AKI and diastolic dysfunction: Opportunity for targeted intervention?

Abstract

Background/aims: Acute kidney injury (AKI) is common, results in nonrenal sequelae, and predisposes patients to long-term cardiovascular disease. The long-term systemic effects of AKI remain unclear. Sex is an important biological variable in ischemia-reperfusion AKI, and the protective role of estrogen has stymied the inclusion of both sexes in preclinical AKI studies. ITF2357 is a nonspecific histone deacetylase inhibitor that has been shown to improve cardiac outcomes in murine models of hypertension. Here, we review recent work that provides new insight into our understanding of cardiovascular sequelae following AKI.

Methods: Adult male and female C57BL/6J mice underwent 25 min (males) and 34 min (females) of bilateral ischemia-reperfusion AKI or sham procedure. A male treatment arm received chow containing the nonspecific histone deacetylase inhibitor ITF2357 starting 3 days after AKI. Serial renal function, echocardiograms, and blood pressure assessments were performed throughout the 1-year study; renal histology and cardiac and plasma metabolomics were evaluated at 1 year.

Results: Measured glomerular filtration rates throughout the 1-year study showed that the female model of AKI matched the male model. Untreated males developed depressed diastolic function after AKI, whereas females and males treated with ITF2357 maintained normal diastolic function. Both untreated males and females developed hypertension after AKI; males treated with ITF2357 remained normotensive.

Conclusions: Ischemic AKI results in long-term cardiovascular sequelae with sex as an important biological variable in outcomes. Histone deacetylase inhibition affects cardiovascular outcomes after AKI.