Non Invasive Assessment of Microcirculation Function and Kidney Disease

项目摘要 这是一份K23申请的提交材料，由肾脏病学家Rakesh Malhotra博士，医学博士，公共卫生硕士， 加州圣地亚哥大学（UCSD）。通过这一提议，马尔霍特拉博士打算将自己确立为 一名研究慢性肾脏疾病非侵入性微血管测量的独立研究者 （CKD）。 候选人：Malhotra博士的培训目标包括：1）熟练掌握测量非 侵入性微血管技术和翻译为以患者为导向的研究; 2）获得专业知识， 与临床试验相关的先进统计方法; 3）学习必要的技能， 独立的研究项目，设计和领导临床试验。马尔霍特拉博士将完成这些 通过指导、课程和参加讲习班实现目标。他已经召集了一个 多学科的科学家团队，包括Joachim IX博士，临床试验专家（主要导师），Boy博士 Houben，微循环领域的领导者（共同导师）; Matthew Allison博士，微循环领域的领导者 血管健康和评估（共同导师）和Florin Vaida博士，博士水平的生物统计学家（统计共同导师）， 导师）。此外，具有肾脏病理学经验的肾脏病理学家张海燕博士和Ithaar博士 拥有微创手术专业知识的泌尿科医生德维什将作为无偿顾问参加。 研究：肾脏微循环在CKD的发病机制中起着重要作用。肾脏活检是 这是评估肾脏微血管异常的标准技术，但具有侵入性，很少使用。博士 Malhotra的总体假设是，非侵入性微血管测量可能会改善我们的 了解肾脏微循环，提高我们识别肾脏疾病风险的能力 进展在目标1中，Malhotra博士将评估非侵入性微血管与 测量（皮肤毛细血管密度和%募集（通过毛细管镜检查）和热诱导皮肤%- 充血（激光多普勒））伴肾小球硬化的100例CKD患者中， 活检和50例CKD患者因疑似肾癌接受肾切除术。在目标2a中，博士 马尔霍特拉将评估临床风险因素与微血管功能障碍的相关性，如所评估的那样 200例CKD患者的毛细血管镜检查和激光多普勒。在目标2b中，马尔霍特拉博士将确定 200例CKD患者皮肤微血管功能与肾功能纵向变化的相关性 科目最后，在目标3中，Malhotra博士将评价在以下情况下毛细血管募集百分比的急性变化是否 对膳食蛋白负荷的反应与eGFR的同时变化相关，eGFR是20例患者RFR的指标。 CKD受试者培训和研究计划都将为使用非侵入性 临床试验中的微血管技术，用于评估肾脏血流动力学和监测反应 在Malhotra博士职业生涯的下一个独立阶段的治疗和临床结果。

PROJECT SUMMARY This is a submission of a K23 application by Dr. Rakesh Malhotra, MD, MPH, a nephrologist at University of California San Diego (UCSD). Through this proposal Dr. Malhotra intends to establish himself as an independent investigator studying non-invasive microvascular measurements in chronic kidney disease (CKD). Candidate: Dr. Malhotra’s training objectives include; 1) to become proficient in the measurement of non- invasive microvascular techniques and translation to patient-oriented research; 2) to gain expertise in advanced statistical methods relevant to clinical trials; and 3) to learn the necessary skills to develop an independent research program and to design and lead clinical trials. Dr. Malhotra will accomplish these objectives through mentorship, coursework, and participation in workshops. He has assembled a multidisciplinary team of scientists including Dr. Joachim Ix, an expert clinical trialist (primary mentor), Dr. Boy Houben, a leader in the field of microcirculation (co-mentor); Dr. Matthew Allison, a leader in the field of vascular health and assessment (co-mentor) and Dr. Florin Vaida, a PhD level biostatistician (statistical co- mentor). In addition, Dr. Haiyan Zhang a renal pathologist with experience in nephropathology and Dr. Ithaar Derweesh a urologist with expertise in minimally invasive surgery will participate as a consultant without pay. Research: Renal microcirculation plays an important role in the pathogenesis of CKD. The kidney biopsy is the standard technique to assess abnormalities in renal microvasculature, but is invasive and rarely done. Dr. Malhotra’s overall hypothesis is that the non-invasive microvascular measurements may improve our understanding of the renal microcirculation, and improve our ability to identify those at risk of kidney disease progression. In Aim 1, Dr. Malhotra will evaluate the relationship between non-invasive microvascular measurements (skin capillary density and % recruitment (by capillaroscopy) and heat-induced skin %- hyperemia (by laser Doppler)) with glomerular sclerosis among 100 individuals with CKD undergoing kidney biopsy and 50 persons with CKD undergoing nephrectomy for suspected kidney cancer. In Aim 2a, Dr. Malhotra will evaluate the association of clinical risk factors with microvascular dysfunction as assessed with capillaroscopy and laser Doppler among 200 CKD subjects. In Aim 2b, Dr. Malhotra will determine the associations between skin microvascular function and longitudinal changes in kidney function in the 200 CKD subjects. Lastly, in Aim 3, Dr. Malhotra will evaluate whether acute changes in % capillary recruitment in response to a dietary protein load is correlated with concurrent changes in eGFR, as measure of RFR in 20 CKD subjects. Both the training and research plans will lay the groundwork for use of non-invasive microvascular techniques in clinical trials to allow assessment of renal hemodynamics and monitor responses to therapies and clinical outcomes in the next and independent phase of Dr. Malhotra’s career.