|Year : 2015 | Volume
| Issue : 1 | Page : 28-32
Focused ultrasound guided relocation of kidney stones
Nitin Abrol, Nitin S Kekre
Department of Urology, Christian Medical College, Vellore, India
|Date of Web Publication||1-Jan-2015|
Dr. Nitin Abrol
Department of Urology, Christian Medical College Hospital, Vellore, Tamil Nadu
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Purpose: Complete removal of all fragments is the goal of any intervention for urinary stones. This is more important in lower pole stones where gravity and spatial orientation of lower pole infundibulum may hinder spontaneous passage of fragments. Various adjuvant therapies (inversion, diuresis, percussion, oral citrate, etc.) are described to enhance stone-free rate but are not widely accepted. Focused ultrasound-guided relocation of fragments is a recently described technique aimed at improving results of intervention for stone disease. Purpose of this review is to discuss development of this technology and its potential clinical applications.
Materials and Methods: Pubmed search was made using key words "Focused ultrasound" and "kidney stone." All English language articles were reviewed by title. Relevant studies describing development and application of focused ultrasound in renal stones were selected for review.
Results: Focused ultrasound has proven its efficacy in successfully relocating up to 8 mm stone fragments in vitro and in pigs. Relocation is independent of stone composition. The latest model allows imaging and therapy with a single handheld probe facilitating its use by single operator. The acoustic energy delivered by the new prototype is even less than that used for extracorporeal shock wave lithotripsy. Therapeutic exposure has not caused thermal injury in pig kidneys.
Conclusion: Focused ultrasound-guided relocation of stones is feasible. Though it is safe in application in pigs, technology is awaiting approval for clinical testing in human beings. This technology has many potential clinical applications in the management of stone disease.
Keywords: Focused ultrasound, relocation, renal calculi, stone-free rate
|How to cite this article:|
Abrol N, Kekre NS. Focused ultrasound guided relocation of kidney stones. Indian J Urol 2015;31:28-32
| Introduction|| |
Contemporary incidence of stone disease and risk of recurrence are known since antiquity with the earliest report in an Egyptian mummy and a reference to stone disease in the Hippocratic oath.  First-time renal stone former has natural cumulative recurrence rate of 14%, 35%, and 52% at 1, 5, and 10 years, respectively.  In a recent longitudinal population-based study the risk of stone recurrence at 1 and 5 years is 6.12% and 34.71%, respectively.  Common treatment options are percutaneous nephrolithotomy (PCNL), extracorporeal shock wave lithotripsy (ESWL), and flexible ureterosopy (FURS). Goal of any treatment is achievement of a stone-free status. In the era of open stone surgery, success was defined as the absence of any residual stone fragment. Introduction of ESWL introduced the concept of "clinically insignificant residual fragments" (CIRFs).  Though PCNL was started before ESWL, ESWL was widely accepted as preferred treatment for all renal stones because of its high reported success rate in initial studies, lack of complications, and non-invasive nature.  Later studies reported dependence of ESWL on stone burden, location, and composition. , A meta-analysis reported lower pole stone-free rate (SFR) 90% and 59% for PCNL and ESWL, respectively.  Also, SFR with PCNL were independent of stone location and burden.  This meta-analysis recommended PCNL for lower pole stone greater than 1 cm. Recent studies also reported superiority of PCNL for management of lower pole calculi.  With miniaturization of ureteroscopes, FURS is considered a reasonable alternative for management of lower pole renal calculi.  Though reported clinical success (CIRF < 3 mm) of FURS for lower pole calculi is 100%, SFR is 64.9%. 
CIRFs are defined as residual fragment of non-struvite stone, less than or equal to 4 mm, non-obstructive, in asymptomatic patient, with sterile urine. , CIRFs are not unique to ESWL. Incidence of CIRFs after these interventions varies widely in the literature depending upon the imaging modality used for follow up. Similarly reported definition and incidence of stone-free rate is variable in the literature depending upon the imaging modality used. When computerized tomography (CT) was used for follow up, SFR at 3 months following PCNL was 74.5%, whereas 22% had CIRFs, most in the lower pole (60.5%).  Similarly, 46-50% have CIRFs after URS when evaluated with CT.  Not all CIRFs are insignificant. On long-term follow up, a significant number grow in size or become symptomatic requiring another intervention. ,, Many consider the term CIRF a misnomer and emphasize on complete clearance as a goal of any treatment for stones. 
Treatment success is dependent on stone fragmentation and clearance of residual fragments. This is more important in the case of lower pole stones where anatomical factors like infundibular length, infundibular height, and infundibulo-pelvic angle may predict success.  While medical expulsive therapy, percussion, inversion, and diuresis have been described as adjuvant therapies after ESWL to augment clearance of lower pole residual fragments, success with these measures is limited. , Recently, a group from University of Washington has developed a novel device for relocation of stone fragments from lower pole using acoustic radiation force delivered by focused ultrasounds.  Development of a focused ultrasound device for stone relocation and its projected clinical applications and limitations are discussed in this review. Though initially developed and tested for improving lower pole stone-free rate, this technology has a potential role in the management of urinary stones at other locations.
| Therapeutic Ultrasound|| |
Ultrasound energy is mainly used as a diagnostic tool. Therapeutic applications of ultrasound depend on clinical effect at desired location in the body without harming intervening tissues. Pioneering work in therapeutic ultrasound began when Langevin observed death of a fish from sonar in 1917.  High-intensity focused ultrasound (HIFU) and ESWL are two established applications of therapeutic ultrasound. Credit for development of focused ultrasound goes to Lynn et al., who built the transducer and reported tissue effects of focused ultrasound.  Focused ultrasound mediated relocation of stones is a new addition to the therapeutic applications of ultrasound. Absorption of ultrasound energy by tissues and conversion to heat is a fundamental physical mechanism of HIFU. At HIFU intensity (1000 W/cm 2 ) tissue temperature is raised to > 70°C in 1-3 sec leading to coagulative necrosis.  For relocation of stones, transfer of acoustic wave momentum to the stone surface generates acoustic radiation force.  When acoustic wave is incident on an absorbing object (stone), its momentum is transferred to it. This transfer of momentum generates acoustic radiation force. This force is contained and principally acts along the propagation axis of acoustic wave. Changing alignment of the focused ultrasound beam can therefore effectively change the direction of the force acting on the stone surface.
| First-Generation Model: In Vitro Feasibility|| |
Based on the above-mentioned physical principal, an experimental ultrasound model (Research System) was developed by joining two separate machines; one for ultrasound imaging and guidance and the other for focused ultrasound. This device has a handheld probe of focal depth of 4.5-8.5 cm [Figure 1] and [Figure 2]. The central probe is for imaging and guidance. The peripheral focused probe consisting of an eight-element annular array with a frequency of 2 MHz is for the therapeutic effect. A laptop computer controls excitation timing of each element.
|Figure 1: Diagrammatic representation of the coaxial arrangement ofthe probe. Focused ultrasound probe (A) and ultrasound imaging probe. (Modified from Shah et al. )|
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|Figure 2: Diagrammatic representation of the therapy beam and the imaging beam. Coaxial arrangement placed the therapy beam within the imaging beam for real-time monitoring. (Modified from Shah et al. )|
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Therapeutic efficacy was tested in a phantom in vitro model of lower pole of kidney created from transparent gel. Human urinary calculi (3-8 mm), artificial stones, and metal-plated glass beads (2.5-4 mm) were placed in a dependent position.  Focused ultrasound (Power 5-40 W, duty cycle 50%, duration 2-5 sec) caused stone motion and relocation as monitored by fluoroscopy and video photography. The calculated stone velocity was 1 cm/sec. The minimum power required to lift largest size stone (8 mm) was 10 W and stone displacement was largest when the angle of focus was parallel to the infundibular axis. At 10 W powers the spatial-averaged pulse-average intensity (I SAPA ) was 30 W/cm 2 and the spatial-peak pulse-averaged intensity (I SPPA ) was 45 W/cm 2 , which is lower than FDA limits for prevention of cavitational injury (I SPPA < 190 W/cm 2 ). I SAPA is ultrasound intensity at the face of a transducer divided by duty cycle. I SPPA is a measure of maximum power given by an ultrasound pulse from the transducer. I SAPA is multiplied with a factor of 1.6 to derive ISPPA.  It is an indicator of bio-effects of ultrasound including cavitational injury.
| First-Generation Model: In Vivo Feasibility and Safety in A Live Porcine Model|| |
Six pigs served as controls. Human kidney stones (1-8 mm) and artificial stones (3-5 mm) were endoscopically placed in other six pigs.  All 12 pigs underwent laparotomy and kidneys were exposed. The probe was placed in direct contact with kidney. After exposure kidneys were harvested for gross and microscopic examination for any evidence of thermal injury. All six pigs showed relocation of stones or beads after total focused ultrasound exposure for less than 2 minutes. At therapeutic exposure (timed-average intensity 325 W/cm 2 ) no thermal injury occurred in any kidney. 1900 W/cm 2 exposure caused thermal coagulation.
| Second-Generation Model: Clinical Prototype|| |
A new second-generation prototype was developed for assessing efficacy in stone relocation and evidence of injury in a porcine model.  This portable device allows imaging as well as therapy with a single probe, a single ultrasound engine, a single computer processor, and a single display monitor. This facilitates operation by a single user. The new prototype delivers much less acoustic energy as compared to its predecessor, even lower than that used for ESWL. It delivers energy in 0 to 1 sec push bursts. One-second push burst consists of 250 focused pulses 0.1 millisecond in duration at 3% duty cycle. At depth of 7 cm peak pressure of 12 MPa and average peak pulse average intensity of 2400 W/cm 2 is produced. These values are much less than that produced with ESWL.
| Second-Generation Model: Efficacy and Safety in An Animal Model|| |
Total 26 calcium oxalate monohydrate stones (2-8 mm) placed in 12 porcine kidneys were tested with a new prototype. All stone motions could be seen with the device. Sixty-five percent (17/26) stones could be successfully relocated requiring 14.2 minutes and 23 push bursts on average. Average linear displacement was 5.6 cm on fluoroscopy.  Relocation seems to be independent of stone composition as mixed calcium stones, calcium phosphate, and cystine stones have been successfully relocated.  All pigs had normal renal function after treatment, none had gross hematuria, and histopathology analysis did not show any evidence of necrosis.
Further proving safety of the clinical prototype a comparative study with ESWL was conducted.  Three kidneys in three female pigs were treated with the clinical prototype machine at maximum output transcutaneously after placement of stones ureteroscopically. Other set of pigs was exposed to overtreatment with the original research system that exceeds the maximum output of the clinical prototype. Lower pole of left kidney of 6 female pigs received ESWL (2400 shocks @ 120 Hz and 24 kV) from unmodified Dornier HM3. Treatment with the clinical prototype did not produce any detectable lesion in kidneys. Overtreatment experiments did not produce a lesion when the probe was placed transcutaneously, whereas placing the probe directly on kidney two types of lesions were produced. High-power low duty cycle (26130 W/cm 2 @ 3.3% duty cycle for 10 minute) exposure produced hemorrhagic lesions and lower power (9320 W/cm 2 @ 100% duty cycle for 10 min) produced thermal coagulation. These lesions were comparable to those in the ESWL group in size. So, measures of energy parameters required for relocating implanted stones are far less than that required for producing tissue lesions [Table 1].
|Table 1: Comparison of energy parameters needed for relocation and causing renal injury|
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| Potential Clinical Therapeutic Applications|| |
After demonstrating efficacy and safety in in vitro and animal models the device is ready for clinical testing in humans after FDA approval. There are many potential therapeutic applications of this novel technology [Table 2]. Asymptomatic renal calculi less than 5 mm are often observed. However, chances of intervention, progression, and spontaneous passage are 7.1%, 45.9%, and 20%, respectively.  Ultrasonic propulsion can be used to facilitate the passage of these small stones. This can prevent unpredictable stone event particularly in pilots, pregnant ladies, and patients with solitary kidney. 
|Table 2: Therapeutic applications and limitations of focused ultrasonic propulsion technology|
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Medical expulsive therapy (MET) is often offered for small non-obstructive ureteric calculi to facilitate spontaneous passage and avoid intervention. Combining ultrasonic propulsion with MET might increase the success rate and decrease colic episodes.  Another application can be stones in pregnancy. Though most of ureteric calculi pass spontaneously during pregnancy, a significant number may require intervention for colic, obstruction, or infection.  Use of this device can avoid radiation hazards associated with other interventions. Though intensities delivered are much less than FDA-approved limits for diagnostic ultrasound imaging, further testing is required before approval of this device for use during pregnancy.
This device can be used to enhance clearance of CIRFs after ESWL, PCNL, or URS. Success rates of ESWL for lower pole stones are consistently lower and many recommend PCNL for stones larger than 15 mm. However, PCNL is more morbid as compared to ESWL. Flexible ureteroscopy for lower pole stone is also technically more demanding. This technology can relocate stones from lower pole and improve results of ESWL and flexible URS.
When there are multiple stones, some may be inaccessible through primary puncture and demand second puncture during PCNL. Intraoperative relocation of stone can prevent second puncture. Similarly, relocation of stone from superior calyx to pelvis can prevent supracostal puncture during PCNL.
This technology can also assist in diagnosis of stones.  Ultrasound sensitivity for renal stones is limited as compared to non-contrast CT because stones are often confused with renal sinus fat and parenchymal calcifications. Ultrasonic propulsion-induced movement of stones can facilitate differential diagnosis and prevent exposure to radiations from CT evaluation.
Though efficacy has been demonstrated in pig models, humans are different from pigs. Humans have greater skin to stone distance than pigs. This can be a limitation in obese patients. In humans, upper pole stones may be difficult to relocate because of poor acoustic window of rib cage. Due to technical difficulty, there is an upper limit to the size of stone that can be implanted in pig. Though all size stones were relocated in pigs, is there upper limit of stone size for humans. These and many other questions will be answered after human trials.
| Conclusion|| |
Focused ultrasonic relocation is a novel non-invasive technique with many potential therapeutic applications in the management of stone disease. Though safe and effective in animal models, its efficacy in humans needs to be determined through clinical trials. This has the potential to change the management algorithm of stone management.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]