Novel Mechanisms and Therapeutic Targets for Pulmonary Hypertension in End-Stage Renal Disease (K23)

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PROJECT SUMMARY Cardiovascular disease is the leading cause of death for persons with chronic kidney disease (CKD) and end- stage renal disease (ESRD). Pulmonary hypertension (PH) is an underappreciated cardiovascular complication of kidney disease that affects up to 60% with ESRD, in whom PH increases the risk of mortality 3-fold. Despite its high prevalence and morbidity in ESRD, the pathophysiology of PH remains poorly understood. The current pathophysiologic paradigm emphasizes volume overload as the main cause of PH in ESRD, but volume removal through dialysis resolves PH in only a fraction of cases. Dr. Edmonston’s long-term goal is to identify novel pathophysiologic targets for PH in ESRD through rigorous prospective studies and investigate new therapies tailored to these targets through efficient clinical trials. Based on published preliminary data in 4772 patients with CKD-ESRD, >60% of PH cases had elevated pulmonary vascular resistance on right heart catheterization. This increased pulmonary vascular resistance implicates mechanisms beyond volume overload which promote pulmonary vasoconstriction and remodeling. The central hypothesis of this proposal is that volume-independent changes in vascular biology caused by reduced kidney function and exacerbated by hemodialysis contribute to PH in ESRD. Increased circulating levels of the vasoactive factors asymmetrical dimethylarginine (ADMA) and serotonin, which cause pulmonary vascular remodeling and vasoconstriction, may serve as pathogenic links between reduced kidney function and PH. Hemodialysis further introduces putative risk factors for PH: subclinical hemolysis caused by hemodialysis releases free hemoglobin (Hb) into circulation that scavenges nitric oxide (NO); and recurrent intradialytic hypoxemia promotes PH through frequent episodes of hypoxia- induced vasoconstriction. In a prospective study, this proposal will investigate the association of each of these volume-independent factors with PH in 150 patients with ESRD receiving maintenance hemodialysis: Aim 1 will investigate ADMA and serotonin as mechanisms of PH in ESRD; Aim 2 will establish subclinical hemolysis and impaired hemoglobin scavenge as hemodialysis-associated mechanisms of PH in ESRD; Aim 3 will quantify the extent of intra- and extradialytic hypoxemia and define its association with PH in ESRD. Supported by new preliminary data for this resubmission, PH will be estimated by tricuspid regurgitant velocity (TRV) on echocardiogram. A longitudinal subcohort of 50 patients found to have PH on initial assessment will determine how changes in these risk factors associate with PH progression after 6 months (Aims 1-3). To discern the contribution of hemodialysis above the influence of ESRD, this proposal will also enroll 10 patients with ESRD undergoing peritoneal dialysis (Aims 1-3). Execution of these scientific aims and completion of the career development activities of this proposal, along with experienced mentorship and strong institutional support, will position Dr. Edmonston to serve as the Principal Investigator on future R01 grants to support interventional trials that target PH in ESRD and prospective studies which identify risk factors for PH in earlier stages of CKD.