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, se rum levels of TNF-alpha are increased after myocardial infarction and after cardiopulmonary bypass. Both cardiopulmonary bypass and renal ischemia-rep erfusion injury induce a cascade of events leading to cellular damage and o rgan dysfunction. Tumor necrosis factor (TNF), a potent proinflammatory cyt okine, is released from both the heart and the kidney in response to ischem ia and reperfusion. TNF released during cardiopulmonary bypass induces glom erular fibrin deposition, cellular infiltration, and vasoconstriction, lead ing to a reduction in glomerular filtration rate (GFR). The signaling casca de through which renal ischemia-reperfusion induces TNF production is begin ning to be elucidated. Oxidants released following reperfusion activate p38 mitogen-activated protein kinase (p38 MAP kinase) and the TNF transcriptio n factor, NF kappa B, leading to subsequent TNF synthesis. In a positive fe edback, proinflammatory fashion, binding of TNF to specific TNF membrane re ceptors can reactivate NF kappa B. This provides a mechanism by which TNF c an upregulate its own expression as well as facilitate the expression of ot her genes pivotal to the inflammatory response. Following its production an d release, TNF results in both renal and myocardial apoptosis and dysfuncti on. 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 i s produced by the heart following cardiopulmonary bypass; (2) to examine th e effect of TNF on myocardial performance; (3) to outline the mechanisms by which the kidney produces significant TNF in response to ischemia and repe rfusion; (5) to investigate the role of TNF in renal ischemia-reperfusion i njury, (6) to describe the mechanisms of TNF-induced renal cell apoptosis, and (7) to suggest potential anti-TNF strategies designed to reduce renal i nsufficiency following cardiac surgery. (C) 1999 Academic Press.