Acute kidney injury (AKI) refers to a sudden decrease in kidney function. Recent population-based epidemiology studies show that the incidence of AKI is rising rapidly, thus emphasizing its clinical and public health importance. AKI is well known to be associated with a high risk of death during hospitalization. More recent data indicate that AKI is also associated with an increased risk of development of and/or acceleration of chronic kidney disease months to years after the AKI episode. However, much remains unknown about other long-term consequences of AKI, including its impact on the risk of cardiovascular events. Our preliminary data demonstrate that dialysis-requiring AKI is associated with an increased risk of subsequent acute coronary syndromes. In the proposed studies, we will use two complementary study cohorts to further test the hypothesis that AKI is a novel risk factor for cardiovascular events. First, using a large population-based cohort at Kaiser Permanente Northern California, we will evaluate the impact of an episode of AKI as well as the severity of AKI on the risk of subsequent cardiovascular events. This analysis will extend our prior work by examining the impact of AKI on different atherosclerotic and non-atherosclerotic cardiovascular events, including acute coronary syndromes, stroke, peripheral arterial disease, and heart failure as well as by examining the impact of non-dialysis-requiring AKI as a risk factor for cardiovascular events. Second, using banked biospecimens from the NIDDK-funded Assessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury Consortium (ASSESS-AKI), a multicenter cohort study focused on the natural history of AKI after hospital discharge, we will test several biochemical pathways that may associate an episode of AKI with subsequent cardiovascular events. These pathways involve dysregulated mineral metabolism (measured using phosphorus, intact parathyroid hormone, 25(OH), 1,25(OH)2 and 24,25(OH)2 vitamin D, FGF-23 and fetuin-A) and inflammation (measured through high-sensitivity C-reactive protein, interleukin-6, and tumor necrosis factor-?). The proposed efforts will establish the association of AKI with the risk for cardiovascular events as well as shed light on the potential biological pathways through which AKI may impact cardiovascular risk. Since several of the biological pathways to be studied are modifiable using currently available therapies, understanding which pathways associate AKI with cardiovascular disease has the potential to directly improve the care of the growing number of hospitalized patients who suffer an episode of AKI.
We propose a series of population and pathway-based studies to better understand how an episode of acute kidney injury may impact the risk of cardiovascular events. Using data from Kaiser Permanente Northern California, a large integrated health care delivery system, we will evaluate the impact of an episode of acute kidney injury on the risk of subsequent cardiovascular events. We will then test several biological pathways through which an episode of acute kidney injury may impact the cardiovascular system using samples from the ongoing NIDDK-sponsored Assessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury Consortium, a study focused on better understanding long term outcomes after acute kidney injury.