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.
One of the greatest challenges to the long-term use of peritoneal dialysis for the treatment of end-stage renal disease is the decline in peritoneal ultrafiltration capacity over time. This proposal to advance our understanding of the biology of peritoneal membrane function will allow for the identification of novel mechanistic pathways that could be targeted to maintain peritoneal health and prolong the length of time that a patient with end-stage renal disease could be treated with peritoneal dialysis. This, in turn, will result in substantial reduction in patient morbidity, and healthcare costs associated with the care of such patients.
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