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Preoperative Endogenous Ouabain Predicts Acute Kidney Injury in Cardiac Surgery Patients*

Bignami, Elena MD1; Casamassima, Nunzia BSc2; Frati, Elena MD1; Lanzani, Chiara MD2; Corno, Laura MD1; Alfieri, Ottavio MD3; Gottlieb, Stephen MD4; Simonini, Marco MD2; Shah, Keyur B. MD5; Mizzi, Anna MD1; Messaggio, Elisabetta MSc2; Zangrillo, Alberto MD1; Ferrandi, Mara PhD6; Ferrari, Patrizia PhD6; Bianchi, Giuseppe MD2; Hamlyn, John M. PhD7; Manunta, Paolo MD, PhD2

doi: 10.1097/CCM.0b013e3182741599
Clinical Investigations

Objectives: Acute kidney injury is a frequent complication of cardiac surgery and increases morbidity and mortality. As preoperative biomarkers predicting the development of acute kidney injury are not available, we have tested the hypothesis that preoperative plasma levels of endogenous ouabain may function as this type of biomarker.

Rationale and Design: Endogenous ouabain is an adrenal stress hormone associated with adverse cardiovascular outcomes. Its involvement in acute kidney injury is unknown. With studies in patients and animal settings, including isolated podocytes, we tested the above mentioned hypothesis.

Patients: Preoperative endogenous ouabain was measured in 407 patients admitted for elective cardiac surgery and in a validation population of 219 other patients. We also studied the effect of prolonged elevations of circulating exogenous ouabain on renal parameters in rats and the influence of ouabain on podocyte proteins both “in vivo” and “in vitro.”

Main Results: In the first group of patients, acute kidney injury (2.8%, 8.3%, 20.3%, p < 0.001) and ICU stay (1.4±0.38, 1.7±0.41, 2.4±0.59 days, p = 0.014) increased with each incremental preoperative endogenous ouabain tertile. In a linear regression analysis, the circulating endogenous ouabain value before surgery was the strongest predictor of acute kidney injury. In the validation cohort, acute kidney injury (0%, 5.9%, 8.2%, p < 0.0001) and ICU stay (1.2±0.09, 1.4±0.23, 2.2±0.77 days, p = 0.003) increased with the preoperative endogenous ouabain tertile. Values for preoperative endogenous ouabain significantly improved (area under curve: 0.85) risk prediction over the clinical score alone as measured by integrate discrimination improvement and net reclassification improvement. Finally, in the rat model, elevated circulating ouabain reduced creatinine clearance (–18%, p < 0.05), increased urinary protein excretion (+ 54%, p < 0.05), and reduced expression of podocyte nephrin (–29%, p < 0.01). This last finding was replicated ex vivo by incubating podocyte primary cell cultures with low-dose ouabain.

Conclusions: Preoperative plasma endogenous ouabain levels are powerful biomarkers of acute kidney injury and postoperative complications and may be a direct cause of podocyte damage.

Supplemental Digital Content is available in the text.

1 Anesthesia and Intensive Care Unit, San Raffaele Scientific Institute, University Vita Salute San Raffaele, Milan, Italy.

2 Nephrology and Dialysis Unit, San Raffaele Scientific Institute, University Vita Salute San Raffaele, Milan, Italy.

3 Cardiovascular and Thoracic Department, San Raffaele Scientific Institute, University Vita Salute San Raffaele, Milan, Italy.

4 Division of Cardiology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.

5 Division of Cardiology, Virginia Commonwealth University, Richmond, VA.

6 Prassis sigma-tau Research Institute, Settimo Milanese, Milan, Italy.

7 Physiology Department, University of Maryland School of Medicine, Baltimore, MD.

* See also p. 914.

At the time of the experiments in rats, M. Ferrandi and P. Ferrari were employees of Prassis Sigma-Tau Research Institute, Settimo Milanese, Milan, Italy.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (

Supported, in part, by USPHS grants HL75584 and 078870 (J.M.H.), European Union grants LSMH-CT-2006–037093 and Italian Ministry of Health RF-FSR-2008-1141719 (P.M.).

The authors have not disclosed any potential conflicts of interest.

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© 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins