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Interorgan communication networks in the kidney–lung axis

Nature Reviews Nephrology volume 20, pages 120–136 (2024)Cite this article

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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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References

  1. Herrlich, A. Interorgan crosstalk mechanisms in disease: the case of acute kidney injury‐induced remote lung injury. FEBS Lett. 596, 620–637 (2022).

    Article  CAS  PubMed  Google Scholar 

  2. Wolterink, R. G. J. K., Wu, G. S., Chiu, I. M. & Veiga-Fernandes, H. Neuroimmune interactions in peripheral organs. Annu. Rev. Neurosci. 45, 339–360 (2022).

    Article  PubMed Central  Google Scholar 

  3. Droujinine, I. A. & Perrimon, N. Interorgan communication pathways in physiology: focus on drosophila. Annu. Rev. Genet. 50, 539–570 (2015).

    Article  Google Scholar 

  4. Perrimon, N. Interorgan crosstalk and metabolism regulation in drosophila. FASEB J. 36, https://doi.org/10.1096/fasebj.2022.36.S1.0I149 (2022).

  5. Llompart-Pou, J. A., Talayero, M., Homar, J., Royo, C. & Semicyuc, G. Multiorgan failure in the serious trauma patient. Med. Intensiva 38, 455–462 (2014).

    Article  CAS  PubMed  Google Scholar 

  6. Bos, L. D. J. & Ware, L. B. Acute respiratory distress syndrome: causes, pathophysiology, and phenotypes. Lancet 400, 1145–1156 (2022).

    Article  PubMed  Google Scholar 

  7. Hotchkiss, R. S. et al. Sepsis and septic shock. Nat. Rev. Dis. Prim. 2, 16045 (2016).

    Article  PubMed  Google Scholar 

  8. Doi, K. Role of kidney injury in sepsis. J. Intensive Care 4, 17 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Prowle, J. R. Sepsis-associated AKI. Clin. J. Am. Soc. Nephrol. 13, 339–342 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Bezerra, R. et al. Outcomes of critically ill patients with acute kidney injury in COVID-19 infection: an observational study. Ren. Fail. 43, 911–918 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Darmon, M. et al. Acute respiratory distress syndrome and risk of AKI among critically Ill patients. Clin. J. Am. Soc. Nephrol. 9, 1347–1353 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lertjitbanjong, P. et al. Acute kidney injury after lung transplantation: a systematic review and meta-analysis. J. Clin. Med. 8, 1713 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Shashaty, M. G. S. et al. The association of post-lung transplant acute kidney injury with mortality is independent of primary graft dysfunction: a cohort study. Clin. Transplant. 33, e13678 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Teixeira, J. P., Ambruso, S., Griffin, B. R. & Faubel, S. Pulmonary consequences of acute kidney injury. Semin. Nephrol. 39, 3–16 (2019).

    Article  PubMed  Google Scholar 

  15. Walcher, A., Faubel, S., Keniston, A. & Dennen, P. In critically Ill patients requiring CRRT, AKI is associated with increased respiratory failure and death versus ESRD. Ren. Fail. 33, 935–942 (2011).

    Article  PubMed  Google Scholar 

  16. Faubel, S. & Edelstein, C. L. Mechanisms and mediators of lung injury after acute kidney injury. Nat. Rev. Nephrol. 12, 48–60 (2016).

    Article  CAS  PubMed  Google Scholar 

  17. Lullo, L. D., Reeves, P. B., Bellasi, A. & Ronco, C. Cardiorenal syndrome in acute kidney injury. Semin. Nephrol. 39, 31–40 (2019).

    Article  PubMed  Google Scholar 

  18. Park, S. W. et al. Cytokines induce small intestine and liver injury after renal ischemia or nephrectomy. Lab. Invest. 91, 63–84 (2011).

    Article  CAS  PubMed  Google Scholar 

  19. Bernard, C. On the production of sugar in the liver of man and animals. Lond. Edinb. Dublin Philos. Mag. J. Sci. 2, 326–330 (1851).

    Article  Google Scholar 

  20. Bayliss, W. M. & Starling, E. H. The mechanism of pancreatic secretion. J. Physiol. 28, 325–353 (1902).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tata, J. R. One hundred years of hormones. EMBO Rep. 6, 490–496 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cannon, W. B. Organization for physiological homeostasis. Physiol. Rev. 9, 399–431 (1929).

    Article  Google Scholar 

  23. Cori, C. F. & Cori, G. T. Carbohydrate metabolism. Annu. Rev. Biochem. 15, 193–218 (1946).

    Article  CAS  PubMed  Google Scholar 

  24. Meex, R. C. R. & Watt, M. J. Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance. Nat. Rev. Endocrinol. 13, 509–520 (2017).

    Article  CAS  PubMed  Google Scholar 

  25. Santos, A. R. & de, O. et al. Adipokines, myokines, and hepatokines: crosstalk and metabolic repercussions. Int. J. Mol. Sci. 22, 2639 (2021).

    Article  Google Scholar 

  26. Giudice, J. & Taylor, J. M. Muscle as a paracrine and endocrine organ. Curr. Opin. Pharmacol. 34, 49–55 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yang, F. T. & Stanford, K. I. Batokines: mediators of inter-tissue communication (a mini-review). Curr. Obes. Rep. 11, 1–9 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Günther, C., Rothhammer, V., Karow, M., Neurath, M. & Winner, B. The gut-brain axis in inflammatory bowel disease — current and future perspectives. Int. J. Mol. Sci. 22, 8870 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Severinsen, M. C. K. & Pedersen, B. K. Muscle-organ crosstalk: the emerging roles of myokines. Endocr. Rev. 41, 594–609 (2020).

  30. Karsenty, G. & Olson, E. N. Bone and muscle endocrine functions: unexpected paradigms of inter-organ communication. Cell 164, 1248–1256 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yang, T., Richards, E. M., Pepine, C. J. & Raizada, M. K. The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease. Nat. Rev. Nephrol. 14, 442–456 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhu, Q. & Scherer, P. E. Immunologic and endocrine functions of adipose tissue: implications for kidney disease. Nat. Rev. Nephrol. 14, 105–120 (2018).

    Article  CAS  PubMed  Google Scholar 

  33. Ito, M. & Adachi-Akahane, S. Inter-organ communication in the regulation of lipid metabolism: focusing on the network between the liver, intestine, and heart. J. Pharmacol. Sci. 123, 312–317 (2013).

    Article  CAS  PubMed  Google Scholar 

  34. Filosa, A. & Sawamiphak, S. Heart development and regeneration — a multi‐organ effort. FEBS J. 290, 913–930 (2021).

    Article  PubMed  Google Scholar 

  35. Kutchy, N. A. et al. Extracellular vesicles in viral infections of the nervous system. Viruses 12, 700 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhang, B., Yang, Y., Xiang, L., Zhao, Z. & Ye, R. Adipose-derived exosomes: a novel adipokine in obesity-associated diabetes. J. Cell. Physiol. 2, 31–11 (2019).

    Google Scholar 

  37. Huang, Z. & Xu, A. Adipose extracellular vesicles in intercellular and inter-organ crosstalk in metabolic health and diseases. Front. Immunol. 12, 608680 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Karpman, D., Ståhl, A.-L. & Arvidsson, I. Extracellular vesicles in renal disease. Nat. Rev. Nephrol. 13, 545–562 (2017).

    Article  CAS  PubMed  Google Scholar 

  39. Veerman, R. E., Akpinar, G. G., Eldh, M. & Gabrielsson, S. Immune cell-derived extracellular vesicles — functions and therapeutic applications. Trends Mol. Med. 25, 382–394 (2019).

    Article  CAS  PubMed  Google Scholar 

  40. Pultz, B. et al. The multifaceted role of extracellular vesicles in metastasis: priming the soil for seeding. Int. J. Cancer 140, 2397–2407 (2017).

    Article  CAS  Google Scholar 

  41. Crewe, C. & Scherer, P. E. Intercellular and interorgan crosstalk through adipocyte extracellular vesicles. Rev. Endocr. Metab. Disord. 23, 61–69 (2021).

    Article  PubMed  Google Scholar 

  42. Droujinine, I. A. & Perrimon, N. The multidimensional organization of interorgan communication networks. Dev. Cell 50, 395–396 (2019).

    Article  CAS  PubMed  Google Scholar 

  43. Sluiter, T. J., Buul, J. D., van, Huveneers, S., Quax, P. H. A. & de Vries, M. R. Endothelial barrier function and leukocyte transmigration in atherosclerosis. Biomedicines 9, 328 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Lochhead, J. J., Yang, J., Ronaldson, P. T. & Davis, T. P. Structure, function, and regulation of the blood-brain barrier tight junction in central nervous system disorders. Front. Physiol. 11, 914 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Kadry, H., Noorani, B. & Cucullo, L. A blood–brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS 17, 69 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Medina, K. L. Overview of the immune system. Handb. Clin. Neurol. 133, 61–76 (2016).

    Article  PubMed  Google Scholar 

  47. Hoyer, F. F. et al. Tissue-specific macrophage responses to remote injury impact the outcome of subsequent local immune challenge. Immunity 51, 899–914.e7 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Andersson, U. & Tracey, K. J. Neural reflexes in inflammation and immunity. J. Exp. Med. 209, 1057–1068 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kraus, A., Buckley, K. M. & Salinas, I. Sensing the world and its dangers: an evolutionary perspective in neuroimmunology. Elife 10, e66706 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Cook, A. D., Christensen, A. D., Tewari, D., McMahon, S. B. & Hamilton, J. A. Immune cytokines and their receptors in inflammatory pain. Trends Immunol. 39, 240–255 (2018).

    Article  CAS  PubMed  Google Scholar 

  51. Chiu, I. M. et al. Bacteria activate sensory neurons that modulate pain and inflammation. Nature 501, 52–57 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chiu, I. M., Hehn, C. Avon & Woolf, C. J. Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nat. Neurosci. 15, 1063–1067 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Godinho-Silva, C., Cardoso, F. & Veiga-Fernandes, H. Neuro-immune cell units: a new paradigm in physiology. Annu. Rev. Immunol. 37, 19–46 (2019).

    Article  CAS  PubMed  Google Scholar 

  54. Tamari, M., Heul, A. M. V. & Kim, B. S. Immunosensation: neuroimmune cross talk in the skin. Annu. Rev. Immunol. 39, 1–25 (2021).

    Article  Google Scholar 

  55. Ordovas-Montanes, J. et al. The regulation of immunological processes by peripheral neurons in homeostasis and disease. Trends Immunol. 36, 578–604 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Chavan, S. S., Pavlov, V. A. & Tracey, K. J. Mechanisms and therapeutic relevance of neuro-immune communication. Immunity 46, 927–942 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Pinho-Ribeiro, F. A., Verri, W. A. & Chiu, I. M. Nociceptor sensory neuron-immune interactions in pain and inflammation. Trends Immunol. 38, 5–19 (2017).

    Article  CAS  PubMed  Google Scholar 

  58. Bellinger, D. L., Felten, S. Y., Lorton, D. & Felten, D. L. Origin of noradrenergic innervation of the spleen in rats. Brain Behav. Immun. 3, 291–311 (1989).

    Article  CAS  PubMed  Google Scholar 

  59. Pavlov, V. A., Wang, H., Czura, C. J., Friedman, S. G. & Tracey, K. J. The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation. Mol. Med. 9, 125–134 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Tracey, K. J. Physiology and immunology of the cholinergic antiinflammatory pathway. J. Clin. Invest. 117, 289–296 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Inoue, T. et al. Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through α7nAChR+ splenocytes. J. Clin. Invest. 126, 1939–1952 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Okusa, M. D., Rosin, D. L. & Tracey, K. J. Targeting neural reflex circuits in immunity to treat kidney disease. Nat. Rev. Nephrol. 13, 669–680 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhang, X. et al. Brain control of humoral immune responses amenable to behavioural modulation. Nature 581, 204–208 (2020).

    Article  CAS  PubMed  Google Scholar 

  64. Cryan, J. F. et al. The microbiota-gut-brain axis. Physiol. Rev. 99, 1877–2013 (2019).

    Article  CAS  PubMed  Google Scholar 

  65. Fregoso, D. R. et al. Skin-brain axis signaling mediates behavioral changes after skin wounding. Brain Behav. Immun. Health 15, 100279 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hadian, Y. et al. Microbiome‐skin‐brain axis: a novel paradigm for cutaneous wounds. Wound Repair. Regen. 28, 282–292 (2020).

    Article  PubMed  Google Scholar 

  67. Ding, J.-H. et al. Role of gut microbiota via the gut-liver-brain axis in digestive diseases. World J. Gastroenterol. 26, 6141–6162 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Chesné, J., Cardoso, V. & Veiga-Fernandes, H. Neuro-immune regulation of mucosal physiology. Mucosal Immunol. 12, 10–20 (2019).

    Article  PubMed  Google Scholar 

  69. Huh, J. R. & Veiga-Fernandes, H. Neuroimmune circuits in inter-organ communication. Nat. Rev. Immunol. 20, 217–228 (2020).

    Article  CAS  PubMed  Google Scholar 

  70. Pavlov, V. A. & Tracey, K. J. Neural regulation of immunity: molecular mechanisms and clinical translation. Nat. Neurosci. 20, 156–166 (2017).

    Article  CAS  PubMed  Google Scholar 

  71. Shurin, G. V., Vats, K., Kruglov, O., Bunimovich, Y. L. & Shurin, M. R. Tumor-induced T cell polarization by Schwann cells. Cells 11, 3541 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Macarthur, H., Wilken, G. H., Westfall, T. C. & Kolo, L. L. Neuronal and non‐neuronal modulation of sympathetic neurovascular transmission. Acta Physiol. 203, 37–45 (2011).

    Article  CAS  Google Scholar 

  73. Antunes-Rodrigues, J., Castro, M. D., Elias, L. L. K., Valença, M. M. & Mccann, S. M. Neuroendocrine control of body fluid metabolism. Physiol. Rev. 84, 169–208 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Agre, P. The aquaporin water channels. Proc. Am. Thorac. Soc. 3, 5–13 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Bellavance, M.-A. & Rivest, S. The HPA–immune axis and the immunomodulatory actions of glucocorticoids in the brain. Front. Immunol. 5, 136 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Schiller, M., Ben-Shaanan, T. L. & Rolls, A. Neuronal regulation of immunity: why, how and where? Nat. Rev. Immunol. 21, 20–36 (2021).

    Article  CAS  PubMed  Google Scholar 

  77. Lee, D. W., Faubel, S. & Edelstein, C. L. Cytokines in acute kidney injury (AKI). Clin. Nephrol. 76, 165–173 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. Faubel, S. Pulmonary complications after acute kidney injury. Adv. Chronic Kidney Dis. 15, 284–296 (2008).

    Article  PubMed  Google Scholar 

  79. Doi, K. The need for disruptive innovation in acute kidney injury. Clin. Exp. Nephrol. 24, 979–988 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  80. White, L. E. & Hassoun, H. T. Inflammatory mechanisms of organ crosstalk during ischemic acute kidney injury. Int. J. Nephrol. 2012, 505197 (2012).

    Article  PubMed  Google Scholar 

  81. White, L. E., Lie, M. L., Santora, R. J., Rabb, H. & Hassoun, H. T. Kidney-lung crosstalk during ischemic AKI: is the T cell the missing link? J. Surg. Res. 172, 265 (2012).

    Google Scholar 

  82. Matsuura, R., Doi, K. & Rabb, H. Acute kidney injury and distant organ dysfunction — network system analysis. Kidney Int. 103, 1041–1055 (2023).

    Article  CAS  PubMed  Google Scholar 

  83. Alge, J. et al. Two to tango: kidney-lung interaction in acute kidney injury and acute respiratory distress syndrome. Front. Pediatrics 9, 744110 (2021).

    Article  Google Scholar 

  84. Hoste, E. A. J. et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 41, 1411–1423 (2015).

    Article  PubMed  Google Scholar 

  85. Gammelager, H. et al. Three-year risk of cardiovascular disease among intensive care patients with acute kidney injury: a population-based cohort study. Crit. Care 18, 492 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Gameiro, J., Fonseca, J. A., Outerelo, C. & Lopes, J. A. Acute kidney injury: from diagnosis to prevention and treatment strategies. J. Clin. Med. 9, 1704 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kelly, K. J. Distant effects of experimental renal ischemia/reperfusion injury. J. Am. Soc. Nephrol. 14, 1549–1558 (2003).

    Article  CAS  PubMed  Google Scholar 

  88. Park, S. W. et al. Paneth cell-mediated multiorgan dysfunction after acute kidney injury. J. Immunol. 189, 5421–5433 (2012).

    Article  CAS  PubMed  Google Scholar 

  89. Hernando, A. A. et al. Prolonged acute kidney injury exacerbates lung inflammation at 7 days post-acute kidney injury. Physiol. Rep. 2, e12084 (2014).

    Article  Google Scholar 

  90. Kim, M., Park, S. W., Kim, M., D’Agati, V. D. & Lee, H. T. Isoflurane activates intestinal sphingosine kinase to protect against renal ischemia–reperfusion-induced liver and intestine injury. Anesthesiology 114, 363–373 (2011).

    Article  CAS  PubMed  Google Scholar 

  91. Liu, M. et al. Acute kidney injury leads to inflammation and functional changes in the brain. J. Am. Soc. Nephrol. 19, 1360–1370 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Levy, E. M., Viscoli, C. M. & Horwitz, R. I. The effect of acute renal failure on mortality: a cohort analysis. JAMA 275, 1489–1494 (1996).

    Article  CAS  PubMed  Google Scholar 

  93. Mehta, R. et al. Sepsis as a cause and consequence of acute kidney injury: program to improve care in acute renal disease. Intensive Care Med. 37, 241–248 (2011).

    Article  PubMed  Google Scholar 

  94. Himmelfarb, J. et al. Impaired monocyte cytokine production in critically ill patients with acute renal failure. Kidney Int. 66, 2354–2360 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Matute-Bello, G., Frevert, C. W. & Martin, T. R. Animal models of acute lung injury. Am. J. Physiol. Lung Cell. Mol. Physiol. 295, L379–L399 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Khamissi, F. Z. et al. Identification of kidney injury released circulating osteopontin as causal agent of respiratory failure. Sci. Adv. 8, eabm5900 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Awad, A. S. et al. Compartmentalization of neutrophils in the kidney and lung following acute ischemic kidney injury. Kidney Int. 75, 689–698 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Polverino, E., Rosales-Mayor, E., Dale, G. E., Dembowsky, K. & Torres, A. The role of neutrophil elastase inhibitors in lung diseases. Chest 152, 249–262 (2017).

    Article  PubMed  Google Scholar 

  99. Ishii, T. et al. Neutrophil elastase contributes to acute lung injury induced by bilateral nephrectomy. Am. J. Pathol. 177, 1665–1673 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Hopps, H. C. & Wissler, R. W. Uremic pneumonitis. Am. J. Pathol. 31, 261–273 (1955).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Kramer, A. A. et al. Renal ischemia/reperfusion leads to macrophage-mediated increase in pulmonary vascular permeability. Kidney Int. 55, 2362–2367 (1999).

    Article  CAS  PubMed  Google Scholar 

  102. Altmann, C. et al. Macrophages mediate lung inflammation in a mouse model of ischemic acute kidney injury. Am. J. Physiol. Renal Physiol. 302, F421–F432 (2012).

    Article  CAS  PubMed  Google Scholar 

  103. Karimi, Z. et al. Renal ischemia/reperfusion against nephrectomy for induction of acute lung injury in rats. Ren. Fail. 38, 1503–1515 (2016).

    Article  CAS  PubMed  Google Scholar 

  104. Kurihara, C. et al. Crosstalk between non-classical monocytes and alveolar macrophages mediates transplant ischemia-reperfusion injury through classical monocyte recruitment. JCI Insight 6, e147282 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Zheng, Z. et al. Donor pulmonary intravascular nonclassical monocytes recruit recipient neutrophils and mediate primary lung allograft dysfunction. Sci. Transl. Med. 9, eaal4508 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Chiu, S. et al. Donor-derived non-classical monocytes recruit recipient neutrophils and mediate primary lung allograft dysfunction. J. Heart Lung Transpl. 36, S121 (2017).

    Article  Google Scholar 

  107. Lie, M. L. et al. Lung T lymphocyte trafficking and activation during ischemic acute kidney injury. J. Immunol. 189, 2843–2851 (2012).

    Article  CAS  PubMed  Google Scholar 

  108. Ahuja, N. et al. Circulating IL-6 mediates lung injury via CXCL1 production after acute kidney injury in mice. Am. J. Physiol. Renal Physiol. 303, F864–F872 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Hoke, T. S. et al. Acute renal failure after bilateral nephrectomy is associated with cytokine-mediated pulmonary injury. J. Am. Soc. Nephrol. 18, 155–164 (2007).

    Article  CAS  PubMed  Google Scholar 

  110. Klein, C. L. et al. Interleukin-6 mediates lung injury following ischemic acute kidney injury or bilateral nephrectomy. Kidney Int. 74, 901–909 (2008).

    Article  CAS  PubMed  Google Scholar 

  111. Hassoun, H. T. et al. Ischemic acute kidney injury induces a distant organ functional and genomic response distinguishable from bilateral nephrectomy. Am. J. Physiol. Renal Physiol. 293, F30–F40 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Doi, K. et al. The high-mobility group protein B1-Toll-like receptor 4 pathway contributes to the acute lung injury induced by bilateral nephrectomy. Kidney Int. 86, 316–326 (2014).

    Article  CAS  PubMed  Google Scholar 

  113. Andres-Hernando, A. et al. Cytokine production increases and cytokine clearance decreases in mice with bilateral nephrectomy. Nephrol. Dial. Transpl. 27, 4339–4347 (2012).

    Article  CAS  Google Scholar 

  114. Lowenstein, J. & Nigam, S. K. Uremic toxins in organ crosstalk. Front. Med. 8, 592602 (2021).

    Article  Google Scholar 

  115. Lim, Y. J., Sidor, N. A., Tonial, N. C., Che, A. & Urquhart, B. L. Uremic toxins in the progression of chronic kidney disease and cardiovascular disease: mechanisms and therapeutic targets. Toxins 13, 142 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Wu, W., Bush, K. T. & Nigam, S. K. Key role for the organic anion transporters, OAT1 and OAT3, in the in vivo handling of uremic toxins and solutes. Sci. Rep. 7, 4939 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Adelibieke, Y. et al. Indoxyl sulfate induces IL-6 expression in vascular endothelial and smooth muscle cells through OAT3-mediated uptake and activation of AhR/NF-κB pathway. Nephron Exp. Nephrol. 128, 1–8 (2014).

    Article  CAS  PubMed  Google Scholar 

  118. Kawakami, T. et al. Indoxyl sulfate inhibits proliferation of human proximal tubular cells via endoplasmic reticulum stress. Am. J. Physiol. Renal Physiol. 299, F568–F576 (2010).

    Article  CAS  PubMed  Google Scholar 

  119. Lekawanvijit, S. et al. Does indoxyl sulfate, a uraemic toxin, have direct effects on cardiac fibroblasts and myocytes? Eur. Heart J. 31, 1771–1779 (2010).

    Article  CAS  PubMed  Google Scholar 

  120. Arinze, N. V. et al. Tryptophan metabolites suppress the Wnt pathway and promote adverse limb events in chronic kidney disease. J. Clin. Invest. 132, e142260 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Rabb, H. et al. Acute renal failure leads to dysregulation of lung salt and water channels. Kidney Int. 63, 600–606 (2003).

    Article  CAS  PubMed  Google Scholar 

  122. Yabuuchi, N. et al. Indoxyl sulfate as a mediator involved in dysregulation of pulmonary aquaporin-5 in acute lung injury caused by acute kidney injury. Int. J. Mol. Sci. 18, 11 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Chang, J.-F. et al. Translational medicine in pulmonary-renal crosstalk: therapeutic targeting of p-cresyl sulfate triggered nonspecific ROS and chemoattractants in dyspneic patients with uremic lung injury. J. Clin. Med. 7, 266 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Ma, T. & Liu, Z. Functions of aquaporin 1 and α-epithelial Na+ channel in rat acute lung injury induced by acute ischemic kidney injury. Int. Urol. Nephrol. 45, 1187–1196 (2013).

    Article  CAS  PubMed  Google Scholar 

  125. Faubel, S. et al. Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1β, IL-18, IL-6, and neutrophil infiltration in the kidney. J. Pharmacol. Exp. Ther. 322, 8–15 (2007).

    Article  CAS  PubMed  Google Scholar 

  126. Kielar, M. L. et al. Maladaptive role of IL-6 in ischemic acute renal failure. J. Am. Soc. Nephrol. 16, 3315–3325 (2005).

    Article  CAS  PubMed  Google Scholar 

  127. Hernando, A. A. et al. Splenectomy exacerbates lung injury after ischemic acute kidney injury in mice. Am. J. Physiol. Renal Physiol. 301, F907–F916 (2011).

    Article  Google Scholar 

  128. Bhargava, R. et al. Intratracheal IL-6 protects against lung inflammation in direct, but not indirect, causes of acute lung injury in mice. PLoS One 8, e61405 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Rose‐John, S. Local and systemic effects of interleukin‐6 (IL‐6) in inflammation and cancer. FEBS Lett. 596, 557–566 (2021).

    Article  PubMed  Google Scholar 

  130. Zhang, H. et al. IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality. J. Clin. Invest. 123, 1019–1031 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Simmons, E. M. et al. Plasma cytokine levels predict mortality in patients with acute renal failure. Kidney Int. 65, 1357–1365 (2004).

    Article  CAS  PubMed  Google Scholar 

  132. Hernando, A. A. et al. Circulating IL-6 upregulates IL-10 production in splenic CD4+ T cells and limits acute kidney injury-induced lung inflammation. Kidney Int. 91, 1057–1069 (2017).

    Article  Google Scholar 

  133. Wei, W., Zhao, Y., Zhang, Y., Jin, H. & Shou, S. The role of IL-10 in kidney disease. Int. Immunopharmacol. 108, 108917 (2022).

    Article  CAS  PubMed  Google Scholar 

  134. Hassoun, H. T. et al. Kidney ischemia-reperfusion injury induces caspase-dependent pulmonary apoptosis. Am. J. Physiol. Renal Physiol. 297, F125–F137 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. White, L. E., Cui, Y., Shelak, C. M. F., Lie, M. L. & Hassoun, H. T. Lung endothelial cell apoptosis during ischemic acute kidney injury. Shock 38, 320–327 (2012).

    Article  CAS  PubMed  Google Scholar 

  136. Kirita, Y., Wu, H., Uchimura, K., Wilson, P. C. & Humphreys, B. D. Cell profiling of mouse acute kidney injury reveals conserved cellular responses to injury. Proc. Natl Acad. Sci. USA 117, 15874–15883 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. White, L. E., Santora, R. J., Cui, Y., Moore, F. A. & Hassoun, H. T. TNFR1-dependent pulmonary apoptosis during ischemic acute kidney injury. Am. J. Physiol. Lung Cell. Mol. Physiol. 303, L449–L459 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Bhargava, R. et al. Acute lung injury and acute kidney injury are established by four hours in experimental sepsis and are improved with pre, but not post, sepsis administration of TNF-α antibodies. PLoS One 8, e79037 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Wu, H. et al. HMGB1 contributes to kidney ischemia reperfusion injury. J. Am. Soc. Nephrol. 21, 1878–1890 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Hepokoski, M. et al. Altered lung metabolism and mitochondrial DAMPs in lung injury due to acute kidney injury. Am. J. Physiol. Lung Cell Mol. Physiol. 320, L821–L831 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Denhardt, D. T. & Guo, X. Osteopontin: a protein with diverse functions. FASEB J. 7, 1475–1482 (1993).

    Article  CAS  PubMed  Google Scholar 

  142. Murugaiyan, G., Mittal, A. & Weiner, H. L. Increased osteopontin expression in dendritic cells amplifies IL-17 production by CD4+ T cells in experimental autoimmune encephalomyelitis and in multiple sclerosis. J. Immunol. 181, 7480–7488 (2008).

    Article  CAS  PubMed  Google Scholar 

  143. Ashkar, S. et al. Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Science 287, 860–864 (2000).

    Article  CAS  PubMed  Google Scholar 

  144. Kruger, T. E., Miller, A. H., Godwin, A. K. & Wang, J. Bone sialoprotein and osteopontin in bone metastasis of osteotropic cancers. Crit. Rev. Oncol. Hematol. 89, 330–341 (2014).

    Article  PubMed  Google Scholar 

  145. Ramaiah, S. K. & Rittling, S. Pathophysiological role of osteopontin in hepatic inflammation, toxicity, and cancer. Toxicol. Sci. 103, 4–13 (2008).

    Article  CAS  PubMed  Google Scholar 

  146. Fisher, L. W., Torchia, D. A., Fohr, B., Young, M. F. & Fedarko, N. S. Flexible structures of SIBLING proteins, bone sialoprotein, and osteopontin. Biochem. Biophys. Res. Commun. 280, 460–465 (2001).

    Article  CAS  PubMed  Google Scholar 

  147. Pichler, R. et al. Tubulointerstitial disease in glomerulonephritis. Potential role of osteopontin (uropontin). Am. J. Pathol. 144, 915–926 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Oldberg, A., Franzén, A. & Heinegård, D. Cloning and sequence analysis of rat bone sialoprotein (osteopontin) cDNA reveals an Arg-Gly-Asp cell-binding sequence. Proc. Natl Acad. Sci. USA 83, 8819–8823 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Someya, H. et al. Osteopontin-induced vascular hyperpermeability through tight junction disruption in diabetic retina. Exp. Eye Res. 220, 109094 (2022).

    Article  CAS  PubMed  Google Scholar 

  150. Icer, M. A. & Gezmen-Karadag, M. The multiple functions and mechanisms of osteopontin. Clin. Biochem. 59, 17–24 (2018).

    Article  CAS  PubMed  Google Scholar 

  151. Mamazhakypov, A., Sartmyrzaeva, M., Sarybaev, A. S., Schermuly, R. & Sydykov, A. Clinical and molecular implications of osteopontin in heart failure. Curr. Issues Mol. Biol. 44, 3573–3597 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Zhao, H. et al. Osteopontin mediates necroptosis in lung injury after transplantation of ischaemic renal allografts in rats. Br. J. Anaesth. 123, 519–530 (2018).

    Article  Google Scholar 

  153. Hirano, Y., Aziz, M., Yang, W.-L., Ochani, M. & Wang, P. Neutralization of osteopontin ameliorates acute lung injury induced by intestinal ischemia-reperfusion. Shock 46, 431–438 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Muteliefu, G., Enomoto, A., Jiang, P., Takahashi, M. & Niwa, T. Indoxyl sulphate induces oxidative stress and the expression of osteoblast-specific proteins in vascular smooth muscle cells. Nephrol. Dial. Transpl. 24, 2051–2058 (2009).

    Article  CAS  Google Scholar 

  155. Adijiang, A., Goto, S., Uramoto, S., Nishijima, F. & Niwa, T. Indoxyl sulphate promotes aortic calcification with expression of osteoblast-specific proteins in hypertensive rats. Nephrol. Dial. Transpl. 23, 1892–1901 (2008).

    Article  CAS  Google Scholar 

  156. Christov, M., Neyra, J. A., Gupta, S. & Leaf, D. E. Fibroblast growth factor 23 and klotho in AKI. Semin. Nephrol. 39, 57–75 (2019).

    Article  CAS  PubMed  Google Scholar 

  157. Sugiura, H. et al. Reduced Klotho expression level in kidney aggravates renal interstitial fibrosis. Am. J. Physiol. Renal Physiol. 302, F1252–F1264 (2012).

    Article  CAS  PubMed  Google Scholar 

  158. Doi, S. et al. Klotho inhibits transforming growth factor-β1 (TGF-β1) signaling and suppresses renal fibrosis and cancer metastasis in mice. J. Biol. Chem. 286, 8655–8665 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Hu, M. C., Bian, A., Neyra, J. & Zhan, M. Klotho, stem cells, and aging. Clin. Interv. Aging 10, 1233–1243 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Shi, M. et al. αKlotho mitigates progression of AKI to CKD through activation of autophagy. J. Am. Soc. Nephrol. 27, 2331–2345 (2016).

    Article  CAS  PubMed  Google Scholar 

  161. Kuro-o, M. et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390, 45–51 (1997).

    Article  CAS  PubMed  Google Scholar 

  162. Kim, A. J. et al. Klotho and S100A8/A9 as discriminative markers between pre-renal and intrinsic acute kidney injury. PLoS One 11, e0147255 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Ravikumar, P. et al. αKlotho deficiency in acute kidney injury contributes to lung damage. J. Appl. Physiol. 120, 723–732 (2016).

    Article  CAS  PubMed  Google Scholar 

  164. Urakawa, I. et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444, 770–774 (2006).

    Article  CAS  PubMed  Google Scholar 

  165. Fox, B. M. et al. Metabolomics assessment reveals oxidative stress and altered energy production in the heart after ischemic acute kidney injury in mice. Kidney Int. 95, 590–610 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Ambruso, S. L. et al. Lung metabolomics after ischemic acute kidney injury reveals increased oxidative stress, altered energy production, and ATP depletion. Am. J. Physiol. Lung Cell Mol. Physiol. 321, L50–L64 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Zhang, Q. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Chaung, W. W., Wu, R., Ji, Y., Dong, W. & Wang, P. Mitochondrial transcription factor A is a proinflammatory mediator in hemorrhagic shock. Int. J. Mol. Med. 30, 199–203 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Goto, D. et al. Nicotinic acetylcholine receptor agonist reduces acute lung injury after renal ischemia-reperfusion injury by acting on splenic macrophages in mice. Am. J. Physiol. Renal Physiol. 322, F540–F552 (2022).

    Article  CAS  PubMed  Google Scholar 

  170. Felten, D. L., Ackerman, K. D., Wiegand, S. J. & Felten, S. Y. Noradrenergic sympathetic innervation of the spleen: I. Nerve fibers associate with lymphocytes and macrophages in specific compartments of the splenic white pulp. J. Neurosci. Res. 18, 28–36 (1987).

    Article  CAS  PubMed  Google Scholar 

  171. Felten, D. L., Felten, S. Y., Carlson, S. L., Olschowka, J. A. & Livnat, S. Noradrenergic and peptidergic innervation of lymphoid tissue. J. Immunol. 135, 755s–765s (1985).

    Article  CAS  PubMed  Google Scholar 

  172. Williams, J. M. et al. Sympathetic innervation of murine thymus and spleen: evidence for a functional link between the nervous and immune systems. Brain Res. Bull. 6, 83–94 (1981).

    Article  CAS  PubMed  Google Scholar 

  173. Meroni, E. et al. Functional characterization of oxazolone-induced colitis and survival improvement by vagus nerve stimulation. PLoS One 13, e0197487 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  174. Rosas-Ballina, M. et al. Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia. Proc. Natl Acad. Sci. USA 105, 11008–11013 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Tanaka, S. et al. Vagus nerve stimulation activates two distinct neuroimmune circuits converging in the spleen to protect mice from kidney injury. Proc. Natl Acad. Sci. USA 118, e2021758118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Mulay, S. R. & Anders, H.-J. Neutrophils and neutrophil extracellular traps regulate immune responses in health and disease. Cells 9, 2130 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Papayannopoulos, V. Neutrophil extracellular traps in immunity and disease. Nat. Rev. Immunol. 18, 134–147 (2018).

    Article  CAS  PubMed  Google Scholar 

  178. Li, P. et al. PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J. Exp. Med. 207, 1853–1862 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Nakazawa, D. et al. Histones and neutrophil extracellular traps enhance tubular necrosis and remote organ injury in ischemic AKI. J. Am. Soc. Nephrol. 28, 1753–1768 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Liu, K. D. et al. Predictive and pathogenetic value of plasma biomarkers for acute kidney injury in patients with acute lung injury. Crit. Care Med. 35, 2755–2761 (2007).

    PubMed  PubMed Central  Google Scholar 

  181. Nisula, S. et al. Incidence, risk factors and 90-day mortality of patients with acute kidney injury in Finnish intensive care units: the FINNAKI study. Intensive Care Med. 39, 420–428 (2013).

    Article  PubMed  Google Scholar 

  182. Joannidis, M. et al. Lung–kidney interactions in critically ill patients: consensus report of the Acute Disease Quality Initiative (ADQI) 21 Workgroup. Intensive Care Med. 46, 654–672 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  183. Chertow, G. M., Christiansen, C. L., Cleary, P. D., Munro, C. & Lazarus, J. M. Prognostic stratification in critically ill patients with acute renal failure requiring dialysis. Arch. Intern. Med. 155, 1505–1511 (1995).

    Article  CAS  PubMed  Google Scholar 

  184. Mehta, R. L., Pascual, M. T., Gruta, C. G., Zhuang, S. & Chertow, G. M. Refining predictive models in critically ill patients with acute renal failure. J. Am. Soc. Nephrol. 13, 1350–1357 (2002).

    Article  PubMed  Google Scholar 

  185. Uchino, S. et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 294, 813–818 (2005).

    Article  CAS  PubMed  Google Scholar 

  186. Starr, M. C. et al. Acute kidney injury is associated with poor lung outcomes in infants born ≥32 weeks of gestational age. Am. J. Perinatol. 37, 231–240 (2020).

    Article  PubMed  Google Scholar 

  187. Liu, K. D. et al. Serum interleukin-6 and interleukin-8 are early biomarkers of acute kidney injury and predict prolonged mechanical ventilation in children undergoing cardiac surgery: a case-control study. Crit. Care 13, R104 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  188. Federspiel, C. K. et al. Duration of acute kidney injury in critically ill patients. Ann. Intensive Care 8, 30 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  189. Vieira, J. M. et al. Effect of acute kidney injury on weaning from mechanical ventilation in critically ill patients. Crit. Care Med. 35, 184–191 (2007).

    Article  PubMed  Google Scholar 

  190. Bass, H. E., Greenberg, D., Singer, E. & Miller, M. A. Pulmonary changes in uremia. J. Am. Med. Assoc. 148, 724–726 (1952).

    Article  CAS  PubMed  Google Scholar 

  191. Gibson, D. G. Haemodynamic factors in the development of acute pulmonary oedema in renal failure. Lancet 2, 1217–1220 (1966).

    Article  CAS  PubMed  Google Scholar 

  192. Rackow, E. C., Fein, I. A., Sprung, C. & Grodman, R. S. Uremic pulmonary edema. Am. J. Med. 64, 1084–1088 (1978).

    Article  CAS  PubMed  Google Scholar 

  193. Henkin, R. I., Maxwell, M. H. & Murray, J. F. Uremic pneumonitis. A clinical, physiological study. Ann. Intern. Med. 57, 1001–1008 (1962).

    Article  CAS  PubMed  Google Scholar 

  194. Zakiyanov, O. et al. Placental growth factor, pregnancy-associated plasma protein-A, soluble receptor for advanced glycation end products, extracellular newly identified receptor for receptor for advanced glycation end products binding protein and high mobility group box 1 levels in patients with acute kidney injury: a cross sectional study. BMC Nephrol. 14, 245 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  195. Chawla, L. S. et al. Elevated plasma concentrations of IL-6 and elevated APACHE II score predict acute kidney injury in patients with severe sepsis. Clin. J. Am. Soc. Nephrol. 2, 22–30 (2007).

    Article  CAS  PubMed  Google Scholar 

  196. Zhang, W. R. et al. Plasma IL-6 and IL-10 concentrations predict AKI and long-term mortality in adults after cardiac surgery. J. Am. Soc. Nephrol. 26, 3123–3132 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Murugan, R. et al. Plasma inflammatory and apoptosis markers are associated with dialysis dependence and death among critically ill patients receiving renal replacement therapy. Nephrol. Dial. Transplant. 29, 1854–1864 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Pike, F. et al. Biomarker enhanced risk prediction for adverse outcomes in critically ill patients receiving RRT. Clin. J. Am. Soc. Nephrol. 10, 1332–1339 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  199. Liangos, O. et al. Interleukin-8 and acute kidney injury following cardiopulmonary bypass: a prospective cohort study. Nephron Clin. Pract. 113, c148–c154 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Lorenzen, J. M. et al. Osteopontin predicts survival in critically ill patients with acute kidney injury. Nephrol. Dial. Transplant. 26, 531–537 (2010).

    Article  PubMed  Google Scholar 

  201. Roderburg, C. et al. Persistently elevated osteopontin serum levels predict mortality in critically ill patients. Crit. Care 19, 271 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  202. Meduri, G. U. et al. Inflammatory cytokines in the BAL of patients with ARDS persistent elevation over time predicts poor outcome. Chest 108, 1303–1314 (1995).

    Article  CAS  PubMed  Google Scholar 

  203. Meduri, G. U. et al. Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS plasma IL-1β and IL-6 levels are consistent and efficient predictors of outcome over time. Chest 107, 1062–1073 (1995).

    Article  CAS  PubMed  Google Scholar 

  204. Puneet, P., Moochhala, S. & Bhatia, M. Chemokines in acute respiratory distress syndrome. Am. J. Physiol. Lung Cell Mol. Physiol. 288, L3–L15 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Castello, L. M. et al. The role of osteopontin as a diagnostic and prognostic biomarker in sepsis and septic shock. Cells 8, 174 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Belperio, J. A. et al. Critical role for CXCR2 and CXCR2 ligands during the pathogenesis of ventilator-induced lung injury. J. Clin. Invest. 110, 1703–1716 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Carbone, F. et al. Early osteopontin levels predict mortality in patients with septic shock. Eur. J. Intern. Med. 78, 113–120 (2020).

    Article  CAS  PubMed  Google Scholar 

  208. Takahashi, F. et al. Osteopontin is strongly expressed by alveolar macrophages in the lungs of acute respiratory distress syndrome. Lung 182, 173–185 (2004).

    Article  CAS  PubMed  Google Scholar 

  209. Kasetty, G. et al. Osteopontin protects against lung injury caused by extracellular histones. Mucosal Immunol. 12, 39–50 (2019).

    Article  CAS  PubMed  Google Scholar 

  210. Jovic, S. et al. Osteopontin is increased in cystic fibrosis and can skew the functional balance between ELR-positive and ELR-negative CXC-chemokines. J. Cyst. Fibros. 14, 453–463 (2015).

    Article  CAS  PubMed  Google Scholar 

  211. Papaporfyriou, A. et al. Increased levels of osteopontin in sputum supernatant in patients with COPD. Chest 146, 951–958 (2014).

    Article  CAS  PubMed  Google Scholar 

  212. Samitas, K. et al. Osteopontin expression and relation to disease severity in human asthma. Eur. Respir. J. 37, 331–341 (2010).

    Article  PubMed  Google Scholar 

  213. Lee, J., Corl, K. & Levy, M. M. Fluid therapy and acute respiratory distress syndrome. Crit. Care Clin. 37, 867–875 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  214. Eworuke, E., Major, J. M. & McClain, L. I. G. National incidence rates for acute respiratory distress syndrome (ARDS) and ARDS cause-specific factors in the United States (2006–2014). J. Crit. Care 47, 192–197 (2018).

    Article  PubMed  Google Scholar 

  215. Tzotzos, S. J., Fischer, B., Fischer, H. & Zeitlinger, M. Incidence of ARDS and outcomes in hospitalized patients with COVID-19: a global literature survey. Crit. Care 24, 516 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  216. Suleyman, G. et al. Clinical characteristics and morbidity associated with coronavirus disease 2019 in a series of patients in metropolitan Detroit. JAMA Netw. Open 3, e2012270 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  217. Ciceri, F. et al. Early predictors of clinical outcomes of COVID-19 outbreak in Milan, Italy. Clin. Immunol. 217, 108509 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Si, M. K. H. et al. Inhibition of poly (adenosine diphosphate-ribose) polymerase attenuates lung-kidney crosstalk induced by intratracheal lipopolysaccharide instillation in rats. Respir. Res. 14, 126 (2013).

    Article  PubMed  Google Scholar 

  219. Kapoor, K., Singla, E., Sahu, B. & Naura, A. S. PARP inhibitor, olaparib ameliorates acute lung and kidney injury upon intratracheal administration of LPS in mice. Mol. Cell Biochem. 400, 153–162 (2015).

    Article  CAS  PubMed  Google Scholar 

  220. Martins, V. et al. Efficacy of clinically used PARP inhibitors in a murine model of acute lung injury. Cells 11, 3789 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Kim, G. et al. FDA approval summary: olaparib monotherapy in patients with deleterious germline BRCA-mutated advanced ovarian cancer treated with three or more lines of chemotherapy. Clin. Cancer Res. 21, 4257–4261 (2015).

    Article  CAS  PubMed  Google Scholar 

  222. Akker, J. P., van den, Egal, M. & Groeneveld, J. A. Invasive mechanical ventilation as a risk factor for acute kidney injury in the critically ill: a systematic review and meta-analysis. Crit. Care 17, R98–R98 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  223. Vemuri, S. V. et al. Association between acute kidney injury during invasive mechanical ventilation and ICU outcomes and respiratory system mechanics. Crit. Care Explor. 4, e0720 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  224. Annat, G. et al. Effect of PEEP ventilation on renal function, plasma renin, aldosterone, neurophysins and urinary ADH, and prostaglandins. Anesthesiology 58, 136–141 (1983).

    Article  CAS  PubMed  Google Scholar 

  225. Verbrugge, F. H. et al. Abdominal contributions to cardiorenal dysfunction in congestive heart failure. J. Am. Coll. Cardiol. 62, 485–495 (2013).

    Article  PubMed  Google Scholar 

  226. Pacher, R., Frass, M., Hartter, E., Woloszczuk, W. & Leithner, C. The role of alpha-atrial natriuretic peptide in fluid retention during mechanical ventilation with positive end-expiratory pressure. Klin. Wochenschr. 64, 64–67 (1986).

    CAS  PubMed  Google Scholar 

  227. Gurkan, O. U., O’Donnell, C., Brower, R., Ruckdeschel, E. & Becker, P. M. Differential effects of mechanical ventilatory strategy on lung injury and systemic organ inflammation in mice. Am. J. Physiol. Lung Cell Mol. Physiol. 285, L710–L718 (2003).

    Article  CAS  PubMed  Google Scholar 

  228. Hegeman, M. A. et al. Ventilator-induced endothelial activation and inflammation in the lung and distal organs. Crit. Care 13, R182 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  229. Network, A. R. D. S. et al. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N. Engl. J. Med. 342, 1301–1308 (2000).

    Article  Google Scholar 

  230. Sammani, S. et al. eNAMPT neutralization preserves lung fluid balance and reduces acute renal injury in porcine sepsis/VILI-induced inflammatory lung injury. Front. Physiol. 13, 916159 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  231. Hepokoski, M. et al. Ventilator-induced lung injury increases expression of endothelial inflammatory mediators in the kidney. Am. J. Physiol. Renal Physiol. 312, F654–F660 (2017).

    Article  CAS  PubMed  Google Scholar 

  232. Vaschetto, R. et al. Renal hypoperfusion and impaired endothelium-dependent vasodilation in an animal model of VILI: the role of the peroxynitrite-PARP pathway. Crit. Care 14, R45 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  233. Camp, S. M. et al. Unique toll-like receptor 4 activation by NAMPT/PBEF induces NFκB signaling and inflammatory lung injury. Sci. Rep. 5, 13135 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Heuer, J. F. et al. Effects of pulmonary acid aspiration on the lungs and extra-pulmonary organs: a randomized study in pigs. Crit. Care 16, R35–R35 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  235. Imai, Y. et al. Injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome. JAMA 289, 2104–2112 (2003).

    Article  PubMed  Google Scholar 

  236. Hoag, J. B. et al. Effects of acid aspiration-induced acute lung injury on kidney function. Am. J. Physiol. Renal Physiol. 294, F900–F908 (2008).

    Article  CAS  PubMed  Google Scholar 

  237. Atchade, E. et al. Acute kidney injury after lung transplantation: perioperative risk factors and outcome. Transplant. Proc. 52, 967–976 (2020).

    Article  CAS  PubMed  Google Scholar 

  238. Wajda-Pokrontka, M. et al. Incidence and perioperative risk factors of acute kidney injury among lung transplant recipients. Transplant. Proc. 54, 1120–1123 (2022).

    Article  CAS  PubMed  Google Scholar 

  239. Bennett, D. et al. Postoperative acute kidney injury in lung transplant recipients. Interact. Cardiovasc. Thorac. Surg. 28, 929–935 (2019).

    Article  PubMed  Google Scholar 

  240. George, T. J. et al. Acute kidney injury increases mortality after lung transplantation. Ann. Thorac. Surg. 94, 185–192 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  241. Ishikawa, S., Griesdale, D. E. G. & Lohser, J. Acute kidney injury within 72 hours after lung transplantation: incidence and perioperative risk factors. J. Cardiothorac. Vasc. Anesth. 28, 931–935 (2014).

    Article  PubMed  Google Scholar 

  242. Knight, J. et al. Intraoperative hypoxia independently associated with the development of acute kidney injury following bilateral orthotopic lung transplant. Transplantation 106, 879–886 (2022).

    Article  CAS  PubMed  Google Scholar 

  243. Banga, A. et al. Characteristics and outcomes among patients with need for early dialysis after lung transplantation surgery. Clin. Transpl. 31, e13106 (2017).

    Article  Google Scholar 

  244. Botros, M. et al. Insights into early postoperative acute kidney injury following lung transplantation. Clin. Transplant. 36, e14568 (2022).

    Article  PubMed  Google Scholar 

  245. Rocha, P. N., Rocha, A. T., Palmer, S. M., Davis, R. D. & Smith, S. R. Acute renal failure after lung transplantation: incidence, predictors and impact on perioperative morbidity and mortality. Am. J. Transplant. 5, 1469–1476 (2005).

    Article  PubMed  Google Scholar 

  246. Jacques, F. et al. Acute renal failure following lung transplantation: risk factors, mortality, and long-term consequences. Eur. J. Cardiothorac. Surg. 41, 193–199 (2012).

    PubMed  Google Scholar 

  247. Forker, C. M. et al. Postreperfusion plasma endothelial activation markers are associated with acute kidney injury after lung transplantation. Am. J. Transplant. 19, 2366–2373 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Xiang, B.-Q., Gao, H., Luo, Z.-Y., Fang, Z.-X. & Wang, W.-T. [Effect of dexmedetomidine on renal injury induced by lung ischemia/reperfusion in mice]. Zhongguo Ying Yong Sheng Li Xue Za 33, 380–384 (2017).

    Google Scholar 

  249. He, L. et al. AKI on CKD: heightened injury, suppressed repair, and the underlying mechanisms. Kidney Int. 92, 1071–1083 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  250. Bollenbecker, S., Czaya, B., Gutiérrez, O. M. & Krick, S. Lung-kidney interactions and their role in chronic kidney disease-associated pulmonary diseases. Am. J. Physiol. Lung Cell Mol. Physiol. 322, L625–L640 (2022).

    Article  CAS  PubMed  Google Scholar 

  251. Mukai, H. et al. Lung dysfunction and mortality in patients with chronic kidney disease. Kidney Blood Press. Res. 43, 522–535 (2018).

    Article  PubMed  Google Scholar 

  252. Navaneethan, S. D. et al. Mortality outcomes of patients with chronic kidney disease and chronic obstructive pulmonary disease. Am. J. Nephrol. 43, 39–46 (2016).

    Article  CAS  PubMed  Google Scholar 

  253. Trudzinski, F. C. et al. Consequences of chronic kidney disease in chronic obstructive pulmonary disease. Respir. Res. 20, 151 (2018).

    Article  Google Scholar 

  254. Schunk, S. J. et al. Measurement of urinary Dickkopf-3 uncovered silent progressive kidney injury in patients with chronic obstructive pulmonary disease. Kidney Int. 100, 1081–1091 (2021).

    Article  CAS  PubMed  Google Scholar 

  255. Kim, C. Y., Kim, Y. N. & Kim, B. K. Lung function decline in chronic kidney disease. Eur. Respir. J. 60, 4599 (2022).

    Google Scholar 

  256. Network, N. H., Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials. et al. Comparison of two fluid-management strategies in acute lung injury. N. Engl. J. Med. 354, 2564–2575 (2006).

    Article  Google Scholar 

  257. Murugan, R. et al. Association of net ultrafiltration rate with mortality among critically Ill adults with acute kidney injury receiving continuous venovenous hemodiafiltration. JAMA Netw. Open 2, e195418 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  258. Assimon, M. M., Wenger, J. B., Wang, L. & Flythe, J. E. Ultrafiltration rate and mortality in maintenance hemodialysis patients. Am. J. Kidney Dis. 68, 911–922 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  259. Nemmar, A. et al. Lung oxidative stress, DNA damage, apoptosis, and fibrosis in adenine-induced chronic kidney disease in mice. Front. Physiol. 8, 896 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  260. Peng, C.-K. et al. Experimental chronic kidney disease attenuates ischemia-reperfusion injury in an ex vivo rat lung model. PLoS One 12, e0171736 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  261. Yang, F. et al. UUO induces lung fibrosis with macrophage-myofibroblast transition in rats. Int. Immunopharmacol. 93, 107396 (2021).

    Article  CAS  PubMed  Google Scholar 

  262. Polverino, F. et al. A pilot study linking endothelial injury in lungs and kidneys in chronic obstructive pulmonary disease. Am. J. Resp. Crit. Care 195, 1464–1476 (2017).

    Article  CAS  Google Scholar 

  263. Amdur, R. L. et al. Inflammation and progression of CKD: the CRIC Study. Clin. J. Am. Soc. Nephrol. 11, 1546–1556 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Barnett, N. & Ware, L. B. Biomarkers in acute lung injury — marking forward progress. Crit. Care Clin. 27, 661–683 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Barnes, P. J. The cytokine network in chronic obstructive pulmonary disease. Am. J. Resp. Cell Mol. 41, 631–638 (2012).

    Article  Google Scholar 

  266. Jung, J. E. et al. Diabetes mellitus due to agenesis of the dorsal pancreas in a patient with heterotaxy syndrome. Ann. Pediatr. Endocrinol. Metab. 22, 125–128 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, Division of Nephrology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA

    Yohei Komaru & Andreas Herrlich

  2. Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, USA

    Yun Zhu Bai & Daniel Kreisel

  3. Department of Pathology & Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA

    Daniel Kreisel

  4. VA Saint Louis Health Care System, John Cochran Division, St. Louis, MO, USA

    Andreas Herrlich

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  1. Yohei Komaru
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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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Competing interests

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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