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Increasing evidence suggests that acute kidney injury (AKI) mediates a systemic response that can lead to multiple organ failure. AKI may manifest in a variety of clinical scenarios including kidney transplantation and is associated with a significantly high mortality. It has been postulated that specific pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α, may mediate a systemic response, resulting in recruitment of pro-inflammatory cells leading to organ failure. However, the specific mechanism by which the cytokine cascade results in distant organ damage is yet to be determined. Furthermore, it remains unclear as to whether cytokines mediate similar or differing responses in different end organs. This review summarizes the effects of AKI on remote organs and explores the role of systemic cytokines in mediating distant organ damage.