working with Joseph Gigliotti, PhD, also of the University of Virginia, and others, Okusa has been developing an ultrasound-based method to deliver drugs specifically to the kidney to prevent or treat ischemia-reperfusion injury. This type of injury contributes to tissue damage and reduced glomerular filtration rate in some patients who undergo major surgery, which can deprive the kidneys of normal blood flow. In addition to developing after procedures such as kidney transplantation and cardiopulmonary bypass, renal ischemia-reperfusion injury contributes to the main pathophysiological processes that occur during sepsis-contrast- and rhabdomyolysis-induced kidney injuries.

In the researchers’ approach, they package a drug in a “microbubble” that is injected into a laboratory animal. When the drug-loaded microbubble enters into the kidney, ultrasound is used to break up the bubbles, thereby releasing the drug and enhancing its delivery to the kidney.

Through careful experiments, the research team was surprised to find that ultrasound alone—without drug-laden microbubbles—protected the kidney from ischemic injury. When the investigators exposed anesthetized mice to ultrasound with a routine clinical imaging system 24 hours prior to blood disruption to the kidneys, the mice exhibited preserved kidney health after blood flow was restored. In contrast, sham-treated mice exhibited significant kidney injury.

Also, ultrasound treatment reduced the infiltration of immune cells that typically occurs in the kidney after ischemia-reperfusion injury, and it caused a greater than 85% reduction in the renal expression of vimentin, α-smooth muscle actin, collagen I, and collagen III mRNA.

Ultrasound treatment prevented the marked decline in kidney function as well as tissue injury, and it also protected the kidneys from subsequent development of fibrosis. The regimen relied on settings within approved Food and Drug Administration guidelines, and the protective effect of a single exposure lasted for two days.

Mechanism of action

Additional experiments—including splenectomies and adoptive transfer studies—revealed that the ultrasound treatment blocked ischemia-reperfusion-induced kidney inflammation through direct action on the spleen, an organ that appears to modulate the response to acute kidney injury.Blockade or genetic deficiency of the α7 nicotinic acetylcholine receptor abolished the protective effect of ultrasound, suggesting the involvement of the cholinergic anti-inflammatory pathway, which mediates the neural control of systemic inflammation.

“Our studies using noninvasive ultrasound now provide us with an active treatment that appears to be simple, effective, and nontoxic for the prevention of acute kidney injury,” said Okusa. “To our knowledge this has never been described for the prevention of tissue or organ injury. Interestingly, we suspect that similar mechanisms that lead to kidney injury may also lead to lung, heart, and liver damage and that this form of therapy might be effective for prevention of injury in other organs as well.”

Future analyses will explore the efficacy of ultrasound in reducing mortality in subjects with more severe kidney injury, perhaps from longer ischemic times. Also, research is needed in larger animals and then humans to apply the concepts learned from this study. Finally, the current study only addresses preventive therapy, and it is unclear whether this form of therapy is effective as a treatment after injury occurs.

In an accompanying editorial, Alain Le Moine, MD, PhD, of the Erasme Hospital in Belgium, and his colleagues noted that opportunities arising from the work are numerous and promising because many procedures that carry a very high risk of AKI are planned.

“In searching for novel approaches to prevent and even cure acute kidney injury, we believe that splenic ultrasound stimulation has a bright future ahead,” they wrote. They also noted that other nonrenal conditions—such as myocardial ischemia, hepatic injury, sepsis, and endotoxemia—also rely on the cholinergic anti-inflammatory pathway and might therefore be prevented or treated with the approach.

Notes

[1] Study co-authors include Liping Huang, Hong Ye, Amandeep Bajwa, PhD, Kryt Chattrabhuti, MD, Sangju Lee, MD, Alexander Klibanov, PhD, Kambiz Kalantari, MD, MPH, and Diane Rosin, PhD.

[2] Mark Okusa has the following disclosures: AM Pharma, Nature Publishing Group, Lilly, Daiichi-Sankyo, American Physiological Society, International Society of Nephrology, PGX Health/Adenosine Therapeutics, LLC, and UVA Patent Office.

[3] Alexander Klibanov has the following disclosures: Targeson, Inc, Philips Research.

[4] The article, entitled “Ultrasound Prevents Renal Ischemia-Reperfusion Injury by Stimulating the Splenic Cholinergic Anti-Inflammatory Pathway,” is available online at http://jasn.asnjournals.org/.