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Neutrophil gelatinase-associated lipocalin predicts the efficacy of tolvaptan for ascites in patients with liver cirrhosis

  • Original Article―Liver, Pancreas, and Biliary Tract
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Abstract

Background

Acute kidney injury (AKI) is associated with liver cirrhosis (LC), water retention, diuretics to treat water retention, and a poor prognosis. Urinary neutrophil gelatinase-associated lipocalin (uNGAL) reportedly predicts a poor prognosis in decompensated LC. This study investigated the usefulness of uNGAL in predicting the short- and long-term effects of tolvaptan (TVP) and the incidence of AKI post-TVP administration.

Methods

Of the LC cases with water retention, 86 with available pre-treatment uNGAL were analyzed. A short-term response was defined as weight loss of ≥ 1.5 kg within the first week; a long-term response was defined as a short-term response without early recurrence. The uNGAL usefulness in predicting the short- and long-term effects of TVP and AKI incidence post-TVP administration was investigated.

Results

Short-term effects of TVP were observed in 52 patients. Of these, 15 patients had an early recurrence. In multivariate analysis, significant short-term predictive factors were C-reactive protein (CRP) < 1.4 mg/dl, uNa/K ratio ≥ 3.51, and uNGAL < 50.2 ng/ml. Patients were classified according to these three cut-off values, with short-term response rates of 92.9%, 68.8%, 26.7%, and 0% for 0, 1, 2, and 3 points, respectively. CRP < 0.94 mg/dl and uNGAL < 50.2 ng/ml were significant factors for predicting the long-term response of TVP. The AKI incidence post-TVP was 8.1% (n = 7) and was significantly higher among those with uNGAL ≥ 38.1 ng/mL.

Conclusion

uNGAL is a useful predictor of the short- and long-term efficacy of TVP and can be useful in predicting AKI incidence post-TVP administration.

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Abbreviations

LC:

Liver cirrhosis

AKI:

Acute kidney injury

TVP:

Tolvaptan

BUN:

Blood urea nitrogen

sCR:

Serum creatinine

uNA:

Urinary NA

uNa/K:

Urinary Na/K

CRP:

C-reactive protein

NGAL:

Neutrophil gelatinase-associated lipocalin

uNGAL:

Urinary neutrophil gelatinase-associated lipocalin

PMI:

Psoas muscle mass index

ROC:

Receiver operating characteristic

HBV:

Hepatitis B

HCV:

Hepatitis C

HCC:

Hepatocellular carcinoma

sBUN:

Serum blood urea nitrogen

MELD:

Median model for end-stage liver disease

MELD-Na:

Median model for end-stage liver disease Na

sNa:

Serum sodium

uL-FABP:

Urinary liver-type fatty acid binding protein

CKD:

Chronic kidney disease

KDIGO:

Kidney disease improving global outcomes

HRS-AKI:

Hepatorenal syndrome acute kidney injury

ACLF:

Acute-on-chronic liver failure

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Acknowledgements

The authors gratefully acknowledge Hatsumi Ueda and Terumi Hatakeyama for their technical support, as well as Ayumi Kachi, Maki Makino, Kazue Yoshida, Hinako Yokoi, and Keiko Sano for their administrative support. Urinary NGAL measurement was performed by Abbott Japan LLC (Tokyo, Japan).

Funding

This work was supported by the Japan Agency for Medical Research and Development (AMED) (JP21fk0310103, JP21fk0210053, JP21fk0210072, JP20fk0210056, JP21fk0310101, JP21fk0210047, JP21fk0210064, JP21fk0210056, JP21fk0210048, JP21fk0210058, JP21fk0210066, and 21fk0210067); and JSPS KAKENHI Grant Number JP20K08371 and JP22K15954.

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-Ku, Sapporo-shi, Hokkaido, 060-8638, Japan

    Masato Nakai, Kenichi Morikawa, Takashi Sasaki, Risako Kohya, Sonoe Yoshida, Shunichi Hosoda, Akinori Kubo, Yoshimasa Tokuchi, Takashi Kitagataya, Ren Yamada, Masatsugu Ohara, Takuya Sho, Goki Suda, Koji Ogawa & Naoya Sakamoto

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  1. Masato Nakai
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Contributions

All authors contributed to the study’s conception and design. Material preparation and data collection were performed by MN, KM, TS, RK, SY, SH, AK, YT, TK, RY, MO, TS, GS, and KO. Analyses were performed by MN. The first draft of the manuscript was prepared by MN, and review and editing were performed by KM and NS. All authors commented on previous versions of the manuscript. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Naoya Sakamoto.

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Conflict of interest

Professor Naoya Sakamoto received lecture fees from Bristol Myers Squibb and Pharmaceutical K. K., grants and endowments from MSD K. K and Chugai Pharmaceutical Co., Ltd. and a research grant from Gilead Sciences Inc. Professor Kenichi Morikawa received research grants from Gilead Sciences, Inc., Bristol Myers Squibb, Otsuka Pharmaceutical Co., Ltd. and Takeda Pharmaceutical Co., Ltd. Professor Goki Suda has received research grants from Bristol Myers Squibb. The other authors declare no conflicts of interest.

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535_2023_1993_MOESM2_ESM.pdf

Supplementary file2 Supplemental Fig. 1 Cumulative survival rate of non-responders, long-term responders, and patients with early recurrence. (a) Cumulative survival rate of patients with or without long-term response to TVP. (b) Cumulative survival rate in three groups of non-responders, early recurrence, and long-term responders. (c) Cumulative survival rates of patients with or without long-term response to TVP when examined in excluded cases with advanced hepatocellular carcinoma exceeding the Milan criteria. (d) The uNGAL level of responders and non-responders in excluded patients with advanced hepatocellular carcinoma exceeding the Milan criteria. (e) The uNGAL levels of non-responders and patients with early recurrence and long-term responders in excluded patients with advanced hepatocellular carcinoma exceeding the Milan criteria. The box charts for the X-axis and Y-axis indicate the median and 25th and 75th percentiles as boxes, the first quartiles -1.5 × IQR (interquartile range), and the third quartiles +1.5 × IQR as lines outside the boxes. NR, non-responders; ER, early recurrence; LR, long-term responders; TVP, tolvaptan. Supplemental Fig. 2 uNGAL level predicts short-term TVP response in patients without baseline AKI. (a) The uNGAL levels of responders and non-responders in patients without baseline AKI. The box charts for the Y-axis indicate the median as bold lines in the boxes, 25th and 75th percentiles as boxes, and 10th and 90th percentiles as lines for each edge. (b) The ROC curve showing the baseline uNGAL value predictive of short-term response of TVP in patients without baseline AKI. (c) The patient rate of TVP short-term responders in patients with uNGAL levels <50.2 ng/ml and ≥50.2 ng/ml. Standard error is represented as lines for the upper edge. AKI, acute kidney injury; uNGAL, urinary neutrophil gelatinase-associated lipocalin; PPV, positive predictive value; NPV, negative predictive value; TVP, tolvaptan; ROC, receiver operating characteristic. Supplemental Fig. 3 Scatter diagram of uNGAL and various factors. Scatter diagram of uNGAL and various renal function markers. (a) sBUN, (b) sCr, (c) estimated glomerular filtration rate (eGFR), (d) uNa/K ratio, (e) uBUN, (f) uL-FABP, (g) serum albumin, (h) serum total bilirubin, and (i) prothrombin international normalized ratio (PT-INR). uNGAL, urinary neutrophil gelatinase-associated lipocalin; sBUN, serum blood urea nitrogen; sCr, serum creatinine; uBUN, urinary blood urea nitrogen; uL-FABP, urinary liver-type fatty acid binding protein; uNa/K, urinary Na/K. Supplemental Fig. 4 The uNGAL value divided by the Child–Pugh score. The uNGAL values are shown on the Y-axis. Box charts for the Y-axis indicate the median as bold lines in the boxes, the 25th and 75th percentiles as boxes, and the 10th and 90th percentiles as lines for each edge. uNGAL, urinary neutrophil gelatinase-associated lipocalin (PDF 600 KB)

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Nakai, M., Morikawa, K., Sasaki, T. et al. Neutrophil gelatinase-associated lipocalin predicts the efficacy of tolvaptan for ascites in patients with liver cirrhosis. J Gastroenterol 58, 656–667 (2023). https://doi.org/10.1007/s00535-023-01993-w

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