Preoperative endogenous ouabain predicts acute kidney injury in cardiac surgery patients

Elena Bignami, Nunzia Casamassima, Elena Frati, Chiara Lanzani, Laura Corno, Ottavio Alfieri, Stephen Gottlieb, Marco Simonini, Keyur B. Shah, Anna Mizzi, Elisabetta Messaggio, Alberto Zangrillo, Mara Ferrandi, Patrizia Ferrari, Giuseppe Bianchi, John M. Hamlyn, Paolo Manunta

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)744-755
Number of pages12
JournalCritical Care Medicine
Issue number3
Publication statusPublished - Mar 2013


  • Critically ill
  • K-ATPase
  • Na
  • Na pump inhibitor
  • Renal damage

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine


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