Preventing acute kidney injury after cardiac surgery.

PURPOSE OF REVIEW: Acute kidney injury (AKI) is a serious complication that significantly increases morbidity, mortality and cost of care after cardiac surgery. In this review we identify the current literature that addresses strategies for renal protection and the prevention of AKI after cardiac surgery. RECENT FINDINGS: Even with aggressive medical care and renal replacement therapy (RRT) the morbidity, mortality and cost of postoperative AKI after cardiac surgery is substantial. An emphasis on preventive strategies would therefore appear to be the most cost-effective approach. Recent literature offers hope that as our understanding of the pathogenesis of AKI after cardiac surgery continues to improve, new directions for the prevention and amelioration of AKI will emerge. Approaches to the prevention of postoperative AKI include careful risk stratification of patients, allowing adequate recovery following a prior AKI, consideration of less extensive surgical procedures, avoidance of cardiopulmonary bypass, minimizing injury from radiocontrast dyes or other nephrotoxic agents, and optimizing cardiovascular function and oxygen delivery. Early identification of AKI and prompt, judicious application of RRT may also improve outcomes. Interest in pharmacologic renoprotection is currently directed toward statins and sodium bicarbonate. SUMMARY: Postoperative AKI is a serious complication after cardiac surgery. Therapeutic interventions and RRT have limited influence on the outcome of AKI, and a preventive strategy remains the mainstay to attenuate its impact.

Conserved glycine residues in the cytoplasmic domain of the aspartate receptor play essential roles in kinase coupling and on-off switching.

The aspartate receptor of the bacterial chemotaxis pathway serves as a scaffold for the formation of a multiprotein signaling complex containing the receptor and the cytoplasmic pathway components. Within this complex, the receptor regulates the autophosphorylation activity of histidine kinase CheA, thereby controlling the signals sent to the flagellar motor and the receptor adaptation system. The receptor cytoplasmic domain, which controls the on-off switching of CheA, possesses 14 glycine residues that are highly conserved in related receptors. In principle, these conserved glycines could be required for static turns, bends, or close packing in the cytoplasmic domain, or they could be required for conformational dynamics during receptor on-off switching. To determine which glycines are essential and to probe their functional roles, we have substituted each conserved glycine with both alanine and cysteine, and then measured the effects on receptor function in vivo and in vitro. The results reveal a subset of six glycines which are required for receptor function during cellular chemotaxis. Two of these essential glycines (G388 and G391) are located at a hairpin turn at the distal end of the folded cytoplasmic domain, where they are required for the tertiary fold of the signaling subdomain and for CheA kinase activation. Three other essential glycines (G338, G339, and G437) are located at the border between the adaptation and signaling subdomains, where they play key roles in CheA kinase activation and on-off switching. These three glycines form a ring around the four-helix bundle that comprises the receptor cytoplasmic domain, yielding a novel architectural feature termed a bundle hinge. The final essential glycine (G455) is located in the adaptation subdomain where it is required for on-off switching. Overall, the findings confirm that six of the 14 conserved cytoplasmic glycines are essential for receptor function because they enable helix turns and bends required for native receptor structure, and in some cases for switching between the on and off signaling states. An initial working model proposes that the novel bundle hinge enables the four-helix bundle to bend, perhaps during the assembly of the receptor trimer of dimers or during on-off switching. More generally, the findings predict that certain human disease states, including specific cancers, could be triggered by lock-on mutations at essential glycine positions that control the on-off switching of receptors and signaling proteins.