IL-6-mediated hepatocyte production is the primary source of plasma and urine neutrophil gelatinase–associated lipocalin during acute kidney injury

Skrypnyk, Nataliya I.; Gist, Katja M.; Okamura, Koji; Montford, John R.; You, Zhiying; Yang, Haichun; Moldovan, Radu; Bodoni, Evelyn; Blaine, Judith; Edelstein, Charles L.; Soranno, Danielle E.; Kirkbride-Romeo, Lara; Griffin, Benjamin R.; Altmann, Chris; Faubel, Sarah

doi:10.1016/j.kint.2019.11.013

Cited by 46 publications

(30 citation statements)

References 41 publications

(57 reference statements)

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“…Based on their result, they predicted that NGAL levels may increase regardless of whether AKI occurs in conditions wherein plasma IL-6 levels can increase. Those authors reported the need for further studies to validate this result with regard to AKI in the general [12].…”

Section: Discussionmentioning

confidence: 90%

“…In a basic research study by Skrypnyk et al, interleukin-6 (IL-6) was shown to mediate hepatic NGAL production in AKI in a mice. Those authors reported that hepatocytes are the primary source of plasma and urine NGAL during AKI [12]. However, AKI is a highly complex systemic disorder, and there are limitations with regard to the generalizability of the abovementioned results.…”

Section: Introductionmentioning

confidence: 99%

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Serum neutrophil gelatinase-associated lipocalin at 3 hours after return of spontaneous circulation in patients with cardiac arrest and therapeutic hypothermia: early predictor of acute kidney injury

Choi

Lee

2020

BMC Nephrol

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Background Serum neutrophil gelatinase-associated lipocalin (NGAL) could be used as a predictive marker of acute kidney injury (AKI) in patients with return of spontaneous circulation (ROSC) after out-of-hospital cardiac arrest (OHCA) who are managed with targeted temperature management (TTM). However, the NGAL measurement timepoints vary from immediately after ROSC to several days later. The primary objective of this study was to determine an association between AKI and NGAL, both immediately (ROSC-NGAL) and 3 h after ROSC (3 h-NGAL), in OHCA patients with TTM. The secondary objective was to ascertain the association between NGAL levels in the early post-ROSC phase and the neurologic outcomes at discharge. Methods This prospective observational study was conducted between January 2016 and December 2018 and enrolled adult OHCA patients (≥18 years) with TTM after ROSC. The serum NGAL level was measured both immediately and 3 h after ROSC. Univariate and multivariate analyses were performed to identify the associations between AKI, poor neurologic outcome, and NGAL. Results Among 861 OHCA patients, 89 patients were enrolled. AKI occurred in 48 (55.1%) patients. On multivariate logistic regression analysis, 3 h-NGAL was significantly associated with AKI (odds ratio [OR] 1.022; 95% confidence interval [CI] 1.009–1.035; p = 0.001). The area under the receiver operating characteristic curve of 3 h-NGAL for AKI was 0.910 (95% CI 0.830–0.960), and a cut-off value of 178 ng/mL was identified. Both ROSC-NGAL and 3 h-NGAL were not significantly associated with poor neurologic outcome on multivariate logistic regression analysis (ROSC-NGAL; OR 1.017; 95% CI 0.998–1.036; p = 0.084, 3 h-NGAL; OR 0.997; 95% CI 0.992–1.001; p = 0.113). Conclusions The serum NGAL concentration measured 3 h after ROSC is an excellent early predictive marker for AKI in OHCA patients treated with TTM. Future research is needed to identify the optimal measurement timepoint to establish NGAL as a predictor of neurologic outcome and to validate the findings of this research.

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Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Serum neutrophil gelatinase-associated lipocalin at 3 hours after return of spontaneous circulation in patients with cardiac arrest and therapeutic hypothermia: early predictor of acute kidney injury

Choi

Lee

2020

BMC Nephrol

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“…In diabetic patients, NGAL produced in tubules could be released in the urine or may reflect proximal tubule dysfunction leading to urinary leak of filtered plasma NGAL, which, as recently shown, is produced in hepatocytes driven by IL-6. 17 In nondiabetic CKD, a recent study on autosomal-dominant polycystic kidney disease patients found MCP1 as a strong predictor of progression. 18 Our linear regression mixed models using a larger number of observations demonstrated significant associations between ACR, RBP, and MCP1 and CKD progression (to stage 3 or 4) in the whole cohort and MCP1 in the ACR <3 cohort but not NGAL or IL-6, as shown in logistic regression models.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Urinary Biomarkers of Proximal Tubular Injury, Inflammation, and Fibrosis in Patients With Albuminuric and Nonalbuminuric Diabetic Kidney Disease

Phanish

Chapman

Yates

et al. 2021

Kidney International Reports

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Introduction: Albuminuric and nonalbuminuric pathways contribute to diabetic kidney disease. Proximal tubule and inflammation play important roles in these processes. Urinary biomarker(s) to detect early kidney damage and predict progression are needed.Methods: Nine urinary biomarkers were measured at baseline in 400 patients with diabetes. Correlation and multivariate logistic and linear regression analyses were performed to assess the association of biomarkers with chronic kidney disease and progression.Results: In the albumin/creatinine ratio (ACR) <3 cohort, the only biomarker significantly associated with estimated glomerular filtration rate < 60 ml/min was N-acetyl-b-D-glucosaminidase. A combination of ACR and monocyte chemoattractant protein 1 (MCP1) were significantly associated with stage 2 chronic kidney disease in this cohort. Logistic models showed that in patients with all levels of albuminuria, ACR, retinol binding protein (RBP), and MCP1 were associated with progression. A model including MCP1, interleukin 6, and neutrophil gelatinase-associated lipocalin showed significant association with progression to chronic kidney disease 3/4 in the ACR <3 cohort. Linear mixed-model regression analyses demonstrated MCP1, RBP, and ACR as significant proteins associated with progression to stage 3 or worse, whereas MCP1 was the only significant biomarker in the ACR <3 cohort. Time-to-event and Cox proportional hazard models confirmed significant hazard ratios for progression for ACR, RBP, and MCP1, with significant differences noted between quantiles of biomarkers for ACR, RBP, and MCP1. Conclusion:In this study of diabetic patients with single baseline measurements of urinary biomarkers, albumin, RBP, and MCP1 were significantly associated with chronic kidney disease progression at all levels of albuminuria. Inflammatory cytokines, neutrophil gelatinase-associated lipocalin, and MCP1 were associated with progression in patients without albuminuria. N-acetyl-b-D-glucosaminidase demonstrated a significant association with an estimated glomerular filtration rate < 60 ml/min in the ACR <3 cohort.

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“…NGAL can be found in blood and urine in several forms: a homodimer of two combined NGAL molecules and/or a heterodimer of NGAL combined with lipocalin (typically of neutrophil original) and/or a monomer of NGAL alone (essentially of tubular origin) 19 . NGAL is also complex in its origin because, even though it can be released into the tubular lumen or, perhaps into the blood stream from the tubules, it is also released by neutrophils under conditions of activation, and most of all by the liver in conditions of inflammation (an interleukin‐6 dependent process) 20 and in a form that can be filtered by the glomerulus. Moreover, if filtered, its absorption is regulated by the expression and availability of megalin, a binding protein that can easily be made less available by the presence of proteinuria 21 .…”

Section: What Do Novel Aki Biomarkers Represent?mentioning

confidence: 99%

Novel renal biomarkers of acute kidney injury and their implications

Bellomo

See

2021

Internal Medicine Journal

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IL-6-mediated hepatocyte production is the primary source of plasma and urine neutrophil gelatinase–associated lipocalin during acute kidney injury

Cited by 46 publications

References 41 publications

Serum neutrophil gelatinase-associated lipocalin at 3 hours after return of spontaneous circulation in patients with cardiac arrest and therapeutic hypothermia: early predictor of acute kidney injury

Serum neutrophil gelatinase-associated lipocalin at 3 hours after return of spontaneous circulation in patients with cardiac arrest and therapeutic hypothermia: early predictor of acute kidney injury

Evaluation of Urinary Biomarkers of Proximal Tubular Injury, Inflammation, and Fibrosis in Patients With Albuminuric and Nonalbuminuric Diabetic Kidney Disease

Novel renal biomarkers of acute kidney injury and their implications

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