Urine Catalytic Iron and Neutrophil Gelatinase-Associated Lipocalin as Companion Early Markers of Acute Kidney Injury after Cardiac Surgery: A Prospective Pilot Study

Akrawinthawong, Krittapoom; Shaw, Michael K.; Kachner, Joshua; Apostolov, Eugene O.; Basnakian, Alexie G.; Shah, Sudhir V.; Tilak, Jacqueline; McCullough, Peter A.

doi:10.1159/000346815

Cited by 23 publications

(22 citation statements)

References 88 publications

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“…However, iron is excreted mainly through sloughed mucosal cells in the gastrointestinal tract rather than in the urine. In addition, urinary catalytic iron levels are increased, not decreased, in patients with AKI (29). Finally, we found no correlation between eGFR and plasma catalytic iron levels.…”

Section: Discussioncontrasting

confidence: 70%

“…In a pilot study of 14 patients undergoing cardiac surgery, urinary catalytic iron levels increased significantly within 8 hours in patients who developed AKI (29). In a larger study (n=806), plasma catalytic iron levels measured 24 hours after radiocontrast administration were higher among patients with versus without established contrast nephropathy (15).…”

Section: Discussionmentioning

confidence: 91%

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Plasma Catalytic Iron, AKI, and Death among Critically Ill Patients

Leaf

Rajapurkar²,

Lele

et al. 2014

Clinical Journal of the American Society of Nephrology

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Background and objectives Catalytic iron has been hypothesized to be a key mediator of AKI. However, the association between plasma catalytic iron levels and AKI has not been well studied in humans.Design, settings, participants, & measurements A single-center, prospective, nonconsecutive cohort study of 121 critically ill patients admitted to intensive care units (ICUs) between 2008 and 2012 was performed. Plasma catalytic iron, free hemoglobin, and other iron markers were measured on ICU days 1 and 4. The primary end point was in-hospital mortality or AKI requiring RRT. Secondary end points included mortality (assessed during hospitalization, at 30 days, and 1 year) and incident AKI, defined by modified Kidney Disease Improving Global Outcomes criteria.Results ICU day 1 plasma catalytic iron levels were higher among patients who reached the primary end point (median, 0.74 mmol/l [interquartile range, 0.31-3.65] versus 0.29 mmol/l [0.22-0.46]; P,0.01). ICU day 1 plasma catalytic iron levels were associated with number of packed red blood cell transfusions before ICU arrival (r s =0.29; P,0.001) and plasma free hemoglobin levels on ICU day 1 (r s =0.32; P,0.001). Plasma catalytic iron levels on ICU day 1 were significantly associated with in-hospital mortality or AKI requiring RRT, even after adjusting for age, enrollment eGFR, and number of packed red blood cell transfusions before ICU arrival (13 events; adjusted odds ratio per 1-SD higher ln[catalytic iron], 3.33; 95% confidence interval, 1.79 to 6.20). ICU day 1 plasma catalytic iron levels were also significantly associated with incident AKI, RRT, hospital mortality, and 30-day mortality.Conclusions Among critically ill patients, elevated plasma catalytic iron levels on arrival to the ICU are associated with a greater risk of incident AKI, RRT, and hospital mortality.

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Section: Discussioncontrasting

confidence: 70%

Section: Discussionmentioning

confidence: 91%

Plasma Catalytic Iron, AKI, and Death among Critically Ill Patients

Leaf

Rajapurkar²,

Lele

et al. 2014

Clinical Journal of the American Society of Nephrology

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“…Further studies, however, are required to investigate whether other mechanisms may supersede Lcn2 to induce/maintain hypoferremia during the later phase of chronic colitis. Although our study did not detect significant correlation between urinary CI and Lcn2, one study reported a positive correlation in patients with high risk in developing acute kidney injury after undergoing open heart surgery (Akrawinthawong et al 2013). Such discrepancy could be due to the differences in (1) the model or pathological condition (murine vs human), (2) the time points in which samples were collected, (3) type of tissue analyzed, and (4) use of any medication.…”

Section: Discussioncontrasting

confidence: 94%

Lipocalin 2 alleviates iron toxicity by facilitating hypoferremia of inflammation and limiting catalytic iron generation

et al. 2016

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Iron is an essential transition metal ion for virtually all aerobic organisms, yet its dysregulation (iron overload or anemia) is a harbinger of many pathologic conditions. Hence, iron homeostasis is tightly regulated to prevent the generation of catalytic iron (CI) which can damage cellular biomolecules. In this study, we investigated the role of iron-binding/trafficking innate immune protein, lipocalin 2 (Lcn2, aka siderocalin) on iron and CI homeostasis using Lcn2 knockout (KO) mice and their WT littermates. Administration of iron either systemically or via dietary intake strikingly upregulated Lcn2 in the serum, urine, feces, and liver of WT mice. However, similarly-treated Lcn2KO mice displayed elevated CI, augmented lipid peroxidation and other indices of organ damage markers, implicating that Lcn2 responses may be protective against iron-induced toxicity. Herein, we also show a negative association between serum Lcn2 and CI in the murine model of dextran sodium sulfate (DSS)-induced colitis. The inability of DSS-treated Lcn2KO mice to elicit hypoferremic response to acute colitis, implicate the involvement of Lcn2 in iron homeostasis during inflammation. Using bone marrow chimeras, we further show that Lcn2 derived from both immune and non-immune cells participate in CI regulation. Remarkably, exogenous rec-Lcn2 supplementation suppressed CI levels in Lcn2KO serum and urine. Collectively, our results suggest that Lcn2 may facilitate hypoferremia, suppress CI generation and prevent iron-mediated adverse effects.

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“…In CKD patients undergoing elective coronary angiography with contrast, postprocedural NGAL increases from baseline in each stage of CKD [46] . In patients undergoing open heart surgery with AKI, urine catalytic iron levels are highly correlated with urine NGAL levels [47] . The difference in AUROC values of NGAL between SHRs and humans may be due to the young age of SHRs (5 months old) in an animal model used by Rouse et al [6]; therefore, the level of NGAL may not yet reflect severely worsening AKI.…”

Section: Similar Pathogenesis Of Ed and Asymmetric Dimethylarginine Imentioning

confidence: 99%

Aging Male Spontaneously Hypertensive Rat as an Animal Model for the Evaluation of the Interplay between Contrast-Induced Acute Kidney Injury and Cardiorenal Syndrome in Humans

Zhang

Fallahzadeh

McCullough³

2016

Cardiorenal Med

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Background:Although there are some animal models for biomarkers of contrast-induced acute kidney injury (CI-AKI), for cardiorenal syndrome (CRS) and for acute renal failure, the interplay between CI-AKI and CRS has yet to be evaluated. Insight into the pathogenesis of CRS is urgently needed from animal models in order to foster the discovery and implementation of novel biomarkers for this disease. Specially designed animal models for type 1 and 3 CRS, particularly CI-AKI, have not yet emerged. Summary: We hypothesize that the aging male spontaneously hypertensive rat (SHR) is likely to be a suitable model. The SHR model is able to mimic risk factors for preclinical CRS that appears in the clinical setting, specifically hypertension, age, preexisting damage and dysfunction of the heart and kidney, endothelial dysfunction, increased level of reactive oxygen species, decreased level and bioavailability of nitric oxide (NO), impairment of the L -arginine-NO pathway, and insulin resistance. In the SHR, CI-AKI results in a different profile of AKI biomarkers than is seen with preexisting chronic kidney injury. Key Messages: The SHR model can be used to evaluate the interaction between CI-AKI and CRS type 1 and 3 and to verify neutrophil gelatinase-associated lipocalin (NGAL) as a reliable CI-AKI biomarker for clinical application. Further research is warranted with a large number of aging male SHRs to prove NGAL as a sensitive, specific, highly predictive, early biomarker for CI-AKI.

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Urine Catalytic Iron and Neutrophil Gelatinase-Associated Lipocalin as Companion Early Markers of Acute Kidney Injury after Cardiac Surgery: A Prospective Pilot Study

Cited by 23 publications

References 88 publications

Plasma Catalytic Iron, AKI, and Death among Critically Ill Patients

Plasma Catalytic Iron, AKI, and Death among Critically Ill Patients

Lipocalin 2 alleviates iron toxicity by facilitating hypoferremia of inflammation and limiting catalytic iron generation

Aging Male Spontaneously Hypertensive Rat as an Animal Model for the Evaluation of the Interplay between Contrast-Induced Acute Kidney Injury and Cardiorenal Syndrome in Humans

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