Prophylactic perioperative sodium bicarbonate to prevent acute kidney injury following open heart surgery: a multicenter double-blinded randomized controlled trial.

BACKGROUND: Preliminary evidence suggests a nephroprotective effect of urinary alkalinization in patients at risk of acute kidney injury. In this study, we tested whether prophylactic bicarbonate-based infusion reduces the incidence of acute kidney injury and tubular damage in patients undergoing open heart surgery. METHODS AND FINDINGS: In a multicenter, double-blinded (patients, clinical and research personnel), randomized controlled trial we enrolled 350 adult patients undergoing open heart surgery with the use of cardiopulmonary bypass. At induction of anesthesia, patients received either 24 hours of intravenous infusion of sodium bicarbonate (5.1 mmol/kg) or sodium chloride (5.1 mmol/kg). The primary endpoint was the proportion of patients developing acute kidney injury. Secondary endpoints included the magnitude of acute tubular damage as measured by urinary neutrophil gelatinase-associated lipocalin (NGAL), initiation of acute renal replacement therapy, and mortality. The study was stopped early under recommendation of the Data Safety and Monitoring Committee because interim analysis suggested likely lack of efficacy and possible harm. Groups were non-significantly different at baseline except that a greater proportion of patients in the sodium bicarbonate group (66/174 [38%]) presented with preoperative chronic kidney disease compared to control (44/176 [25%]; p = 0.009). Sodium bicarbonate increased urinary pH (from 6.0 to 7.5, p<0.001). More patients receiving bicarbonate (83/174 [47.7%]) developed acute kidney injury compared with control patients (64/176 [36.4%], odds ratio [OR] 1.60 [95% CI 1.04-2.45]; unadjusted p = 0.032). After multivariable adjustment, a non-significant unfavorable group difference affecting patients receiving sodium bicarbonate was found for the primary endpoint (OR 1.45 [0.90-2.33], p = 0.120]). A greater postoperative increase in urinary NGAL in patients receiving bicarbonate infusion was observed compared to control patients (p = 0.011). The incidence of postoperative renal replacement therapy was similar but hospital mortality was increased in patients receiving sodium bicarbonate compared with control (11/174 [6.3%] versus 3/176 [1.7%], OR 3.89 [1.07-14.2], p = 0.031). CONCLUSIONS: Urinary alkalinization using sodium bicarbonate infusion was not found to reduce the incidence of acute kidney injury or attenuate tubular damage following open heart surgery; however, it was associated with a possible increase in mortality. On the basis of these findings we do not recommend the prophylactic use of sodium bicarbonate infusion to reduce the risk of acute kidney injury. Discontinuation of growing implementation of this therapy in this setting seems to be justified. TRIAL REGISTRATION: ClinicalTrials.gov NCT00672334 Please see later in the article for the Editors' Summary.

Low preoperative hepcidin concentration as a risk factor for mortality after cardiac surgery: a pilot study.

OBJECTIVE: Hepcidin regulates iron absorption and recycling and is central to host defense, protection from reactive iron species, and a biomarker of iron-related pathophysiology. We assessed the value of hepcidin measured preoperatively for the prediction of in-hospital mortality and renal outcomes. METHODS: We studied 100 adult patients undergoing cardiac surgery in the control arm of a randomized, controlled trial. Plasma and urine were sampled before induction of anesthesia, and hepcidin-25 was quantified by competitive enzyme-linked immunoassay. Renal outcomes were acute kidney injury defined by risk, injury, failure, loss of function, end-stage renal disease (RIFLE) classification and need for renal replacement therapy. Variables with the potential to influence hepcidin expression were investigated. RESULTS: Low preoperative hepcidin concentration in urine (median, 15.3 ng/mL; 25-75 percentiles, 0-129.1) and plasma (median, 49.2 ng/mL; 25th-75th percentile, 0-52.2) predicted mortality (area under the curve-receiver operating characteristic [AUC-ROC] for urine hepcidin, 0.89; 95% confidence interval, 0.73-0.99; cutoff, 130 ng/mL; sensitivity, 73%; specificity, 100%; and AUC-ROC for plasma hepcidin, 0.90; 95% confidence interval, 0.80-0.99; cutoff, 55 ng/mL; sensitivity, 83%; specificity, 100%). Survivors had median preoperative hepcidin concentrations of 325.3 ng/mL (25th-75th percentile, 120-770.1 ng/mL) in urine and 113.1 ng/mL (25th-75th percentile, 77.7-203.1 ng/mL) in plasma. Preoperative serum creatinine did not predict mortality (AUC-ROC, 0.50; 95% confidence interval, 0.10-0.94). Furthermore, preoperative urine, plasma hepcidin, and serum creatinine did not distinguish patients requiring postoperative renal replacement therapy from those without (urine: AUC-ROC, 0.62; 95% confidence interval, 0.38-0.86; plasma: AUC-ROC, 0.63; 95% confidence interval, 0.34-0.91; serum creatinine: AUC-ROC, 0.61; 95% confidence interval, 0.22-0.99). Preoperative renal function and hemoglobin did not correlate with hepcidin indices whereas plasma markers of inflammation did. CONCLUSIONS: Low preoperative hepcidin concentration might be a risk factor for in-hospital mortality. Findings should be validated in larger patient cohorts with a greater number of events.

Urine hepcidin has additive value in ruling out cardiopulmonary bypass-associated acute kidney injury: an observational cohort study.

INTRODUCTION: Conventional markers of acute kidney injury (AKI) lack diagnostic accuracy and are expressed only late after cardiac surgery with cardiopulmonary bypass (CPB). Recently, interest has focused on hepcidin, a regulator of iron homeostasis, as a unique renal biomarker. METHODS: We studied 100 adult patients in the control arm of a randomized, controlled trial http://www.clinicaltrials.gov/NCT00672334 who were identified as being at increased risk of AKI after cardiac surgery with CPB. AKI was defined according to the Risk, Injury, Failure, Loss, End-stage renal disease classification of AKI classification stage. Samples of plasma and urine were obtained simultaneously (1) before CPB (2) six hours after the start of CPB and (3) twenty-four hours after CPB. Plasma and urine hepcidin 25-isoforms were quantified by competitive enzyme-linked immunoassay. RESULTS: In AKI-free patients (N = 91), urine hepcidin concentrations had largely increased at six and twenty-four hours after CPB, and they were three to seven times higher compared to patients with subsequent AKI (N = 9) in whom postoperative urine hepcidin remained at preoperative levels (P = 0.004, P = 0.002). Furthermore, higher urine hepcidin and, even more so, urine hepcidin adjusted to urine creatinine at six hours after CPB discriminated patients who did not develop AKI (area under the curve (AUC) receiver operating characteristic curve 0.80 [95% confidence interval (95% CI) 0.71 to 0.87] and 0.88 [95% CI 0.78 to 0.97]) or did not need renal replacement therapy initiation (AUC 0.81 [95% CI 0.72 to 0.88] 0.88 [95% CI 0.70 to 0.99]) from those who did. At six hours, urine hepcidin adjusted to urine creatinine was an independent predictor of ruling out AKI (P = 0.011). Plasma hepcidin did not predict no development of AKI. The study findings remained essentially unchanged after excluding patients with preoperative chronic kidney disease. CONCLUSIONS: Our findings suggest that urine hepcidin is an early predictive biomarker of ruling out AKI after CPB, thereby contributing to early patient risk stratification.