Urinary Neutrophil Gelatinase–Associated Lipocalin/Hepcidin-25 Ratio for Early Identification of Patients at Risk for Renal Replacement Therapy After Cardiac Surgery: A Substudy of the BICARBONATE Trial

Abstract

BACKGROUND: Acute kidney injury requiring renal replacement therapy (AKI-RRT) is strongly associated with mortality after cardiac surgery; however, options for early identification of patients at high risk for AKI-RRT are extremely limited. Early after cardiac surgery, the predictive ability for AKI-RRT even of one of the most extensively evaluated novel urinary biomarkers, neutrophil gelatinase–associated lipocalin (NGAL), appears to be only moderate. We aimed to determine whether the NGAL/hepcidin-25 ratio (urinary concentrations of NGAL divided by that of hepcidin-25) early after surgery may compare favorably to NGAL for identification of high-risk patients after cardiac surgery. METHODS: This is a prospective substudy of the BICARBONATE trial, a multicenter parallel-randomized controlled trial comparing perioperative bicarbonate infusion for AKI prevention to usual patient care. At a tertiary referral center, 198 patients at increased kidney risk undergoing cardiac surgery with cardiopulmonary bypass were included into the present study. The primary outcome measure was defined as AKI-RRT. Secondary outcomes were in-hospital mortality and long-term mortality. We compared area under the curve of the receiver operating characteristic (AUC-ROC) of urinary NGAL with that of the urinary NGAL/hepcidin-25 ratio within 60 minutes after end of surgery. We compared adjusted AUC and performed cross-validated reclassification statistics of the (logarithmic) urinary NGAL/hepcidin-25 ratio adjusted to Cleveland risk score/EuroScore, cross-clamp time, age, volume of packed red blood cells, and (logarithmic) urinary NGAL concentration. The association of the NGAL/hepcidin-25 ratio with long-term patient survival was assessed using Cox proportional hazard regression analysis adjusting for EuroScore, aortic cross-clamp time, packed red blood cells and urinary NGAL. RESULTS: Patients with AKI-RRT (n = 13) had 13.7-times higher NGAL and 3.3-times lower hepcidin-25 concentrations resulting in 46.9-times higher NGAL/hepcidin-25 ratio early after surgery compared to patients without AKI-RRT. The NGAL/hepcidin-25 ratio had higher AUC-ROC compared with NGAL for risk of AKI-RRT and in-hospital mortality (unadjusted AUC-ROC difference 0.087, 95% confidence interval [CI], 0.036–0.138, P < .001; 0.082, 95% CI, 0.018–0.146, P = .012). For AKI-RRT, the NGAL/hepcidin-25 ratio increased adjusted category-free net reclassification improvement (cfNRI; 0.952, 95% CI, 0.437–1.468; P < .001) and integrated discrimination improvement (IDI; 0.040, 95% CI, 0.008–0.073; P = .016) but not AUC difference. For in-hospital mortality, the ratio improved AUC of the reference model (AUC difference 0.056, 95% CI, 0.003–0.108; P = .037) and cfNRI but not IDI. The urinary NGAL/hepcidin-25 ratio remained significantly associated with long-term mortality after adjusting for the model covariates. CONCLUSIONS: The urinary NGAL/hepcidin-25 ratio appears to early identify high-risk patients and outperform NGAL after cardiac surgery. Confirmation of our findings in other cardiac surgery centers is now needed.

Advances in laboratory detection of acute kidney injury

“…The BICARBONATE trial, a multicenter, parallel randomized controlled trial comparing perioperative bicarbonate infusion for preventing AKI to usual patient care, explored whether urinary NGAL and the urinary NGAL/hepcidin-25 ratio could predict AKI stage 3D in patients undergoing cardiac surgery with cardiopulmonary bypass [ 72 ]. The samples were collected within 1 h after the end of surgery.…”

“…Therefore, it is expected that insults leading to kidney damage would likely increase NGAL and reduce hepcidin-25 concentrations. The analysis included 198 patients, of whom 13 (6.6%) developed AKI stage 3D [ 72 ]. The urinary NGAL/hepcidin-25 ratio outperformed urinary NGAL for predicting AKI requiring hemodialysis and in-hospital mortality [ 72 ].…”

“…The analysis included 198 patients, of whom 13 (6.6%) developed AKI stage 3D [ 72 ]. The urinary NGAL/hepcidin-25 ratio outperformed urinary NGAL for predicting AKI requiring hemodialysis and in-hospital mortality [ 72 ]. Setting the cutoff value for a ratio ≥0.3 established a specificity of 85%.…”

“…On average, patients requiring KRT had urinary NGAL levels 17 times higher and urinary hepcidin-25 reduced by around 70% compared to people with no AKI. It should be noted that the preoperative NGAL/hepcidin-25 ratio was higher in patients who subsequently developed AKI stage 3D [ 72 ].…”

Urinary and plasma hepcidin-25 as indicators of labile iron involvement in acute kidney injury after cardiac surgery

“…In our cohort, the combination of plasma NGAL and plasma hepcidin-25 or urine NGAL and urine hepcidin-25 at ICU admission expressed as the NGAL:hepcidin-25-ratio improved the predictive value for the diagnosis of AKI over NGAL and hepcidin-25 alone with AUC values of 0.89 (0.82–0.97) and 0.89 (0.81–0.98) for urine and plasma, respectively [ 2 , 5 ]. Additionally, the urinary NGAL:hepcidin-25-ratio may identify patients at risk for postoperative need of renal replacement therapy [ 9 ]. We acknowledge that the sample size used in this study is a limitation precluding the generalization of the findings.…”