Vitamin D Deficiency in Glomerular Disease

描述（由申请人提供）：该候选人是儿科肾病学的初级研究员，在临床流行病学方面接受过高级培训。她的研究重点是维生素D在骨骼外的作用，以及在肾小球疾病合并肾范围蛋白尿的患者中处理维生素D缺乏的独特挑战。维生素D缺乏可能是这些患者肾脏疾病进展和并发症的重要可改变危险因素。许多小型研究表明，肾病患者的总25-羟基维生素D [25(OH)D]水平非常低，但其潜在的病理生理机制尚不清楚。此外，必须确定在这个庞大的患者群体中补充的安全性和有效性，以防止潜在的毒性和治疗不足。候选人的初步工作表明，肾小球疾病，特别是局灶节段性肾小球硬化（FSGS），是慢性肾病儿童总和游离25(OH) D水平低和维生素D结合蛋白（DBP）低的独立危险因素。这些发现暗示了25(OH) D- dbp复合物的小管重吸收受损和/或维生素D分解代谢增加。拟议的项目包括：(1)在nih资助的肾病综合征研究网络（NEPTUNE）中对450名参与者进行辅助横断面研究；(2)在35名患有FSGS的儿童和年轻人中进行胆钙化醇补充的试点研究。利用NEPTUNE独特的标准化组织病理学数据库，这项工作将首次确定小管间质损伤与维生素D代谢物之间的关系，并描绘成纤维细胞生长因子23促进分解代谢对这些患者维生素D水平的影响。补充研究将探讨钙化醇补充在蛋白尿FSGS患者中的安全性和有效性，并使用新的先天性免疫和肾内炎症的转化测量来评估补充的反应。这项工作的发现将对后续维生素D试验的设计和实施以及补充指南的制定至关重要。候选人的综合职业发展计划包括临床试验和免疫学方面的教学培训，以及流行病学、生物统计学、肾脏病学和免疫学方面的领导指导。她将利用CHOP研究所和CTSA、临床流行病学和生物统计中心以及NEPTUNE等优秀资源。她的短期目标是：(1)将75%的精力投入到这项研究和培训计划中；(2)随后争夺NIH资金，支持维生素D补充及其对肾小球疾病患者免疫功能和感染性并发症影响的试验；(3)扩大NEPTUNE研究，将基线维生素D水平和矿物质代谢指标与心血管疾病、感染和肾脏疾病进展联系起来。她的长期目标是领导美国国立卫生研究院资助的儿童和成人肾小球疾病的转化研究项目，重点是干预以减少这一高危人群的并发症和疾病进展。

DESCRIPTION (provided by applicant): The candidate is a junior investigator in pediatric nephrology with advanced training in clinical epidemiology. Her research is focused on the extra-skeletal actions of vitamin D and the unique challenges of managing vitamin D deficiency in patients with glomerular diseases complicated by nephrotic-range proteinuria. Vitamin D deficiency may be an important modifiable risk factor for renal disease progression and complications in these patients. Many small studies documented very low total 25-hydroxyvitamin D [25(OH)D] levels in nephrotic patients, but the underlying pathophysiology is poorly understood. Further, the safety and efficacy of supplementation in this sizeable patient population must be determined in order to prevent both potential toxicity and under-treatment. The candidate's preliminary work demonstrated that glomerular disease, particularly focal segmental glomerulosclerosis (FSGS), was an independent risk factor for low total and free 25(OH) D levels and vitamin D-binding protein (DBP) in children with chronic kidney disease. These findings implicate impaired tubular reabsorption of 25(OH) D-DBP complexes and/or increased vitamin D catabolism. The proposed project comprises: (1) an ancillary cross-sectional study of 450 participants in the NIH-funded Nephrotic Syndrome Study Network (NEPTUNE) and (2) a pilot study of cholecalciferol supplementation in 35 children and young adults with FSGS. Leveraging NEPTUNE's unique repository of standardized histopathology data, this work will be the first to determine the association between tubulointerstitial injury an vitamin D metabolites and to delineate the impact of fibroblast growth factor 23-promoted catabolism on vitamin D levels in these patients. The supplementation study will address the safety and efficacy of calciferol supplementation in proteinuric FSGS patients and use novel translational measures of innate immunity and intra-renal inflammation to assess the response to supplementation. The findings of this work will be critical to the design and conduct of subsequent vitamin D trials, and to the development of supplementation guidelines. The candidate's comprehensive career development plan includes didactic training in clinical trials and immunology, and mentorship by leaders in epidemiology, biostatistics, nephrology and immunology. She will draw on outstanding resources including the CHOP Research Institute and CTSA, the Center for Clinical Epidemiology and Biostatistics, and NEPTUNE. Her short-term goals are to: (1) dedicate 75% effort to this research and training program; (2) subsequently compete for NIH funds to support a trial of vitamin D supplementation and its impact on immune function and infectious complications in patients with glomerular diseases; and (3) expand the NEPTUNE study to relate baseline vitamin D levels and measures of mineral metabolism to cardiovascular disease, infections and renal disease progression. Her long-term goal is to lead an NIH-funded translational research program in children and adults with glomerular disease, with an emphasis on interventions to reduce complications and disease progression in this high-risk population.