Urinary neutrophil gelatinase-associated lipocalin: a useful biomarker for tacrolimus-induced acute kidney injury in liver transplant patients

PLoS One. 2014 Oct 20;9(10):e110527. doi: 10.1371/journal.pone.0110527. eCollection 2014.


Tacrolimus is widely used as an immunosuppressant in liver transplantation, and tacrolimus-induced acute kidney injury (AKI) is a serious complication of liver transplantation. For early detection of AKI, various urinary biomarkers such as monocyte chemotactic protein-1, liver-type fatty acid-binding protein, interleukin-18, osteopontin, cystatin C, clusterin and neutrophil gelatinase-associated lipocalin (NGAL) have been identified. Here, we attempt to identify urinary biomarkers for the early detection of tacrolimus-induced AKI in liver transplant patients. Urine samples were collected from 31 patients after living-donor liver transplantation (LDLT). Twenty recipients developed tacrolimus-induced AKI. After the initiation of tacrolimus therapy, urine samples were collected on postoperative days 7, 14, and 21. In patients who experienced AKI during postoperative day 21, additional spot urine samples were collected on postoperative days 28, 35, 42, 49, and 58. The 8 healthy volunteers, whose renal and liver functions were normal, were asked to collect their blood and spot urine samples. The urinary levels of NGAL, monocyte chemotactic protein-1 and liver-type fatty acid-binding protein were significantly higher in patients with AKI than in those without, while those of interleukin-18, osteopontin, cystatin C and clusterin did not differ between the 2 groups. The area under the receiver operating characteristics curve of urinary NGAL was 0.876 (95% confidence interval, 0.800-0.951; P<0.0001), which was better than those of the other six urinary biomarkers. In addition, the urinary levels of NGAL at postoperative day 1 (p = 0.0446) and day 7 (p = 0.0006) can be a good predictive marker for tacrolimus-induced AKI within next 6 days, respectively. In conclusion, urinary NGAL is a sensitive biomarker for tacrolimus-induced AKI, and may help predict renal event caused by tacrolimus therapy in liver transplant patients.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / chemically induced*
  • Acute Kidney Injury / urine*
  • Acute-Phase Proteins / urine*
  • Adult
  • Biomarkers / urine
  • Female
  • Humans
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / adverse effects*
  • Lipocalin-2
  • Lipocalins / urine*
  • Liver Transplantation*
  • Male
  • Middle Aged
  • Proto-Oncogene Proteins / urine*
  • Tacrolimus / administration & dosage
  • Tacrolimus / adverse effects*
  • Time Factors


  • Acute-Phase Proteins
  • Biomarkers
  • Immunosuppressive Agents
  • LCN2 protein, human
  • Lipocalin-2
  • Lipocalins
  • Proto-Oncogene Proteins
  • Tacrolimus

Grant support

This work was supported in part by a Grant-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Science, Culture, Sports, and Technology of Japan (MEXT); a grant-in-aid for Research on Biological Markers for New Drug Development and Health and Labour Sciences Research Grants from the Ministry of Health, Labour, and Welfare of Japan (08062855); and a funding program for Next Generation World-Leading Researchers (NEXT Program: LS073 to SM) initiated by the Council for Science and Technology Policy of the Japan Society for the Promotion of Science. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.