Acute kidney injury (AKI) is a systemic syndrome capable of inducing remote organ dysfunction. Kidney–lung crosstalk is a form of interorgan communication in acute nephrology, with the heart acting as a pivotal intermediary. Emerging evidence supports the involvement of a gut–lung–kidney axis. Complement activation in these multiorgan crosstalk has emerged as a central amplifier of multiorgan damage. We reviewed the literature on kidney–lung interactions and complement activation in AKI through a bibliographic search of PubMed, Scopus, and Web of Science. Most available data derive from experimental studies or intensive care unit (ICU) populations, often reported in reviews. We further report our real-world experience in a non-ICU nephrology setting, including 186 consecutive patients with AKI. Pulmonary involvement was present at hospital admission in 118 patients (63%). AKI stage 1 was observed in 20/118 patients (17%) with pulmonary involvement compared with 18/68 patients (27%) without pulmonary involvement (p < 0.001). In conclusion, AKI should be regarded as a systemic disease from its earliest stages. Kidney–lung interactions are clinically relevant even in mild AKI and outside critical care settings, underscoring the need for integrated organ assessment in routine nephrology practice. This review integrates complement activation as a central amplifier of kidney–lung crosstalk and multiorgan dysfunction, bridging experimental evidence with real-world observations from a non-critical care AKI population. By focusing on early AKI stages and the timing of pulmonary involvement, we highlight AKI as an active driver of systemic organ interactions rather than a late consequence of critical illness.