ARFI for KIDNEYS: AFFECTIONS of TISSUE FIBROSIS or RENAL BLOOD FLOW

ABSTRACT:

Objectives—The aim of this study was to identify the main influencing factor of the shear wave velocity (SWV) of the kidneys measured by acoustic radiation force impulse elastography.

Methods—The SWV was measured in the kidneys of 14 healthy volunteers and 319 patients with chronic kidney disease. The estimated glomerular filtration rate was calculated by the serum creatinine concentration and age. As an indicator of arteriosclerosis of large vessels, the brachial-ankle pulse wave velocity was measured in 183 patients.

Results—Compared to the degree of interobserver and intraobserver deviation, a large variance of SWV values was observed in the kidneys of the patients with chronic kidney disease. Shear wave velocity values in the right and left kidneys of each patient correlated well, with high correlation coefficients (r = 0.580–0.732). The SWV decreased concurrently with a decline in the estimated glomerular filtration rate. A low SWV was obtained in patients with a high brachial-ankle pulse wave velocity. Despite progression of renal fibrosis in the advanced stages of chronic kidney disease, these results were in contrast to findings for chronic liver disease, in which progression of hepatic fibrosis results in an increase in the SWV. Considering that a high brachial-ankle pulse wave velocity represents the progression of arteriosclerosis in the large vessels, the reduction of elasticity succeeding diminution of blood flow was suspected to be the main influencing factor of the SWV in the kidneys.

Conclusions—This study indicates that diminution of blood flow may affect SWV values in the kidneys more than the progression of tissue fibrosis. Future studies for reducing data variance are needed for effective use of acoustic radiation force impulse elastography in patients with chronic kidney disease. 

Key Words—acoustic radiation force impulse; brachial-ankle pulse wave velocity; chronic kidney disease; genitourinary ultrasound; renal blood flow; shear wave velocity.

Quantification of Kidney Stiffness by ARFI Elastography 

The SWV was measured with an Acuson S2000 ultrasound system (Siemens Medical Solutions) using a 3.5-MHz convex probe. Kidney images were obtained in the prone position so that the longitudinal section was visible on the monitor. An ROI of 10 × 5 mm was set adjacent to the inferior pole of the cortex in the dorsal area of the renal parenchyma to exclude vessels depicted by the color Doppler mode. Placement of the ROI was accurate in almost all participants. To prevent respiratory motion the SWV was measured on inhalation breath holding 5 to 6 times consecutively by a sonographer. The mean SWV values were calcul ated in the right and left kidneys, respectively. While being blinded to the clinical data, 2 experienced sonographers (J.T. and  Y.T.) performed ARF elastography.

Discussion

In ARFI elastography for chronic liver disease, the SWV increases in more advanced stages because progressing interstitial fibrosis predominantly affects tissue elasticity, as observed in liver cirrhosis.

However, the main affecting factor of ARFI elastography in the kidneys has not been elucidated presumably for two reasons. Namely, a large variance of SWV values in the kidneys, as demonstrated by Goertz et al, has yielded results with low reliability, and the degree of interstitial fibrosis in the kidneys of patients with chronic kidney disease is not as marked as that in chronic liver disease. Since approximately 20% of cardiac output flows into the kidneys, which constitute less than 1% of body mass, we suspected that renal blood flow might be the main influencing factor of the SWV in the kidneys instead of interstitial fibrosis.

In the feasibility study, interobserver and intraobserver deviation was proven to be small when the SWV was measured in the kidney of a healthy volunteer. Although no significant correlation was obtained between SWV and estimated GFR values in 14 healthy volunteers in the first trial, a significant correlation was found between the SWV and estimated GFR when the ROI setting and measurement timing during arterial pulsation were reviewed. Interestingly, the SWV decreased concurrently with a decline in the estimated GFR in all cohorts of patients with chronic kidney disease despite the large variance noted. This finding means that kidney tissue stiffness decreases at advanced stages of chronic kidney disease despite the increasing prominence of interstitial fibrosis. Low SWV values were obtained in patients with a high brachial-ankle PWV. Considering that the brachial-ankle PWV represents arteriosclerosis of large vessels, we hypothesized that diminution of renal blood flow succeeding atherosclerosis of renal arteries may cause decreased elasticity of renal parenchyma in advanced chronic kidney disease. We also assumed that the large variance of SWV values in the kidneys of patients with chronic kidney disease derived from the structural heterogeneity of renal parenchyma and pressure fluctuation resulting from pulsating blood flow, rather than technical variance in measurement.

Renal parenchyma is grossly divided into the cortex and medulla. The cortex consists of proximal and distal tubules and renal glomeruli. The medulla mostly consists of the loop of Henle and the lower part of the collecting tubule. To meet the large oxygen consumption for massive reabsorption, the renal tubules are surrounded by a dense vascular plexus in both the cortex and medulla.  In kidneys  with low estimated GFRs, the number of glomeruli with global sclerotic changes increases. The renal tubule, located downstream of the sclerosing glomerulus, becomes atrophic, and peritubular fibrosis subsequently progresses.

Blood flow in the peritubular vascular plexus decreases according to sclerotic changes of the glomeruli, since blood flows from the glomeruli to the vascular plexus. Considering the remarkable damage of microcirculation in advanced chronic kidney disease, it is conceivable that blood flow rather than interstitial fibrosis dominantly affects the elasticity of kidney tissue in chronic kidney disease. In addition, it is widely known that the incidence of cardiovascular events increases concurrently with a decline  in the estimated GFR. As shown in Figure 6, patients with chronic kidney disease who had a high brachial-ankle PWV tended to have a low SWV in the kidney. From these results, we strongly suspected that a combination of microcirculatory damage in the renal tissue and arteriosclerosis of renal arteries diminished renal blood flow and reduced kidney stiffness in patients with chronic kidney disease.

This study had several limitations. Since our hypothesis was based on hemodynamic changes in the kidneys, parameters directly related to renal blood flow and renal vessel resistance should be demonstrated. We measured the peak systolic velocity (Vmax) and end-diastolic velocity (Vmin) by using Doppler sonography and calculated the resistive index by the following equation: resistive index =(Vmax– Vmin)/Vmax. However, the data fit between the estimated GFR and Vmax and the estimated GFR and resistive index was poor (data not shown). For the ARFI measurement, ROI setting was frequently difficult when measuring the SWV in the kidneys of patients with advanced chronic kidney disease. In patients with high estimated GFRs, the SWV could be measured at the cortex because the thickness of the renal parenchyma was still sufficient.

However, for patients with advanced chronic kidney disease, the renal parenchyma was atrophic, and distinction between the cortex and medulla was often difficult.

Renal atrophy prevented accurate SWV measurement in 4 patients and Vmax and Vmin measurement in 16 patients. Several potential future studies are proposed. Instead of the brachial-ankle PWV, the cardio-ankle vascular index could be used as a novel indicator of arterial stiffness. Since the cardio-ankle vascular index is less affected by systemic blood pressure, it can be used as an alternative method to evaluate large-vessel arteriosclerosis. Shear wave velocity values can be normalized by systemic blood pressure and synchronization with electrocardiography, which ensures consistent aortic pressure during the cardiac cycle. Early-stage SWV assessment of the kidneys in diabetic patients may be feasible because of the hyperdynamic blood flow of the diabetic kidney in the early stages. If our hypothesis is correct, SWV values should be high in those kidneys. A comparison of ARFI assessment with surrogate markers of tissue fibrosis could be performed.

In conclusion, our study suggests that the SWV measured by ARFI elastography in patients with chronic kidney disease may represent the diminution of blood flow that succeeds arteriosclerosis, as opposed to the development of renal fibrosis. In our results, the standard deviations of SWV values were considerably high. However, further improvement of this method may result in obtainment of more consistent SWV values in the kidneys.

ULTRASOUND IMPROVING SENSORY DISCRIMINATION

New research has demonstrated that ultrasound can be employed to modulate brain activity to heighten sensory perception in humans, similar to how bats use ultrasound to help guide them at night.

Virginia Tech Carilion Research Institute (Roanoke, VA, USA; http://research.vtc.vt.edu) scientists have demonstrated that ultrasound directed to a specific region of the brain can improve performance in sensory discrimination. The study’s findings, published online January 12, 2014, in the journal Nature Neuroscience, provides the first validation that low-intensity, transcranial focused ultrasound can modulate human brain activity to raise perception.

“Ultrasound has great potential for bringing unprecedented resolution to the growing trend of mapping the human brain’s connectivity,” said Dr. William Tyler, an assistant professor at the Virginia Tech Carilion Research Institute, who led the study. “So we decided to look at the effects of ultrasound on the region of the brain responsible for processing tactile sensory inputs.”

The scientists delivered focused ultrasound to an area of the cerebral cortex that processes sensory information received from the hand. To stimulate the median nerve, they positioned a small electrode on the wrist of human volunteers and recorded their brain responses using electroencephalography (EEG). Then, right before stimulating the nerve, they began delivering ultrasound to the targeted brain region.

The investigators discovered that the ultrasound both decreased the EEG signal and weakened the brain waves responsible for encoding tactile stimulation. The scientists then administered two classic neurologic tests: the two-point discrimination test, which gauges an individual’s ability to distinguish whether two close by objects touching the skin are truly two distinct points, instead of one; and the frequency discrimination task, a test that measures sensitivity to the frequency of a chain of air puffs.

What the scientists found was unanticipated. The study participants receiving ultrasound showed substantial improvements in their capability to differentiate pins at closer distances and to single out small frequency differences between successive air puffs. “Our observations surprised us,” said Dr. Tyler. “Even though the brain waves associated with the tactile stimulation had weakened, people actually got better at detecting differences in sensations.”

The researchers wanted to know why would brain response suppression to sensory stimulation heighten perception, and Dr. Tyler theorized that the ultrasound affected an important neurologic balance. “It seems paradoxical, but we suspect that the particular ultrasound waveform we used in the study alters the balance of synaptic inhibition and excitation between neighboring neurons within the cerebral cortex,” Dr. Tyler said. “We believe focused ultrasound changed the balance of ongoing excitation and inhibition processing sensory stimuli in the brain region targeted and that this shift prevented the spatial spread of excitation in response to stimuli resulting in a functional improvement in perception.”

To determine how well they could isolate the effect, the researchers moved the acoustic beam 1 cm in either direction of the original site of brain stimulation, and the effect disappeared. “That means we can use ultrasound to target an area of the brain as small as the size of an M&M [a popular US candy about 1 cm in diameter,]” Dr. Tyler said. “This finding represents a new way of noninvasively modulating human brain activity with a better spatial resolution than anything currently available.”

The scientists, based on the findings of the current study and an earlier one, concluded that ultrasound has a greater spatial resolution than two other leading noninvasive brain stimulation technologies – transcranial magnetic stimulation, which uses magnets to activate the brain, and transcranial direct current stimulation, which uses slight electrical currents delivered directly to the brain through electrodes positioned on the head.

“The work by Jamie Tyler and his colleagues is at the forefront of the coming tsunami of developing new, safe, yet effective noninvasive ways to modulate the flow of information in cellular circuits within the living human brain,” said Dr. Michael Friedlander, executive director of the Virginia Tech Carilion Research Institute and a neuroscientist who specializes in brain plasticity.

“This approach is providing the technology and proof of principle for precise activation of neural circuits for a range of important uses, including potential treatments for neurodegenerative disorders, psychiatric diseases, and behavioral disorders. Moreover, it arms the neuroscientific community with a powerful new tool to explore the function of the healthy human brain, helping us understand cognition, decision-making, and thought. This is just the type of breakthrough called for in President Obama’s BRAIN [Brain Research through advancing Innovative Neurotechnologies, also referred to as the Brain Activity Map Project] Initiative to enable dramatic new approaches for exploring the functional circuitry of the living human brain and for treating Alzheimer’s disease and other disorders.”

Image: William Tyler, an assistant professor at the Virginia Tech Carilion Research Institute, studied the effects of ultrasound on the region of the brain responsible for processing tactile sensory inputs (Photo courtesy of Jim Stroup / Virginia Tech)