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Decreased Catecholamine Degradation Associates with Shock and Kidney Injury after Cardiac Surgery

Anja Haase-Fielitz^*,, Michael Haase^*,, Rinaldo Bellomo^*, Gavin Lambert, George Matalanis, David Story, Laurie Doolan, Brian Buxton, Geoff Gutteridge^*, Friedrich C. Luft^||, Wolf-Hagen Schunck^¶ and Duska Dragun^,**

^* Department of Intensive Care, Austin Health, Melbourne, Australia; Department of Nephrology and Intensive Care Medicine, Campus Virchow Clinic, Medical Faculty of the Charité, Berlin, Germany; Baker Heart Research Institute, Melbourne, Australia; Departments of Anaesthesiology and Cardiac Surgery, Austin Health, Melbourne, Australia; ^|| Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and HELIOS Klinikum, Berlin, Germany; ^¶ Max Delbrück Center for Molecular Medicine, Berlin, Germany; ^** Center for Cardiovascular Research, Charité, Berlin, Germany

Correspondence: Dr. Duska Dragun, Medizinische Klinik mit Schwerpunkt Nephrologie und Intensivmedizin, Charité Universitätsmedizin Berlin - Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. Phone: +49-30-450653485; Fax: +49-30-450553916; E-mail: duska.dragun{at}charite.de

Received for publication August 30, 2008. Accepted for publication January 27, 2009.

Enzymatic pathways involving catechol-O-methyltransferase (COMT) catabolize circulating catecholamines. A G-to-A polymorphism in the fourth exon of the COMT gene results in a valine-to-methionine amino acid substitution at codon 158, which leads to thermolability and low ("L"), as opposed to high ("H"), enzymatic activity. We enrolled 260 patients postbypass surgery to test the hypothesis that COMT gene variants impair circulating catecholamine metabolism, predisposing to shock and acute kidney injury (AKI) after cardiac surgery. In accordance with the Hardy-Weinberg equilibrium, we identified 64 (24.6%) homozygous (LL), 123 (47.3%) heterozygous (HL), and 73 (28.1%) homozygous (HH) patients. Postoperative catecholamines were higher in homozygous LL patients compared with heterozygous HL and homozygous HH patients (P < 0.01). During their intensive care stay, LL patients had both a significantly greater frequency of vasodilatory shock (LL: 69%, HL: 57%, HH: 47%; P = 0.033) and a significantly longer median duration of shock (LL: 18.5 h, HL: 14.0 h, HH: 11.0 h; P = 0.013). LL patients also had a greater frequency of AKI (LL: 31%, HL: 19.5%, HH: 13.7%; P = 0.038) and their AKI was more severe as defined by a need for renal replacement therapy (LL: 7.8%, HL: 2.4%, HH: 0%; P = 0.026). The LL genotype associated with intensive care and hospital length of stay (P < 0.001 and P = 0.002, respectively), and we observed a trend for higher mortality. Cross-validation analysis revealed a similar graded relationship of adverse outcomes by genotype. In summary, this study identifies COMT LL homozygosity as an independent risk factor for shock, AKI, and hospital stay after cardiac surgery. (ClinicalTrials.gov number, NCT00334009)

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J. Am. Soc. Nephrol. 2009 20: A14. [Full Text] [PDF]

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673