Biological Determinants of Peritoneal Dialysis Outcomes

描述(申请人提供)：接受腹膜透析(PD)治疗的终末期肾病(ESRD)患者的长期存活率与接受In-Center治疗的患者相似 血液透析但患者报告的结果更好，而且该疗法可以以较低的社会成本提供。在美国，使用PD治疗终末期肾病的人数正在增加，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。腹膜溶质转运速率(PSTR)在腹膜透析开始时较高 与较低的超滤能力和较高的技术故障风险相关。腹膜超滤能力也随着时间的推移而下降，多达三分之一的患者和50%的患者因超滤失败而发生技术失败。在最初的PSTR和随后的腹膜超滤能力的变化中，存在着实质性的、至今仍未解释的变异性。候选基因关联研究表明，腹膜功能的这种变异性的一部分是可遗传的。然而，到目前为止，这样的研究规模很小，只检查了有限数量的机械途径，而且这些发现很少被重复。由于美国个别透析机构的帕金森病患者普查极低，因此不可能进行足够有力的前瞻性队列研究。2013年推出腹膜透析结果和实践模式(P-DOPPS)的资金已经获得，这是一项国际性的多中心前瞻性队列研究，将使用随机抽样设计来登记具有代表性的PD患者群体。P-DOPPS代表着每一代人一次研究腹膜功能遗传决定因素的机会。我们试图利用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通路以及超滤能力的变化。这项研究将通过另外三个队列得到丰富：(1)欧洲多中心队列(n=510)；(2)在英国进行的PD-CRATE研究(n=1700)；(3)在西雅图生物储存库中的受试者(n=200)。这两种表型中的每一种都是数量性状，重复性很高；这种表型的精确度增强了统计能力，确保了成功的高可能性。此外，该建议还包括对两种表型的独立重复队列中的研究结果进行验证。这项研究的成功完成有可能极大地提高我们对腹膜生物学的理解。这反过来可以用来开发用于早期识别腹膜损伤的生物标记物，并识别保持超滤能力的新的治疗靶点。影响腹膜功能的生物途径可能与影响其他组织的微血管健康、血管生成和纤维化的生物途径相同。因此，我们的研究也可能加强我们对这些常见生物过程的理解。

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.