Letter to the Editor: Posthepatic-ischemia-reperfusion injury-related AKI: A need for better biomarkers and interventions to mitigate the risk.

To the editor, We read with great interest a recent randomized controlled trial by Kim et al1 in which the authors studied the correlation between serum albumin and neutrophil gelatinase–associated lipocalin (NGAL) levels to predict post-liver transplantation (LT)-acute kidney injury (AKI). In this proof of concept study, 20% albumin infusion during the reperfusion phase was neither associated with a decrease in plasma NGAL levels nor a decrease in the incidence of post-transplant AKI. This study is mainly based on 3 hypotheses: (1) hepatic ischemia-reperfusion-injury (IRI) is associated with post-LT-AKI. (2) Serum NGAL can detect post-LT-AKI 1 hour after graft reperfusion. (3) Intraoperative hypertonic albumin therapy decreases plasma NGAL level 1 hour after the graft reperfusion. We have specific essential points to note: First, in LT surgery, several preoperative and perioperative factors have been linked to the development of AKI, including IRI. IRI is an unavoidable consequence of the preservation process in deceased-donor liver transplantation due to longer cold-ischemia time. In living-donor liver transplantation, a partial liver graft is usually transplanted after a brief cold-ischemia time, leading to minimal IRI. In this study, only 21% of 136 adult recipients underwent deceased-donor LT. Thus, this study’s negative results are unsurprising and need better generalizability. The pathophysiology of post-LT-AKI in living-donor liver transplantation versus deceased-donor liver transplantation setting and the impact of IRI on AKI in living-donor liver transplantation settings should be studied. Second, although NGAL is a surrogate marker for perioperative AKI,2 there are a few concerns regarding its use as the marker of post-LT-AKI. There is new evidence from a preclinical study pointing toward the liver as the primary site of NGAL production in ischemic AKI. Increased plasma IL-6 was associated with increased hepatic NGAL mRNA and plasma NGAL levels. In mice with hepatic-specific NGAL deletion and ischemic AKI, plasma and urinary NGAL levels were reduced.3 Hepatic IRI is associated with an increase in IL-6, which may increase the level of NGAL in the blood. Thus, higher NGAL may not truly represent the development of AKI following graft reperfusion. It would be interesting to know if the NGAL levels are elevated in the living donors, as most living donors have a normal renal function posthepatectomy, which will further clarify if the source of NGAL is the liver. Third, the association of low serum albumin levels with a higher incidence of AKI and the protective antioxidant effects of albumin against IRI has been suggested. However, in this study, albumin infusion and increasing serum albumin levels are not protective against AKI. The association of low serum albumin levels with post-LT-AKI is not equivalent to causation. Thus, this idea that intraoperative hypertonic albumin therapy might decrease post-LT-AKI is too simplistic for this essentially complex and multifactorial entity. In conclusion, the novel idea of albumin infusion to decrease the effects of ischemia-reperfusion injury–related AKI is commendable. However, NGAL may not be the best marker to identify the risk of AKI immediately after LT. Further studies are required to address the need for better markers and interventions to mitigate the risk of ischemia-reperfusion injury-related AKI.