Decoding Lung-Kidney Interactions in Sepsis: An Integrated View of Molecular Mechanisms, Pathophysiology, and Therapeutic Interventions

Chenye MaHongyi LiZirong ChenHeng SongYuze WangZhihui LiuXuefan BuXianfei DingHanfang SiJing-Hua YangTongwen Sun^*

• First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

Sepsis, a great health concern globally, is characterized by multi-organ dysfunction and high mortality rate. As highly vascularized organs, the kidney and lung are the most susceptible in sepsis. Moreover, the loss of normal function in either of them may increase the risk of injury to the other, and the combined dysfunction of the respiratory system and the renal system may significantly increase the mortality rate of sepsis patients. As a part of systematic response, soluble cytokines and inflammatory mediators released from lung and kidney would exacerbate overall immune disorder, while bio-active substances like lipocalin-2, α-klotho, osteopontin released by kidney, metabolites and extracellular vesicles in sepsis can spread by circulation and induce injuries of distant tissues in lung. Furthermore, water-sodium and acid-base imbalance, as well as oxidative stress induced by kidney injury exacerbate respiratory distress in sepsis patients; while hypoxemia, hypercapnia, hemodynamic changes and endothelial injury induced by lung injury in sepsis can reduce the glomerular filtration rate. In addition, hemodynamic, neurohormonal, and immune-mediated processes induced by invasive mechanical ventilation exacerbate kidney dysfunction; pulmonary hypertension and the subsequent series of changes induced by renal replacement therapy also reduce the oxygenation in sepsis patients. As an important example of organ function network imbalance induced by sepsis, lung-kidney crosstalk involves multi-level interactions and may serve as the basis for sequential organ failure in sepsis. In this review, we summarized the scattered research advancement related to the lung-kidney interaction in sepsis, covering molecular mechanisms, pathophysiological mechanisms, as well as the impact of support therapies. Despite the lack of therapeutic targets verified by clinical research, preclinical studies have nonetheless uncovered some promising results that may offer new intervention strategies. A deep understanding of organ-organ axes represented by lung-kidney crosstalk, may provide insights into the early mechanisms of sepsis-related multiple-organ dysfunction and potential therapeutic strategies. Future research needs to distinguish the relationship between therapeutic interventions and lung-kidney interactions, integrating a broader molecular landscape and more precise animal models, or organ chips, to deeply disclose the dysregulation of organ interaction in sepsis, in order to develop more precise intervention strategies.