Angiotensin-Neprilysin Inhibition in Hemodialysis Initiation

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PROJECT SUMMARY Each year over 107,000 patients initiate hemodialysis (HD) for the treatment of advanced kidney failure in the United States alone. The risk of death is startling, with peak mortality observed during the first two months, most of which relates to cardiovascular (CV) disease. The majority of incident HD patients are hypervolemic and have evidence of cardiac structural abnormalities, which are associated with a higher risk of adverse CV outcomes. Furthermore, patients who lose residual renal function rapidly appear to be at highest risk of adverse outcomes. Pharmacologic inhibition of the renin-angiotensin system is known to reduce CV outcomes in non-HD patients and slow the progression of kidney disease in patients with type 2 diabetes, but these beneficial effects have not been observed in the HD population. Combining an angiotensin receptor blocker with a neprilysin inhibitor has been shown to reduce CV outcomes in patients with heart failure, while at the same time slowing the rate of kidney function decline. Therefore, there is strong biologic rationale to test the effects of this therapy in incident HD patients. Thus, building on our prior data, in we propose a pilot randomized placebo-controlled parallel group clinical trial to test the safety and tolerability of sacubitril/valsartan and test the effects (vs. placebo) on the reduction of left atrial volume index and preservation of residual renal function in incident HD patients. The results of our studies will inform the design and development of a larger multi-center outcomes trial, which is urgently needed to address the unacceptably high rates of mortality in incident HD. In summary, our proposals are clinically relevant, feasible, innovative, and are supported by preliminary data. Building on the underlying pathophysiology and our experience in performance of clinical trials, our proposals have the potential to improve care for patients undergoing initiation of HD for kidney failure.