Improving Kidney Stone Detection In Space Analogs (First Award Fellowship)
Julianna C. Simon, Ph.D.
University of Washington
Astronauts are at an increased risk of developing kidney stones due to the dehydration, stasis, and bone demineralization that occur in space. While innocuous in the kidney, a stone could cause debilitating pain as it passes and may become obstructing, which could lead to sepsis, kidney failure, or death. The “twinkling artifact”, a rapid color-shift that selectively highlights hard objects in color-Doppler ultrasound imaging, has the potential to improve kidney stone detection; however its inconsistent appearance has limited its use in the clinic. Recently, it was hypothesized that crevice bubbles on the surface of stones cause twinkling, and bubbles are going to be very sensitive to the changes in pressure that occur during space travel.
Dr. Julianna C. Simon and colleagues are developing an ultrasound imaging protocol to enhance twinkling for kidney stone detection in space. Using modeling and experimentation, the researchers will evaluate the effects of Doppler imaging parameters, ambient pressure, pH, stone type, and gas composition on the appearance of twinkling in ex vivo stones. The end result will be an increased understanding of the etiology of the twinkling artifact and stone disease, in addition to an improved ultrasound imaging protocol for kidney stone detection in space.
Video: Watch this highlight of First Award Fellow Dr. Julianna Simon, working at University of Washington Applied Physics Laboratory.
The formation of kidney stones in-flight poses a significant crewmember health risk and could greatly impact mission success. Thus far, one event that has been attributed to kidney stones has occurred in-flight; the dehydration, stasis, and altered bone metabolism that are experienced in-flight put astronauts at an increased risk of forming kidney stones. While innocuous in the kidney, a stone could cause debilitating pain as it passes and even worse, may become obstructing, which could lead to sepsis, urinary tract infection, renal failure, or even death. Early stone detection is essential for maintaining crewmember health, as it would allow for planned intervention through administration of pharmaceuticals, scheduled transport to Earth, or utilization of the ultrasonic propulsion technique developed at the University of Washington.
The current gold standard of kidney stone detection on Earth is x-ray computed tomography (CT), which is not possible in space due to the radiation exposure and the size of the equipment. B-mode, or greyscale, ultrasound has been used to diagnose kidney stones, but the sensitivity of the technique is highly dependent on the skills of the operator. The “twinkling artifact,” a rapid color-shift that selectively highlights hard objects in color-Doppler ultrasound imaging, has the potential to improve kidney stone detection and has been shown to improve the sensitivity of ultrasound for stone detection; however its inconsistent appearance has limited its use in the clinic. Recently, it was shown that bubbles cause twinkling, and bubbles are going to be very sensitive to the changes in gravity and pressure that occur during space travel. Variations in urine pH, stone type, bubble gas composition, and ambient pressure will all occur during space travel, and will affect the appearance of the twinkling artifact. Therefore, the goal of this fellowship research project is to develop a refined kidney stone imaging protocol that will enhance kidney stone detection specifically for the unique environment in space.
Using the programmable research Verasonics Ultrasound Engine, the color-Doppler ultrasound imaging parameters will be modified to excite and enlarge existing crevice bubbles on the kidney stone surface. The bubble activity will be evaluated with high-magnification, high-speed imaging while varying the color-Doppler ultrasound imaging parameters (i.e., the number of cycles in a Doppler ensemble, the number of Doppler ensembles, the pulse repetition frequency, and the amplitude of the Doppler pulse). After determining how best to excite the bubbles, the timing of the color Doppler imaging pulse will be modified to detect the enlarged bubbles. These experiments will be performed on ex vivo calcium oxalate monohydrate human kidney stones, the most common type of kidney stones that have been reported in astronauts and the stone size will be decreased until it is no longer detectable by the imaging algorithms. These imaging algorithms will be further refined based on the results from the subsequent modeling and experimental aims.
To aid in refining kidney stone detection protocols, an existing linear elastic wave model developed by Dr. Oleg Sapozhnikov will be coupled to an existing bubble dynamics model developed by Dr. Wayne Kreider to allow for the inclusion of small bubbles around the circumference of a cylindrical stone. With the model, the effects of bubble size, ambient pressure, liquid-gas solubility, liquid viscosity, and liquid-gas surface tension on the backscattered ultrasound signal can be evaluated. The imaging protocols and processing algorithms will be refined based on the predicted changes in the backscattered signal and the modeling will be used to support the experimental results from the following three aims.
Changes in the ambient pressures occur during spaceflight, particularly in astronauts performing extravehicular activities, and have been shown to increase (for hypobaric conditions) or decrease (for hyperbaric conditions) bubble diameters; twinkling is expected to be similarly affected. Ex vivo human kidney stones will be placed in a high pressure chamber that can exert overpressure levels up to 1500 psi (pounds per square inch) and twinkling will be monitored before, during, and after overpressure is applied. The same pressure chamber will be used to apply under-pressure, or hypobaric conditions, down to approximately 3 psi by pulling the liquid from the chamber. As in the overpressure experiments, twinkling will be monitored before, during, and after the under-pressure is applied.
To confirm the presence of bubbles on the stone in situ, patients with a history of kidney stones will be recruited for monitoring the twinkling artifact in a hyperbaric chamber. The pressure in the chamber will be increased up to a maximum of 4 ATA (atmospheres absolute) with continuous monitoring of the ultrasound twinkling artifact. Should the microbubble hypothesis of twinkling be correct, the twinkling artifact should be diminished when the pressure increases but return when the pressure is reduced.
In space, due to the dehydration, diet, changes in bone metabolism, low urinary citrate and genetic factors, urine becomes saturated with salts, volume decreases, and pH decreases, creating an ideal environment for the formation of kidney stones. The decrease in pH and saturation of salts is expected to influence the size and number of microbubbles on the stone surface. Various types of kidney stones will be placed in solutions composed of salts that have been shown to contribute to kidney stone formation and have been shown to be changed between pre-flight and post-flight. In addition, the effect of pH on the twinkling artifact will be evaluated by submerging stones in solutions and using concentrated acids and bases to change the pH.
On all space travel vehicles, carbon dioxide levels in air are more than ten times what is found on Earth, with local carbon dioxide levels reaching even higher. Carbon dioxide has been shown to dehydrate tissues, which is one of the factors that contribute to stone formation. Increased carbon dioxide has also been shown to make urine more alkaline, which is expected to alter the twinkling artifact through changes in urine chemistry and gas content. Common types of ex vivo kidney stones will be placed in solutions and the concentrations of carbon dioxide, nitrogen, and oxygen will be varied while monitoring the twinkling artifact. In addition, stones will be placed in solutions with increased sodium bicarbonate concentrations, (based on the results of urinalyses in humans after two hours of breathing increased carbon dioxide) and the twinkling artifact will be monitored. As all of the changes in urine gas chemistry might not be represented in the benchtop studies, three swine will be implanted with a single calcium oxalate monohydrate stone via retrograde ureteroscopy and will be exposed to increased carbon dioxide levels for approximately 3 hours. The twinkling artifact will be monitored continuously and changes in urine chemistry will be linked to changes in the twinkling artifact to determine the effect of increased carbon dioxide levels on kidney stone detection.
The results from the experiments and modeling will be used to refine the ultrasound kidney stone imaging protocol specifically for enhanced stone detection in space. These experiments will also provide information as to the etiology of the twinkling artifact and will potentially increase our understanding of the etiology of stone disease and the origin of the bubbles. The final deliverable of this project will be a refined ultrasound imaging protocol for improved kidney stone detection in space.
Currently, 1 in 11 Americans have been diagnosed with kidney stones and the prevalence is increasing worldwide. In the United States, more than three million diagnoses and treatments are made annually at a cost calculated to be over two billion dollars. Currently, stones are detected with x-ray or computed tomography (CT), both of which expose the patients to ionizing radiation. By making ultrasound a more robust tool to detect kidney stones, this research reduces patient exposure to ionizing radiation as well as reducing the cost associated with kidney stones. This technology would also allow emergency rooms to diagnose kidney stones immediately, rather than sending the patient to radiology for a CT. In addition, with more than 50% of stone-formers having a repeat stone incident within 5 years, this technology could allow for more routine monitoring so steps could be taken to avoid emergency surgery.