Contrast-induced acute kidney injury (CI-AKI) is a common complication of intravenous, iodinated contrast media, that is widely used for cardiac catheterization and percutaneous coronary intervention (PCI) in patients with coronary artery disease (CAD). In the United States, CAD remains the number one cause of death in both men and women, despite improvement in the care of patients over the last decade. Although PCI restores blood flow to the heart, the contrast media used for the procedure can cause CI-AKI, possibly mediated by contrast?induced vasoconstriction of renal blood vessels and free radical?mediated direct renal tubular toxicity. The incidence of CI-AKI is estimated to range between 10 and 40% in patients undergoing cardiac catheterization with higher rates in patients with acute myocardial infarction. In the United States, approximately 1.4 million cardiac catheterization procedures are performed each year, and this estimate is expected to increase exponentially in the next few decades. With increasing use of contrast media, the prevalence of CI-AKI is also expected to rise. CI-AKI predicts elevated risk of heart attack, longer in-hospital stay, more complicated hospitalization course, and higher in-hospital mortality. Unfortunately, there is no effective prophylactic regimen to prevent CI-AKI. Remote ischemic pre-conditioning (RIPC), elicited by application of one or more, brief episodes of ischemia and reperfusion of a limb, is a promising therapy for preventing or attenuating CI-AKI. Given that renal ischemic injury and tubular toxicity are the most common pathophysiological concepts of CI- AKI, it stands to reason that RIPC may prevent CI-AKI via nitrite-induced vasodilation and damage associated molecular protein -mediated renal cell protection. Our preliminary data suggest that RIPC provides renal protection, and indicates a connection between RIPC-induced changes in protective molecules (nitrite, cyclic guanosine monophosphate (cGMP), tissue inhibitor of metalloproteinases 2 (TIMP-2) and insulin-like growth factor?binding protein 7 (IGFBP7) and organ protection. However, the effect of RIPC on CI-AKI in patients with CAD undergoing cardiac catheterization is not well-established, and the underlying mechanism of such effect remains unclear. Therefore, this study is intended to fill a critical void in our understanding of mechanism of renal protection by this emerging therapy, RIPC. We propose a randomized controlled trial (RCT) to determine the effect of RIPC on CI-AKI (primary outcome) and the mediating biomarkers of vascular (nitrite, cGMP, reactive oxygen species, asymmetric dimethylarginine) and renal (TIMP-2, IGFBP7, neutrophil gelatinase?associated lipocalin, kidney injury molecule-1) function (secondary outcomes) in high risk patients with CAD undergoing cardiac catheterization. The findings from this study will inform the design of a larger (R01), efficacy trial to determine the long-term effect of RIPC on kidney function, and also help develop new therapy for CI-AKI.

Public Health Relevance

Contrast-induced acute kidney injury occurs frequently after cardiac catheterization in patients with coronary artery disease, and is associated with increased hospital length of stay, cost and mortality. Unfortunately, there is no effective prophylactic regimen to prevent contrast- induced acute kidney injury. In this project, we will determine the effect of remote ischemic preconditioning on contrast-induced acute kidney injury, and assess the mediating biomarkers in patients with coronary artery disease undergoing cardiac catheterization.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK113486-02
Application #
9552148
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Waddy, Salina P
Project Start
2017-09-01
Project End
2020-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213