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Introduction: Cross-Talk Between the Kidneys and Remote Organ Systems in AKI

      Cross-talk between the kidneys and the heart has long been appreciated. The kidneys are referred to in the Talmud—the central text of Judaism, written during approximately the 4th century AD—as the organs that “give the heart advice and counsel.”
      • Kottek SS.
      "The kidneys give advice": some thoughts on nephrology in the Talmud and Midrash.
      During the Middle Ages, the Italian physician Gentile da Foligno referred to heart disease as one of the major conditions that affected the color and output of urine.
      • Timio M
      Gentile da Foligno, a pioneer of cardionephrology: commentary on Carmina de urinarum iudiciis and De pulsibus.
      In the 19th century the English physician, Richard Bright, observed that cardiac hypertrophy was a common disorder in patients suffering from chronic kidney disease (CKD).
      • Keith NM
      • Keys TE
      Contributions of Richard Bright and his associates to renal disease.
      Today, the pathophysiology that underlies the complex and bidirectional nature of heart–kidney interactions is increasingly well understood, and is referred to as the cardiorenal syndrome.
      • Ronco C
      • Haapio M
      • House AA
      • et al.
      Cardiorenal syndrome.
      However, the heart is only one of many organs that affects, and is affected by, the kidneys. Numerous interactions have been documented between the kidneys and remote organ systems in CKD. Notable examples include the following: (1) impaired iron absorption/utilization and decreased production of erythropoietin, which contributes to anemia; (2) dysregulated mineral metabolism, which contributes to renal osteodystrophy and cardiovascular disease; (3) impaired immunity, which increases susceptibility to infection; (4) dysfunctional platelets, which increase bleeding risk; and (5) water and salt retention, which affects all organs, particularly the heart and lungs.
      As in CKD, important cross-talk also occurs between the kidneys and remote organ systems in the setting of acute kidney injury (AKI). These interactions often are bidirectional. For example, portal hypertension, a nearly universal complication of advanced cirrhosis, causes renal arteriolar vasoconstriction,
      • Koyama S
      • Nishida K
      • Terada N
      • et al.
      Reflex renal vasoconstriction on portal vein distension.
      which reduces renal blood flow and can lead to hepatorenal syndrome. AKI, in turn, up-regulates the hepatic inflammatory response
      • Park SW
      • Chen SW
      • Kim M
      • et al.
      Cytokines induce small intestine and liver injury after renal ischemia or nephrectomy.
      and also may impair hepatic drug metabolism through unclear mechanisms.
      • Kirwan CJ
      • MacPhee IA
      • Lee T
      • et al.
      Acute kidney injury reduces the hepatic metabolism of midazolam in critically ill patients.
      Bidirectional interactions also have been noted between the kidneys and the lungs,
      • Faubel S
      • Edelstein CL
      Mechanisms and mediators of lung injury after acute kidney injury.
      • Darmon M
      • Clec'h C
      • Adrie C
      • et al.
      Acute respiratory distress syndrome and risk of AKI among critically ill patients.
      the spleen,
      • Gigliotti JC
      • Huang L
      • Ye H
      • et al.
      Ultrasound prevents renal ischemia-reperfusion injury by stimulating the splenic cholinergic anti-inflammatory pathway.
      • Inoue T
      • Abe C
      • Sung SS
      • et al.
      Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through alpha7nAChR+ splenocytes.
      the bone and mineral metabolism axis,
      • Leaf DE
      • Wolf M
      • Waikar SS
      • et al.
      FGF-23 levels in patients with AKI and risk of adverse outcomes.
      • Leaf DE
      • Christov M
      • Juppner H
      • et al.
      Fibroblast growth factor 23 levels are elevated and associated with severe acute kidney injury and death following cardiac surgery.
      • Leaf DE
      • Jacob KA
      • Srivastava A
      • et al.
      Fibroblast growth factor 23 levels associate with AKI and death in critical illness.
      and many other organ systems (Fig. 1).
      Figure 1.
      Figure 1Cross-talk between the kidneys and remote organ systems in AKI. Abbreviations: 1,25D, 1,25-dihydroxyvitamin D; ARDS, acute respiratory distress syndrome; Ca, calcium; FGF23, fibroblast growth factor 23; PO4, phosphate, PTH, parathyroid hormone.
      In this issue of Seminars in Nephrology, we have invited leading experts, including basic, translational, and patient-oriented research and clinician scientists, to provide a comprehensive discussion of cross-talk between the kidneys and remote organ systems in AKI. We hope that their contributions will generate enthusiasm for continued research in this important area, and that investigation into these interconnected pathways ultimately will translate into new opportunities for therapeutic intervention in AKI.

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