Biological Determinants of Peritoneal Dialysis Outcomes

腹膜透析结果的生物决定因素

• 批准号: 8696291
• 负责人: RAJNISH MEHROTRA
• 金额: $ 64.03万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-23 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696291
• 关键词: Ancillary Study; Animals; Biological; Biological Markers; Biology; Canada; Candidate Disease Gene; Caring; Censuses; Clinical Research; Cohort Studies; Data; Dialysis patients; Dialysis procedure; Early identification; End stage renal failure; Enrollment; Epidemiology; European; Failure; Funding; Generations; Genetic; Genetic Determinism; Genetic Markers; Genetic Variation; Genomics; Genotype; Goals; Grant; Health; Health Care Costs; Hemodialysis; Human; Individual; Industry; Injury; International; Intervention; Kidney; Knowledge; Length; Life Expectancy; Liquid substance; Maintenance; Measurable; Measures; Membrane; Membrane Biology; Morbidity - disease rate; Movement; National Institute of Diabetes and Digestive and Kidney Diseases; Outcome; Participant; Pathway interactions; Patient Outcomes Assessments; Patients; Pattern; Peritoneal; Peritoneal Dialysis; Phenotype; Population; Process; Research Institute; Risk; Sample Size; Sampling; Specific qualifier value; Techniques; Testing; Time; Tissues; Toxin; Ultrafiltration; United States; Validation; angiogenesis; base; clinically relevant; cohort; cost; design; fibrogenesis; follow-up; genetic variant; genome wide association study; high risk; improved; new therapeutic target; novel; prospective; public health relevance; repository; research study; response; solute; success; trait

DESCRIPTION (provided by applicant): Patients with end-stage renal disease (ESRD) treated with peritoneal dialysis (PD) have similar long-term survival as of patients treated with in-center hemodialysis but have better patient-reported outcomes and the therapy can be delivered at a lower societal cost. The use of PD for the treatment of ESRD is increasing in the United States but annually, 20% of patients still transfer to hemodialysis from PD-related complications (technique failure). A higher peritoneal solute transport rate (PSTR) at the time of start of PD is associated with lower ultrafiltration capacity and a higher risk for technique failure. The peritoneal ultrafiltration capacity also declines over time in up to one third of patients and 50% f these individuals develop technique failure from ultrafiltration failure. There is a substantial an yet unexplained variability in the initial PSTR and the subsequent change in peritoneal ultrafiltration capacity. Candidate gene association studies have indicated that a part of this variability in peritoneal membrane function is heritable. However, such studies to date have been small, examined a limited number of mechanistic pathways, and few of these findings have been replicated. Since the PD patient census in individual dialysis facilities in the United States is extremely low, it has not been possible to perform adequately powered prospective cohort studies. Funding has been obtained to launch Peritoneal Dialysis Outcomes and Practice Patterns (P- DOPPS) in 2013, an international, multi-center prospective cohort study that will use a random sampling design to enroll representative populations of PD patients. P-DOPPS represents once-a-generation opportunity to study the genetic determinants of peritoneal membrane function. We seek to leverage P- DOPPS to identify the common genetic variants associated with initial PSTR and the biologic pathways among genetic markers associated with initial PSTR and the change in ultrafiltration capacity. The study will be enriched by three additional cohorts: (1) a European multi-center cohort (n=510); (2) PD-CRAFT, a study in the UK (n=1700), and (3) subjects in a bio-repository in Seattle (n=200). Each of the two phenotypes is a quantitative trait and highly reproducible; this precision of the phenotypes enhances statistical power and assures high likelihood of success. Furthermore, the proposal includes validation of the findings in independent replication cohorts for both phenotypes. Successful completion of this study has the potential to substantially enhance our understanding of peritoneal membrane biology. This, in turn, could be used to develop biomarkers for early identification of peritoneal membrane injury, and identify new therapeutic targets for preserving ultrafiltration capacity. The biologic pathways that influence peritoneal membrane function are likely to be the same as those that influence the health of microvasculature, angiogenesis, and fibrogenesis in other tissues. Thus, our study is also likely to enhance our understanding of these common biologic processes.

描述（由申请人提供）：接受腹膜透析（PD）治疗的终末期肾病（ESRD）患者与接受中心内治疗的患者具有相似的长期生存率 血液透析，但具有更好的患者报告结果，并且可以以较低的社会成本提供治疗。在美国，使用 PD 治疗 ESRD 的情况不断增加，但每年仍有 20% 的患者因 PD 相关并发症（技术失败）而转为血液透析。 PD 开始时腹膜溶质转运率 (PSTR) 较高 与较低的超滤能力和较高的技术失败风险相关。多达三分之一的患者和 50% 的患者的腹膜超滤能力也会随着时间的推移而下降，这些患者因超滤失败而出现技术失败。初始 PSTR 和随后的腹膜超滤能力变化存在显着但无法解释的变化。候选基因关联研究表明，腹膜功能的这种变异部分是可遗传的。然而，迄今为止，此类研究规模较小，检查的机制途径数量有限，而且这些发现很少被重复。由于美国个体透析机构的帕金森病患者普查数量极低，因此不可能进行足够有力的前瞻性队列研究。已获得资金于 2013 年启动腹膜透析结果和实践模式 (P-DOPPS)，这是一项国际、多中心前瞻性队列研究，将采用随机抽样设计来招募具有代表性的腹膜透析患者群体。 P-DOPPS 代表了研究腹膜功能遗传决定因素的千载难逢的机会。我们寻求利用 P-DOPPS 来识别与初始 PSTR 相关的常见遗传变异以及与初始 PSTR 相关的遗传标记之间的生物学途径以及超滤能力的变化。该研究将通过另外三个队列来丰富：(1) 欧洲多中心队列 (n=510)； (2) PD-CRAFT，英国的一项研究 (n=1700)，以及 (3) 西雅图生物样本库中的受试者 (n=200)。两种表型均为数量性状，且重复性高；表型的这种精确性增强了统计能力并确保了成功的高可能性。此外，该提案还包括对两种表型的独立复制队列中的研究结果进行验证。这项研究的成功完成有可能大大增强我们对腹膜生物学的理解。反过来，这可用于开发早期识别腹膜损伤的生物标志物，并确定保持超滤能力的新治疗靶点。影响腹膜功能的生物途径可能与影响其他组织中微脉管系统、血管生成和纤维发生的健康的生物途径相同。因此，我们的研究也可能增强我们对这些常见生物过程的理解。