A novel electroceutical tool for treatment of kidney-based diseases

摘要 肾神经的慢性过度活动导致肾功能的生理和病理变化， 会导致肾脏疾病高血压与交感神经活动增加有关， 在临床前模型中的肾脏，并且在大多数这些模型中，高血压通过肾脏去神经支配而减弱 （RDN）。基于这些模型的临床试验已经证明，基于导管的RDN在以下方面是有效的： 降低高血压患者的动脉压。导管引导的RDN治疗高血压的成功 催化了新兴的电化学领域，这是基于器官特异性的概念， 神经调节（而不是消融）用于心脏代谢疾病。而消融是不可逆的， 不可研磨的神经调节可以被并入闭环反馈设计中以精确地调节 神经活动如所愿。此外，神经调节可以根据需要关闭和重新启动。 结合起来，我们的实验室对肾神经在肾脏疾病发病机制中的作用有着广泛的了解。 高血压和介导RDN的抗高血压作用的机制（Co-PI 奥斯本）以及开发计算建模工具以设计神经技术的经验（Co-PI 约翰逊。我们的目标是将这些知识转化为一种新型植入式技术的发展， 用于治疗平移大型动物中神经介导的肾脏病理的肾脏神经调节 肾脏病理学模型（DOCA-盐绵羊）。在特定目标1中，我们将开发双向肾神经袖带 接口，首先在计算机中，然后在实验室中，以电阻断（E-Block）和感知（E-Sense）肾神经活动 在羊身上。在具体目标2中，我们将通过比较急性E-block的刺激参数， 麻醉DOCA高血压患者手术消融后对E-Block的肾反应 羊这种用于治疗肾脏疾病的神经调节工具的成功开发可以转化为 治疗与肾神经过度活动相关的其他慢性疾病，包括慢性肾病， 终末期肾衰竭此外，这种相同的技术可以潜在地用于调节其他器官（例如， 肝、胰腺、脾）用于治疗与过度神经紧张相关的慢性心脏代谢疾病 活动

ABSTRACT Chronic overactivity of renal nerves results in physiological and pathological changes in renal function that contribute to kidney-based diseases. Hypertension is correlated with increased activity of sympathetic nerves to the kidneys in preclinical models, and in most of these models, hypertension is attenuated by renal denervation (RDN). Clinical trials building on these models have demonstrated that catheter-based RDN is effective in lowering arterial pressure in hypertensive patients. The success of catheter-based RDN to treat hypertension has catalyzed the emerging field of electroceuticals, which is based on the concept of organ-specific neuromodulation (rather than ablation) for cardiometabolic diseases. Whereas ablation is non-reversible and non-tritratable, neuromodulation can be incorporated into a closed-loop feedback design to precisely regulate the activity of nerves as desired. Moreover, neuromodulation can be turned off and restarted as needed. Combined, our laboratories have extensive knowledge on the role of renal nerves in the pathogenesis of hypertension and the mechansims mediating the anti-hypertensive effect of RDN in rodent models (Co-PI Osborn) as well as experience in developing computational modeling tools to design neurotechnologies (Co-PI Johnson. We aim to translate this knowledge to the development of a novel implantable technology for neuromodulation of the kidney for treatment of neurally-mediated renal pathology in a translational large animal model of renal pathology (DOCA-salt sheep). In Specific Aim 1, we will develop a bidirectional renal nerve cuff interface, first in silico and then in the lab, to electrically block (E-Block) and sense (E-Sense) renal nerve activity in sheep. In Specific Aim 2, we will optimize stimulus parameters of renal E-block in vivo by comparing the acute renal responses to E-Block to those observed following surgical ablation in anesthetized DOCA-hypertensive sheep. Successful development of this neuromodulatory tool for treatment of renal disease can be translated to treat other chronic diseases associated with overactivity of renal nerves including chronic kidney disease and end-stage renal failure. Moreover, this same technology can potentially be used to modulate other organs (e.g. liver, pancreas, spleen) for the treatment of chronic cardiometabolic diseases that are linked to excessive nerve activity.