PROJECT SUMMARY/ABSTRACT There are currently no cardiovascular (CV) risk prediction tools for patients with Chronic Kidney Disease (CKD) in clinical practice today. In fact, the optimal approach to CV risk stratification in patients with CKD is uncertain, highly contested and confounded by a paucity of published data. Furthermore, traditional risk prediction models fail in their predictive accuracy for CV events in patients with CKD, underestimating risk by up to 50%. This is exceedingly problematic, given that CVD is the leading cause of death in CKD. This has forced clinicians to consider alternative approaches such as the assessment of coronary artery calcification (CAC) score (by cardiac CT) or myocardial fibrosis (by native T1 MRI) as risk stratification tools, however there remains considerable clinical equipoise regarding their prognostic utility in CKD. Moreover, emerging evidence suggests that evaluation of CV structure at rest rather than ascertainment of function under the stress of exercise, may be insufficiently sensitive to accurately reflect the risk of premature CV death in CKD. Although exercise has been shown to be among the most potent predictors of future CV evens, it is rarely assessed in patients with CKD. Recent work by our group suggests that global indices of CV functional capacity (as assessed by oxygen uptake (VO2) at peak exercise) using cardiopulmonary exercise testing (CPET) may offer a potential solution for accurately prognosticating CV risk in CKD. If CPET could be used to accurately predict future CV events and risk stratify CKD patients, this could have practice changing implications. Potential applications include the identification of patients for earlier or more intensive medical or dialytic therapies, in the selection and prioritization of patients for timely kidney transplantation, in pre-operative risk assessment for major surgery and to help guide the selection of patients for coronary angiography. The overall aim of the proposed study is therefore to define the optimal diagnostic test and CV functional index for CV risk discrimination and prognostication. The central hypothesis of this proposal is that measurement of VO2Peak by CPET will be superior to other diagnostic tests for predicting future CV events in patients with advanced CKD. The present study is a proof-of-concept single-center prospective study that will recruit a total of n=140 racially and ethnically diverse advanced CKD stage 5D (hemodialysis) patients. All patients will undergo functional (physical function testing and CPET) and structural (cardiac CT and T1 MRI) assessments at baseline and repeat functional testing at 1-year. CV outcomes will be assessed prospectively at 3-years. AIM 1 (A) will determine the predictive value of VO2Peak compared to other clinically used tests (cardiac CT, T1 MRI, physical function testing) for predicting CV outcomes at 3-years; and (B) determine if changes in VO2Peak is superior to single baseline VO2Peak for predicting cardiovascular outcomes at 3-years. AIM 2 will develop a new risk stratification model and assess whether the inclusion of functional indices can better prognosticate future cardiovascular outcomes in CKD compared to traditional risk scores.

PROJECT NARRATIVE The optimal approach to predicting cardiovascular risk in patients with chronic kidney disease (CKD) is unknown. Emerging evidence suggests that global indices of cardiovascular functional capacity (VO2Peak) may offer a potential solution for better risk stratifying patients with CKD using state-of-the-art cardiopulmonary exercise testing (CPET) technology. The present study will be the first to compare head-to-head CPET with clinically used diagnostic tools, and to develop a new risk stratification model for predicting cardiovascular outcomes in patients with advanced CKD stage 5D (on hemodialysis).