Harvard Chronic Kidney Disease Research Biopsy Center

项目总结 慢性肾脏疾病(CKD)影响了美国10%的成年人口，造成数百亿美元的损失 每年，并可导致进行性肾功能衰竭、心血管疾病(CVD)和早期死亡。CKD是 不是一个单一的实体，而是一种具有广泛潜在原因、病理的不同情况 和临床表现，以及进展率。因为肾活检样本的稀少 常见形式的CKD患者和公认的动物模型的局限性，我们对 CKD的病理机制和分子机制目前尚不清楚。对人类CKD的更深层次的理解将需要 应用快速发展的分子病理学技术对慢性肾脏病患者的肾组织进行研究。 在这项提案中，我们建立了一个多学科调查小组，并概述了一个多中心的计划 Brigham参与的肾脏精准医学项目(KPMP)CKD招聘网站[RFA-DK-16-026] 妇女医院、乔斯林糖尿病中心、贝丝以色列女执事医疗中心和马萨诸塞州 综合医院。该提案建立在已建立的基础设施波士顿肾活检的基础上 联盟(BKBC，R01DK093574)，已成功登记，收集生物标本，并纵向 跟踪观察了在这四家机构接受肾活组织检查的800名患者。我们会分享血浆，尿液， BKBC的DNA、RNA和档案肾组织标本与KPMP一起检测，以便加速 UG3阶段及以后的进展。我们还将分享U01DK104308的样本，这项研究收集了 肾切除术中非癌肾皮质肾组织标本的研究 纤维化症。对于UG3阶段，我们建议参与协作讨论，以定义科学 目的探讨慢性肾脏病肾活检的伦理和安全性。UG3阶段的试点研究将 包括通常不接受肾脏活组织检查的CKD患者的研究活组织检查，以及研究核心 来自正在接受临床指定的慢性肾脏病活组织检查的患者。在UH3阶段，我们建议扩大 这项研究包括CKD不同阶段的大量研究活组织检查。我们还建议做活组织检查 在长期患有1型糖尿病但没有肾脏病理证据的个人中，为了 确定预防糖尿病肾病的分子基础。我们还概述了一项关于 10名肾小球滤过率每年快速丢失(5毫升/分钟/年)的参与者和10名参与者的重复活检 参与者估计的GFR没有变化(&lt；1毫升/分钟/年)。我们致力于协作协议 开发、分享最佳实践和团队科学，以实现KPMP的目标 精准医疗，以改善我们CKD患者和有CKD风险的患者的生活。拟议的研究计划， 通过提高我们对CKD病理生理学的理解，CKD有可能极大地影响公众健康。

PROJECT SUMMARY Chronic kidney disease (CKD) affects >10% of the adult US population, costs tens of billions of dollars annually, and can lead to progressive kidney failure, cardiovascular disease (CVD), and early mortality. CKD is not a single entity but rather a heterogeneous condition with a wide spectrum of underlying causes, pathologic and clinical manifestations, and rates of progression. Because of the paucity of kidney biopsy samples from patients with common forms of CKD and the acknowledged limitations of animal models, our understanding of the pathology and molecular mechanisms of CKD is limited. Deeper understanding of human CKD will require investigation of kidney tissue from patients with CKD, using rapidly evolving techniques in molecular pathology. In this proposal we have established a multidisciplinary investigative team and outline plans for a multicenter CKD recruitment site for the Kidney Precision Medicine Project (KPMP) [RFA-DK-16-026] involving Brigham and Women’s Hospital, Joslin Diabetes Center, Beth Israel Deaconess Medical Center, and Massachusetts General Hospital. The proposal builds upon an established infrastructure, the Boston Kidney Biopsy Consortium (BKBC, R01DK093574) that has successfully enrolled, collected biospecimens, and longitudinally followed > 800 patients undergoing native kidney biopsy at the four institutions. We will share plasma, urine, DNA, RNA, and archival kidney tissue specimens from the BKBC with the KPMP in order to accelerate progress in the UG3 phase and beyond. We will also share samples from U01DK104308, a study that collects intraoperative kidney tissue samples from non-cancer cortex during nephrectomy for research in kidney fibrosis. For the UG3 phase we propose participating in collaborative discussions to define the scientific objectives and to address the ethics and safety of kidney biopsy in CKD. Pilot studies in the UG3 phase will include research biopsies in patients with CKD who do not typically undergo kidney biopsy, and research cores from patients undergoing clinically indicated biopsies for CKD. In the UH3 phase, we propose expanding the study to include larger numbers of research biopsies across different stages of CKD. We also propose biopsies in individuals with longstanding Type 1 diabetes mellitus with no evidence of kidney pathology, in order to identify molecular underpinnings of protection against diabetic kidney disease. We also outline a proposal for repeat biopsies in 10 participants with rapid annual loss of estimated GFR (>5 ml/min/year) and in 10 participants with no change in estimated GFR (<1ml/min/year). We are committed to collaborative protocol development, sharing best practices, and team science to achieve the KPMP’s objectives of advancing precision medicine to improve the lives of our patients with and at risk for CKD. The proposed research plan, by improving our understanding of CKD pathophysiology, has the potential to dramatically impact public health.