Kidney injury induced by elevated histones in community-acquired pneumonia

Gao, Min; Wan, Xin; Ma, Mengqing; Pan, Binbin; Gendoo, Yasser; Chen, Fan; Shao, Wei; Cao, Changchun

doi:10.1007/s11010-020-03775-x

Cited by 2 publications

(2 citation statements)

References 27 publications

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“…32 It was reported that extracellular histones associate with kidney injury in infectious diseases such as sepsis and COVID-19, rhabdomyolysis, and renal ischemia-reperfusion, and it associates with the ischemic damage on the donor kidney for transplantation. [1][2][3][4][5]33,34 Histones are suggested as one of the potential molecular targets for therapeutics in the previous studies. [1][2][3][4][5] In recent studies, new efforts are also underway to remove histones by extracorporeal blood purification.…”

Section: Discussionmentioning

confidence: 99%

Urinary liver‐type fatty acid binding protein is a biomarker reflecting renal damage and the ameliorative effect of drugs at an early stage of histone‐induced acute kidney injury

Ohata,

Sugaya,

Nguyen

et al. 2023

Nephrology

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AimCirculated histones play a crucial role in the pathogenesis of infectious diseases and severe trauma, and it is one of the potential molecular targets for therapeutics. Recently, we reported that histone is one of the causative agents for urinary L‐FABP increase. However, the mechanism is still unclear, especially in severe cases. We further investigated the mechanism of urinary L‐FABP increase using a more severe mouse model with histone‐induced kidney injury. This study also aims to evaluate the therapeutic responsiveness of urinary L‐FABP as a preliminary study.MethodsHuman L‐FABP chromosomal transgenic mice were administrated 30 mg/kg histone from a tail vein with a single dose. We also performed a comparative study in LPS administration model. For the evaluation of the therapeutic responsiveness of urinary L‐FABP, we used heparin and rolipram.ResultsThe histological change with cast formation as a characteristic of the models was observed in proximal tubules. Urinary L‐FABP levels were significantly elevated and these levels tended to be higher in those with more cast formation. Heparin and rolipram had the ameliorative effect of the cast formation induced by histone and urinary L‐FABP levels significantly decreased.ConclusionHistone is one of the causative agents for the increase of urinary L‐FABP at an early stage of AKI. In addition, it suggested that urinary L‐FABP may be useful as a subclinical AKI marker reflecting kidney damage induced by histone. Furthermore, urinary L‐FABP reflected the degree of the damage after the administration of therapeutic agents such as heparin and PDE4 inhibitor.

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Section: Discussionmentioning

confidence: 99%

Urinary liver‐type fatty acid binding protein is a biomarker reflecting renal damage and the ameliorative effect of drugs at an early stage of histone‐induced acute kidney injury

Ohata,

Sugaya,

Nguyen

et al. 2023

Nephrology

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“…We defined the relationship of early serial plasma concentrations of three nucleic acid DAMPs with the development of AKI in critically ill trauma patients. Circulating nDNA, mtDNA, and nucleosomes cause kidney injury in preclinical models ( 48 , 53 – 55 ), and therapeutics targeting these DAMPs in human populations are under active study ( 17 , 19 , 20 , 23 , 24 , 26 , 28 , 54 , 56 ). Our study addresses key knowledge gaps in understanding how these targeted therapies might apply to severely injured patients, in whom pathophysiologic processes rapidly evolve.…”

Section: Discussionmentioning

confidence: 99%

Early Plasma Nuclear DNA, Mitochondrial DNA, and Nucleosome Concentrations Are Associated With Acute Kidney Injury in Critically Ill Trauma Patients

Faust

Oniyide

Wang

et al. 2022

Critical Care Explorations

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OBJECTIVES: Circulating nucleic acids, alone and in complex with histones as nucleosomes, have been proposed to link systemic inflammation and coagulation after trauma to acute kidney injury (AKI). We sought to determine the association of circulating nucleic acids measured at multiple time points after trauma with AKI risk. DESIGN: We conducted a prospective cohort study of trauma patients, collecting plasma on presentation and at 6, 12, 24, and 48 hours, defining AKI over the first 6 days by Kidney Disease Improving Global Outcomes serum creatinine and dialysis criteria. We determined kinetics of plasma mitochondrial DNA (mtDNA), nuclear DNA (nDNA), and nucleosome levels across time points and associations with AKI using multivariable linear mixed-effects models, adjusted for injury characteristics and blood transfusions. We evaluated the association of presentation nucleic acid damage-associated molecular patterns (DAMP) concentrations with subsequent AKI, adjusting for injury severity using multivariable logistic regression. SETTING: Academic level I trauma center. PATIENTS: Trauma patients (n = 55) requiring intensive care for greater than or equal to 24 hours after presentation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: AKI developed in 17 patients (31%), a median of 12.0 hours (interquartile range, 6.2–24.1 hr) after presentation. mtDNA demonstrated a time-varying association with AKI (p = 0.022, interaction with time point), with differences by AKI status not emerging until 24 hours (β = 0.97 [95% CI, 0.03–1.90] log copies/uL; p = 0.043). Patients who developed AKI had higher nDNA across all time points (overall β = 1.41 log copies/uL [0.86–1.95 log copies/uL]; p < 0.001), and presentation levels were significantly associated with subsequent AKI (odds ratio [OR], 2.55 [1.36–4.78] per log copy/uL; p = 0.003). Patients with AKI had higher nucleosome levels at presentation (β = 0.32 [0.00–0.63] arbitrary unit; p = 0.048), a difference that was more pronounced at 24 hours (β = 0.41 [0.06–0.76]; p = 0.021) and 48 hours (β = 0.71 [0.35–1.08]; p < 0.001) (p = 0.075, interaction with time point). CONCLUSIONS: Plasma nucleic acid DAMPs have distinct kinetics and associations with AKI in critically ill trauma patients. nDNA at presentation predicts subsequent AKI and may be amenable to targeted therapies in this population.

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Kidney injury induced by elevated histones in community-acquired pneumonia

Cited by 2 publications

References 27 publications

Urinary liver‐type fatty acid binding protein is a biomarker reflecting renal damage and the ameliorative effect of drugs at an early stage of histone‐induced acute kidney injury

Urinary liver‐type fatty acid binding protein is a biomarker reflecting renal damage and the ameliorative effect of drugs at an early stage of histone‐induced acute kidney injury

Early Plasma Nuclear DNA, Mitochondrial DNA, and Nucleosome Concentrations Are Associated With Acute Kidney Injury in Critically Ill Trauma Patients

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