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Acute kidney injury is a major complication of cardiovascular surgery. Therapies to reduce or prevent acute kidney injury are highly desirable, and recent advances have helped refine the targets for such therapy, albeit with surprises and controversies. Among these therapies, natriuretic peptides have received the most scrutiny owing to the difficulty in explaining the conflicting evidence for effectiveness in some, but lack thereof, in other studies. This article examines the possible reasons for the conflicting results reported with natriuretic peptides in various clinical conditions.