Harvard Chronic Kidney Disease Research Biopsy Center

项目摘要 慢性肾脏疾病（CKD）影响超过10%的美国成年人口，花费数百亿美元 每年，并可能导致进行性肾衰竭，心血管疾病（CVD）和早期死亡。CKD是 不是一个单一的实体，而是一种异质性疾病，具有广泛的潜在原因，病理 临床表现和进展率。由于缺乏肾脏活检样本， 常见CKD患者和公认的动物模型局限性，我们对 CKD的病理和分子机制是有限的。深入了解人类CKD需要 使用分子病理学中快速发展的技术对CKD患者的肾组织进行研究。 在本提案中，我们建立了一个多学科研究小组，并概述了多中心研究计划。 涉及Brigham的肾脏精准医学项目（KPMP）的CKD招募中心[RFA-DK-16-026] 妇女医院、乔斯林糖尿病中心、贝斯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一个既定的基础设施，波士顿肾活检 联盟（BKBC，R 01 DK 093574）已成功入组、采集生物标本，并纵向 在这四个机构中随访了超过800名接受自体肾活检的患者。我们会分享血浆，尿液， BKBC的DNA、RNA和存档肾组织标本与KPMP一起使用，以加速 在UG 3阶段及以后取得进展。我们还将分享来自U 01 DK 104308的样本，该研究收集了 在肾切除术期间来自非癌皮质的术中肾组织样本用于肾研究 纤维化对于UG 3阶段，我们建议参与合作讨论，以确定科学的 目的，并讨论CKD患者肾活检的伦理学和安全性。UG 3阶段的试点研究将 包括在通常不进行肾活检CKD患者中进行的研究性活检，以及研究性核心 来自接受CKD临床指征活检的患者。在UH 3阶段，我们建议扩大 研究纳入了大量CKD不同阶段的研究活检。我们还建议进行活检 在没有肾脏病理学证据的长期1型糖尿病患者中， 确定保护糖尿病肾病分子基础。我们还提出了一项建议， 在10名估计GFR快速年度损失（>5 ml/min/年）的参与者和10名 GFR估计值无变化（<1 ml/min/年）的受试者。我们致力于合作协议 开发，分享最佳实践和团队科学，以实现KPMP的目标， 精准医疗，改善CKD患者和高危患者的生活。拟议的研究计划， 通过提高我们对CKD病理生理学的理解，有可能极大地影响公共卫生。

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.