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. 2015 Jul 10;10(7):e0132539.
doi: 10.1371/journal.pone.0132539. eCollection 2015.

Low Serum Neutrophil Gelatinase-associated Lipocalin Level as a Marker of Malnutrition in Maintenance Hemodialysis Patients

Hirotaka Imamaki  1 , Akira Ishii  1 , Hideki Yokoi  1 , Masato Kasahara  2 , Takashige Kuwabara  3 , Keita P Mori  1 , Yukiko Kato  1 , Takashi Kuwahara  4 , Masugi Satoh  5 , Kimihiko Nakatani  6 , Yoshihiko Saito  6 , Naohisa Tomosugi  7 , Akira Sugawara  8 , Kazuwa Nakao  9 , Masashi Mukoyama  3 , Motoko Yanagita  10 , Kiyoshi Mori  11
Affiliations

Low Serum Neutrophil Gelatinase-associated Lipocalin Level as a Marker of Malnutrition in Maintenance Hemodialysis Patients

Hirotaka Imamaki et al. PLoS One. .

Abstract

Background: Neutrophil gelatinase-associated lipocalin (NGAL or LCN2) is an iron-transporting factor which possesses various activities such as amelioration of kidney injury and host defense against pathogens. Its circulating concentrations are elevated in acute and chronic kidney diseases and show a positive correlation with poor renal outcome and mortality, but its clinical significance in maintenance hemodialysis (HD) patients remains elusive.

Methods: Serum NGAL levels were determined by enzyme-linked immunosorbent assay in out-patient, Japanese HD subjects. Their correlation to laboratory findings and morbidity (as development of severe infection or serum albumin reduction) was investigated using linear regression analysis and χ2 test.

Results: Pre-dialysis serum NGAL levels in HD patients were elevated by 13-fold compared to healthy subjects (n=8, P<0.001). In a cross-sectional study of 139 cases, serum NGAL concentrations were determined independently by % creatinine generation rate (an indicator of muscle mass, standardized coefficient β=0.40, P<0.001), peripheral blood neutrophil count (β=0.38, P<0.001) and anion gap (which likely reflects dietary protein intake, β=0.16, P<0.05). Iron administration to anemic HD patients caused marked elevation of peripheral blood hemoglobin, serum ferritin and iron-regulatory hormone hepcidin-25 levels, but NGAL levels were not affected. In a prospective study of 87 cases, increase in serum albumin levels a year later was positively associated to baseline NGAL levels by univariate analysis (r=0.36, P<0.01). Furthermore, within a year, patients with the lowest NGAL tertile showed significantly increased risk for marked decline in serum albumin levels (≥0.4 g/dl; odds ratio 5.5, 95% confidence interval 1.5-20.3, P<0.05) and tendency of increased occurrence of severe infection requiring admission (odds ratio 3.1, not significant) compared to the middle and highest tertiles.

Conclusion: Low serum NGAL levels appear to be associated with current malnutrition and also its progressive worsening in maintenance HD patients.

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Conflict of interest statement

Competing Interests: KM is a part of patent co-inventors for blood and urinary NGAL as a diagnostic and monitoring tool of chronic renal disease (PCT/US2005/015799 by Jonathan Barasch, Prasad Devarajan, Thomas L. Nickolas and Kiyoshi Mori). NGAL measurement to detect kidney injury was licensed to Abbott Labs and Biosite-Alere. The rest of authors declared no competing interests. Additionally, this work was supported in part by research funds from Mitsubishi Tanabe Pharma Corporation. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Linear correlation of baseline pre-dialysis serum NGAL levels with clinical parameters.
Correlations of serum NGAL level with (A) peripheral blood neutrophil count, (B) % creatinine generation rate (%CGR) and (C) anion gap are shown. (D) Correlation between neutrophil count and serum C-reactive protein (CRP) level is also shown. Linear line in each graph shows regression line. N = 139.
Fig 2
Fig 2. Linear correlation of baseline pre-dialysis serum NGAL levels with serum creatinine, dialysis efficiency, age and HD period.
Correlations with (A) creatinine (Cr), (B) HD period, (C) single-pool Kt/V (Kt/Vsp), and (D) age are shown. (E) Correlation between HD period and age. N = 139.
Fig 3
Fig 3. Effects of iron administration upon clinical parameters in maintenance HD patients.
Mean±SD. Comparison between different time points was carried out by repeated-measures ANOVA with Dunnett post test. N = 6.
Fig 4
Fig 4. Removal of circulating substances by HD session.
Blood was serially drawn from the arterial and venous ends of HD circuit (closed circle and open box, respectively) during HD session. End points varied from 3.0 to 4.5 h. Mean±SD. (A) Comparison of arterial blood NGAL levels between before and after HD session (left, n = 139). Time course of arterial and venous NGAL levels are also shown (right, n = 9). (B) Serum levels of K, BUN, creatinine (Cr), β2-microglobulin (MG), albumin (Alb) and IgG, as well as blood WBC and neutrophil counts are shown (n = 9). Arterial levels of K, BUN, Cr, β2-MG were always higher than venous levels, indicating active removal by HD. On the other hand, venous levels of albumin and IgG tended to be higher than arterial levels, reflecting hemoconcentration by HD. #P<0.05, significant difference from time 0 by repeated-measures ANOVA. *P<0.05, significant difference between arterial and venous blood.
Fig 5
Fig 5. Change in serum albumin levels in a year among 3 groups assigned by baseline serum NGAL tertiles.
Comparison was carried out by paired t-test. N = 87.
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