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Interorgan communication networks in the kidney–lung axis

Abstract

The homeostasis and health of an organism depend on the coordinated interaction of specialized organs, which is regulated by interorgan communication networks of circulating soluble molecules and neuronal connections. Many diseases that seemingly affect one primary organ are really multiorgan diseases, with substantial secondary remote organ complications that underlie a large part of their morbidity and mortality. Acute kidney injury (AKI) frequently occurs in critically ill patients with multiorgan failure and is associated with high mortality, particularly when it occurs together with respiratory failure. Inflammatory lung lesions in patients with kidney failure that could be distinguished from pulmonary oedema due to volume overload were first reported in the 1930s, but have been largely overlooked in clinical settings. A series of studies over the past two decades have elucidated acute and chronic kidney–lung and lung–kidney interorgan communication networks involving various circulating inflammatory cytokines and chemokines, metabolites, uraemic toxins, immune cells and neuro-immune pathways. Further investigations are warranted to understand these clinical entities of high morbidity and mortality, and to develop effective treatments.

Key points

  • Interorgan communication networks consist of soluble circulating factors, the immune system and the nervous system, and involve neuro-immune and neuro-endocrine interactions.

  • Acute kidney injury (AKI) causes long-recognized complications, such as uraemia and volume overload, and less well understood “non-traditional” complications, such as remote organ dysfunction and immune dysfunction, which contribute to increased morbidity and mortality.

  • AKI-induced remote lung inflammation depends on the actions of soluble circulating factors that are released by the kidney and other organs, including osteopontin, HMGB1, IL-6, IL-8 and TNF, and of immune cells, including neutrophils, monocytes, macrophages and T cells.

  • Primary lung injury due to infection, acid aspiration, ischaemia–reperfusion injury or barotrauma can lead to AKI in rodents and humans; some of the mechanisms of lung–kidney crosstalk are similar to those implicated in kidney–lung crosstalk, but more mechanistic studies are required.

  • Studies in preclinical models and correlative evidence from clinical studies suggest a bidirectional detrimental relationship between chronic kidney disease and chronic lung disease; however, the molecular mechanisms are largely unknown.

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Fig. 1: Role of ICNs in remote organ responses after localized tissue injury or stress.
Fig. 2: Mediators and mechanisms of AKI-induced remote lung inflammation.
Fig. 3: Mechanisms by which acute lung injury may cause acute kidney injury.
Fig. 4: Kidney–lung and lung–kidney interactions in chronic kidney and lung diseases.

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Y.K., Y.Z.B., D.K. and A.H. researched data for the article. All authors contributed substantially to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Andreas Herrlich.

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A.H. holds patent T-019663 together with Washington University on the “Method of targeting osteopontin for treatment and prevention of acute kidney injury-induced acute lung injury”. This is a US non-provisional patent application, with serial number 17/858,065 and was filed on 2 July 2021. A.H. is the sole inventor on the patent application and Washington University, St. Louis, MO, USA, is the applicant and assignee. The other authors declare no competing interests.

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Nature Reviews Nephrology thanks Michael Joannidis, Atul Malhotra, who co-reviewed with Mark Hepokoski, and the other, anonymous, reviewers for their contribution to the peer review of this work.

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Komaru, Y., Bai, Y.Z., Kreisel, D. et al. Interorgan communication networks in the kidney–lung axis. Nat Rev Nephrol 20, 120–136 (2024). https://doi.org/10.1038/s41581-023-00760-7

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