Innovative Strategies for Improved outcomes in Nephrolithiasis

描述（由申请人提供）：改善肾结石结局的创新策略。该计划项目赠款的主要重点是开发和完善基于超声的技术和治疗方案，以改善肾脏结石的非侵入性清除，目标是改善患者的预后。在这项工作中，我们将改进新技术，使用超声推进（UP）将结石和残余结石碎片推出肾盂肾盏系统，并到达输尿管-肾盂连接处，以便沿输尿管下行。UP系统建立在市售超声（US）平台上，我们已将其配置为提供一套独特的结石特异性成像模式（S模式），专门用于检测结石（甚至非常小，<1 mm，结石碎片），确定碎片尺寸，检测指示干扰结石破碎的声屏蔽的空化，并定位组织中的空化，其发出组织损伤开始的信号。我们将使用UP和S模式成像来提高冲击波碎石术（SWL）的效率，方法是分散产生屏蔽的碎片，并精确确定碎石终点，从而避免对患者进行不必要的过度治疗。我们还将追求一种新的非侵入性方法的开发，改进和验证，该方法使用聚焦，低频脉冲US（突发波碎石术，BWL）将结石减少到小的，临床上不重要的颗粒，对周围组织的损伤最小。SWL的过度治疗与不良反应增加有关，并且是FDA对SW剂量限制的基础，这些限制通常会阻止使用足以使患者无结石的剂量进行治疗。我们将建立在我们发现的保护肾脏免受损伤的SWL治疗策略的基础上，设计出大大超过目前FDA对SW剂量限制的治疗方案，但完全安全。也就是说，我们将证明可以超过SWL的单次治疗限值，而不会造成额外的损伤，从而允许使用足够的SW进行治疗，以完全粉碎大的结石负荷或消除难以破碎的结石。与我们改善结石患者治疗结果的目标一致，我们将进行一项多中心前瞻性临床试验，以确定通过输尿管肾镜（UP辅助）清除“亚临床”附着结石是否会预防结石复发，从而改善长期结局。

DESCRIPTION (provided by applicant): Innovative Strategies for Improved Outcomes in Nephrolithiasis. The main focus of this Program Project Grant is to develop and refine ultrasound-based technologies and treatment protocols to improve the noninvasive removal of stones from the kidney with the goal of improving patient outcomes. In this effort, we will refine new technology that uses ultrasonic propulsion (UP) to push stones and residual stone fragments out of the renal pelvicalyceal system and on to the uretero-pelvic junction for passage down the ureter. The UP system is built upon a commercially available ultrasound (US) platform that we have configured to deliver a suite of unique stone-specific imaging modalities (S-mode) specifically tailored to detect stones (even very small, <1 mm, stone fragments), determine fragment size, detect cavitation indicative of the acoustic shielding that interferes with stone breakage, and localize the cavitation in tissue that signals the on- set of tissue injury. We will use UP and S-mode imaging to improve the efficiency of shock wave lithotripsy (SWL) by dispersing fragments that create shielding and by enabling precise determination of the stone breakage endpoint so that patients are not needlessly over-treated. We will also pursue the development, refinement, and validation of a novel noninvasive method that uses focused, low-frequency pulsed US (burst wave lithotripsy, BWL) to reduce stones to small, clinically insignificant particles with minimal injury to surrounding tissue. Over-treatment by SWL is linked to increased adverse effects and is the basis for FDA limits on SW-dose, limits that often prevent treatment with a dose sufficient to render the patient stone free. We will build upon our discovery of SWL treatment strategies that protect the kidney from injury to devise treatment protocols that dramatically exceed current FDA limits for SW dose, yet are entirely safe. That is, we will demonstrate that single session treatment limits for SWL can be exceeded without causing added injury, thus allowing treatment with enough SWs to fully comminute a large stone burden or eliminate stones otherwise difficult to break. Consistent with our goal of improving treatment outcomes for stone patients, we will conduct a multicenter prospective clinical trial to determine if the removal of 'subclinical' attached stones by ureterorenoscopy (assisted by UP) will forestall stone recurrence, thereby improving long-term outcomes.