Role of TNF in mediating renal insufficiency following cardiac surgery: evidence of a postbypass cardiorenal syndrome.
Recent evidence has implicated proinflammatory mediators such as TNF-alpha in the pathophysiology of ischemia-reperfusion (I/R) injury. Clinically, serum levels of TNF-alpha are increased after myocardial infarction and after cardiopulmonary bypass. Both cardiopulmonary bypass and renal ischemia-reperfusion injury induce a cascade of events leading to cellular damage and organ dysfunction. Tumor necrosis factor (TNF), a potent proinflammatory cytokine, is released from both the heart and the kidney in response to ischemia and reperfusion. TNF released during cardiopulmonary bypass induces glomerular fibrin deposition, cellular infiltration, and vasoconstriction, leading to a reduction in glomerular filtration rate (GFR). The signaling cascade through which renal ischemia-reperfusion induces TNF production is beginning to be elucidated. Oxidants released following reperfusion activate p38 mitogen-activated protein kinase (p38 MAP kinase) and the TNF transcription factor, NFkappaB, leading to subsequent TNF synthesis. In a positive feedback, proinflammatory fashion, binding of TNF to specific TNF membrane receptors can reactivate NFkappaB. This provides a mechanism by which TNF can upregulate its own expression as well as facilitate the expression of other genes pivotal to the inflammatory response. Following its production and release, TNF results in both renal and myocardial apoptosis and dysfunction. An understanding of these mechanisms may allow the adjuvant use of anti-TNF therapeutic strategies in the treatment of renal injury. The purposes of this review are: (1) to evaluate the evidence which indicates that TNF is produced by the heart following cardiopulmonary bypass; (2) to examine the effect of TNF on myocardial performance; (3) to outline the mechanisms by which the kidney produces significant TNF in response to ischemia and reperfusion; (5) to investigate the role of TNF in renal ischemia-reperfusion injury, (6) to describe the mechanisms of TNF-induced renal cell apoptosis, and (7) to suggest potential anti-TNF strategies designed to reduce renal insufficiency following cardiac surgery.
Meldrum
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DR
Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado, 80262, USA. danmeldrum@netscape.net
Donnahoo
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D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis; D006348:Cardiac Surgical Procedures / Q000009:adverse effects; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D050822:Cytokine Receptor gp130; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D019157:Ischemic Preconditioning, Myocardial; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D051437:Renal Insufficiency / Q000209:etiology*; D015427:Reperfusion Injury / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013577:Syndrome; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects* / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*
D015703:Antigens, CD; D006360:Heat-Shock Proteins; C494199:IL6ST protein, human; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; D050822:Cytokine Receptor gp130