Biological Determinants of Peritoneal Dialysis Outcomes

描述（由申请方提供）：接受腹膜透析（PD）治疗的终末期肾病（ESRD）患者的长期生存率与接受中心内 血液透析，但具有更好的患者报告结果，并且可以以更低的社会成本提供治疗。在美国，PD治疗ESRD的使用正在增加，但每年仍有20%的患者因PD相关并发症（技术失败）转为血液透析。腹膜透析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。腹膜超滤能力也随着时间的推移而下降，高达三分之一的患者和50%的这些个体发展为超滤失败的技术失败。在初始PSTR和腹膜超滤能力的后续变化中存在大量尚未解释的变异性。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，迄今为止，此类研究规模较小，研究了有限数量的机制途径，并且很少有这些发现被复制。由于美国单个透析机构的PD患者普查率极低，因此无法进行充分把握度的前瞻性队列研究。已获得资金，以在2013年启动腹膜透析结局和实践模式（P-DOPPS），这是一项国际多中心前瞻性队列研究，将使用随机抽样设计招募PD患者的代表性人群。P-DOPPS代表了研究腹膜功能遗传决定因素的一代机会。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学途径和超滤能力的变化。本研究将通过三个额外的队列进行丰富：（1）欧洲多中心队列（n=510）;（2）PD-CRAFT，一项在英国进行的研究（n=1700），以及（3）西雅图生物储存库中的受试者（n=200）。两种表型中的每一种都是数量性状，并且具有高度的可重复性;表型的这种精确性增强了统计功效，并确保了成功的高可能性。此外，该提案还包括验证两种表型的独立复制队列中的发现。本研究的成功完成有可能大大提高我们对腹膜生物学的理解。反过来，这可以用于开发早期识别腹膜损伤的生物标志物，并确定新的治疗靶点以保持超滤能力。影响腹膜功能的生物学途径可能与影响其他组织中微血管健康、血管生成和纤维化的生物学途径相同。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。

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.