Urinary neutrophil gelatinase-associated lipocalin (NGAL) for the detection of acute kidney injury after orthotopic liver transplantation

Abstract

Acute kidney injury (AKI) is a frequent complication after orthotopic liver transplantation (OLT). The incidence of post-operative AKI according to acute kidney injury network criteria can be estimated to be as high as 60% of all patients after liver transplantation [1–3]. Besides increasing morbidity and length of hospitalization, graft survival is significantly reduced, even with only modest increase of serum creatinine (> 0.5 mg/dL, AKIN Stage 1) [3, 4]. Postoperative AKI is also an independent risk factor for mortality during the first year after transplantation [1]. The development of AKI following liver transplantation is multifactorial and influenced by numerous pre-, intraand post-operative factors. During the preoperative period, conditions predisposing for post-operative AKI can be present. The most commonly observed preoperative renal dysfunction is due to the hepato-renal syndrome characterized by arterial vasodilatation mainly in the splanchnic vessel area and severe renal vasoconstriction. Intraoperative factors include long periods of vascular crossclamping, hypotension, high doses of vasopressors and large volume load. Post-operative hypotension and calcineurin inhibitors such as cyclosporine and tacrolimus also support conditions potentially culminating in AKI [4]. Currently, there are no effective measures or treatment strategies available for the prevention or treatment of AKI. The development of effective interventions is hampered by the limited ability of early detection of AKI [5, 6]. In order to develop and evaluate strategies for the prevention and treatment of AKI, there is a great need for early biomarkers. In this issue of Nephrology Dialysis Transplantation, Wagener et al. [7] propose increased urinary neutrophil gelatinase-associated lipocalin (NGAL)/creatinine ratio as an early predictor of AKI following OLT. The data source is a prospective cohort study of 92 patients undergoing OLT at a single centre between 2008 and 2010 (18 living related, 74 deceased). Patients underwent OLT for different reasons (hepatitis C, hepatitis B, nutritive toxic liver cirrhosis, primary sclerosing cholangitis) and showed a modified end stage liver disease score of 21.9 7.4 prior to surgery. Patients did not require renal replacement therapy preoperatively and apparently had intact kidney function according to the serum creatinine (0.99 0.64 mg/dL). Urine samples were collected after induction of anaesthesia prior to incision, immediately after portal reperfusion of the liver graft and then 3, 18 and 24 h later. To compensate for possible urinary dilution or concentration, the results of the NGAL measurements are given as urinary NGAL/creatinine ratio. AKI was defined according to the RIFLE criteria by an increased serum creatinine of >150% after OLT compared to preoperative values. Thirty-seven patients (40.2%) developed AKI during the post-operative period. In those patients, serum creatinine concentration significantly increased at Day 2 after transplantation, whereas urinary NGAL/creatinine ratio already showed a significant increase after 3 h. According to the study, there is a diagnostic benefit of ~2 days using urinary NGAL compared to serum creatinine for the diagnosis of AKI after OLT. Interestingly, in patients with AKI, NGAL already declined between 3 and 18 h after OLT and there was no significant difference between the AKI and nonAKI group after 24 h. This time course suggests that the increase in urinary NGAL/creatinine is specific for the kidney injury during OLT. Just before transplantation, and immediately after reperfusion, there were no differences in urinary NGAL/creatinine concentration between patients with AKI and those without AKI. The investigators conclude that urinary NGAL/creatinine ratio is an early marker of AKI after liver transplantation, which, because of its high sensitivity and specificity, might be a useful surrogate end point of AKI in clinical trials. Urinary NGAL might be a more sensitive marker for AKI, especially in patients after liver transplantation, than serum creatinine because unlike serum creatinine, it is not dependent on drugs, muscle mass or liver metabolism [8]. Urinary NGAL is mainly produced by the distal nephron after injury and is immediately secreted into the urine. In contrast, plasma NGAL is a product of multiple sources. Nevertheless, AKI also triggers increasing amounts of messenger RNA in other tissues than the distal nephron including liver and lung [9]. This might explain why both urinary and plasma NGAL proved to be reliable markers for AKI in children after cardiac surgery with an AUC–ROC of >0.9 [14]. But also in patients with AKI after liver transplantation, it was shown to be of benefit. In a prospective study of