Acute kidney injury (AKI) is a serious complication in critically-ill patients and portends a high mortality. The incidence of AKI continues to increase and is often underestimated. The intriguing question to both the intensivists and nephrologists is whether the kidney is an innocent bystander in the process of multi-organ systems failure or whether the kidney is initiating various complex metabolic and humoral pathways affecting distant organs contributing to the overall mortality. There is a renewed interest in the last two decades to gain greater insight into various disease pathways and to understand the role of the kidney in multi-organ failure. It is well known that AKI results in significant physiological derangements that underpin remote organ failure. For example, risk of infection and bleeding increase with AKI. Volume overload and acid-base derangements typical of renal dysfunction have serious consequences in the duration and weaning of mechanical ventilation. Recent animal studies suggest that acutely ischaemic kidneys may induce both functional and transcriptional changes in the lung, independent of uraemia. In this review, we have attempted to discuss various physiological derangements and their clinical effects, in the setting of AKI.