Effects of Changes in the Levels of Damage-Associated Molecular Patterns Following Continuous Veno–Venous Hemofiltration Therapy on Outcomes in Acute Kidney Injury Patients With Sepsis

Pathophysiologically, the classification of acute kidney injury (AKI) can be divided into three categories: (1) prerenal, (2) intrinsic, and (3) postrenal. Emerging evidence supports the involvement of renal tubular epithelial cells and the innate and adaptive arms of the immune system in the pathogenesis of intrinsic AKI. Pro-inflammatory damage-associated molecular patterns, pathogen-associated molecular patterns, hypoxia inducible factors, toll-like receptors, complement system, oxidative stress, adhesion molecules, cell death, resident renal dendritic cells, neutrophils, T and B lymphocytes, macrophages, natural killer T cells, cytokines, and secreted chemokines contribute to the immunopathogenesis of AKI. However, other immune cells and pathways such as M2 macrophages, regulatory T cells, progranulin, and autophagy exhibit anti-inflammatory properties and facilitate kidney tissue repair after AKI. Thus, therapies for AKI include agents such as anti-inflammatory (e.g., recombinant alkaline phosphatase), antioxidants (iron chelators), and apoptosis inhibitors. In preclinical toxicity studies, drug-induced kidney injury can be seen after exposure to a nephrotoxicant test article due to immune mechanisms and dysregulation of innate, and/or adaptive cellular immunity. The focus of this review will be on intrinsic AKI, as it relates to the immune and renal systems cross talks focusing on the cellular and pathophysiologic mechanisms of AKI.

Download Full-text

Toll-like Receptors as Potential Therapeutic Targets in Kidney Diseases

Current Medicinal Chemistry ◽

10.2174/0929867325666190603110907 ◽

2020 ◽

Vol 27 (34) ◽

pp. 5829-5854 ◽

Cited By ~ 1

Author(s):

Qian Ren ◽

Lu Cheng ◽

Jing Yi ◽

Liang Ma ◽

Jing Pan ◽

...

Keyword(s):

Acute Kidney Injury ◽

Kidney Diseases ◽

Kidney Injury ◽

Host Immunity ◽

Toll Like Receptors ◽

Chronic Kidney Diseases ◽

Inflammatory Cascade ◽

Molecular Patterns ◽

Dying Cells ◽

Damage Associated Molecular Patterns

Toll-like Receptors (TLRs) are members of pattern recognition receptors and serve a pivotal role in host immunity. TLRs response to pathogen-associated molecular patterns encoded by pathogens or damage-associated molecular patterns released by dying cells, initiating an inflammatory cascade, where both beneficial and detrimental effects can be exerted. Accumulated evidence has revealed that TLRs are closely associated with various kidney diseases but their roles are still not well understood. This review updated evidence on the roles of TLRs in the pathogenesis of kidney diseases including urinary tract infection, glomerulonephritis, acute kidney injury, transplant allograft dysfunction and chronic kidney diseases.

Download Full-text

Pathogen-Associated Molecular Patterns, Damage-Associated Molecular Patterns, and Their Receptors in Acute Kidney Injury

Critical Care Nephrology ◽

10.1016/b978-0-323-44942-7.00021-2 ◽

2019 ◽

pp. 121-127.e3

Author(s):

David R. Emlet ◽

Hernando Gomez ◽

John A. Kellum

Keyword(s):

Acute Kidney Injury ◽

Kidney Injury ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns

Download Full-text

Role of Damage-Associated Molecular Patterns in Septic Acute Kidney Injury, From Injury to Recovery

Frontiers in Immunology ◽

10.3389/fimmu.2021.606622 ◽

2021 ◽

Vol 12 ◽

Author(s):

Pierre-Olivier Ludes ◽

Charles de Roquetaillade ◽

Benjamin Glenn Chousterman ◽

Julien Pottecher ◽

Alexandre Mebazaa

Keyword(s):

Acute Kidney Injury ◽

Tissue Injury ◽

High Mobility ◽

Kidney Injury ◽

Blood Perfusion ◽

Tubular Damage ◽

Organ Protection ◽

Tubular Necrosis ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns

Damage-associated molecular patterns (DAMPs) are a group of immunostimulatory molecules, which take part in inflammatory response after tissue injury. Kidney-specific DAMPs include Tamm-Horsfall glycoprotein, crystals, and uromodulin, released by tubular damage for example. Non-kidney-specific DAMPs include intracellular particles such as nucleus [histones, high-mobility group box 1 protein (HMGB1)] and cytosol parts. DAMPs trigger innate immunity by activating the NRLP3 inflammasome, G-protein coupled class receptors or the Toll-like receptor. Tubular necrosis leads to acute kidney injury (AKI) in either septic, ischemic or toxic conditions. Tubular necrosis releases DAMPs such as histones and HMGB1 and increases vascular permeability, which perpetuates shock and hypoperfusion via Toll Like Receptors. In acute tubular necrosis, intracellular abundance of NADPH may explain a chain reaction where necrosis spreads from cell to cell. The nature AKI in intensive care units does not have preclinical models that meet a variation of blood perfusion or a variation of glomerular filtration within hours before catecholamine infusion. However, the dampening of several DAMPs in AKI could provide organ protection. Research should be focused on the numerous pathophysiological pathways to identify the relative contribution to renal dysfunction. The therapeutic perspectives could be strategies to suppress side effect of DAMPs and to promote renal function regeneration.

Download Full-text

The Mechanism of Contrast-Induced Acute Kidney Injury and Its Association with Diabetes Mellitus

Contrast Media & Molecular Imaging ◽

10.1155/2020/3295176 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Yanfei Li ◽

Ke Ren

Keyword(s):

Diabetes Mellitus ◽

Acute Kidney Injury ◽

Signaling Pathways ◽

Kidney Injury ◽

Renal Perfusion ◽

Ion Pump ◽

Predisposing Factor ◽

Vasoactive Substances ◽

Molecular Patterns ◽

Hospital Acquired

Contrast-induced acute kidney injury (CI-AKI) is the third most common hospital-acquired AKI after AKI induced by renal perfusion insufficiency and nephrotoxic drugs, taking great adverse effects on the prognosis and increasing hospital stay and medical cost. Diabetes nephropathy (DN) is a common chronic complication of DM (diabetes mellitus), and DN is an independent risk factor for chronic kidney disease (CKD) and CI-AKI. The incidence of CI-AKI significantly increases in patients with renal injury, especially in DM-related nephropathy. The etiology of CI-AKI is not fully clear, and research studies on how DM becomes a facilitated factor of CI-AKI are limited. This review describes the mechanism from three aspects. ① Pathophysiological changes of CI-AKI in kidney under high-glucose status (HGS). HGS can enhance the oxidative stress and increase ROS which next causes stronger vessel constriction and insufficient oxygen supply in kidney via vasoactive substances. HGS also aggravates some ion pump load and the latter increases oxygen consumption. CI-AKI and HGS are mutually causal, making the kidney function continue to decline. ② Immunological changes of DM promoting CI-AKI. Some innate immune cells and pattern recognition receptors (PRRs) in DM and/or DN may respond to some damage-associated molecular patterns (DAMPs) formed by CI-AKI. These effects overlap with some pathophysiological changes in hyperglycemia. ③ Signaling pathways related to both CI-AKI and DM. These pathways involved in CI-AKI are closely associated with apoptosis, inflammation, and ROS production, and some studies suggest that these pathways may be potential targets for alleviating CI-AKI. In conclusion, the pathogenesis of CI-AKI and the mechanism of DM as a predisposing factor for CI-AKI, especially signaling pathways, need further investigation to provide new clinical approaches to prevent and treat CI-AKI.

Download Full-text

Apoptotic cell therapy for cytokine storm associated with acute severe sepsis

Cell Death and Disease ◽

10.1038/s41419-020-02748-8 ◽

2020 ◽

Vol 11 (7) ◽

Author(s):

Netanel Karbian ◽

Avraham Abutbul ◽

Raja el-Amore ◽

Ran Eliaz ◽

Ronen Beeri ◽

...

Keyword(s):

Severe Sepsis ◽

Apoptotic Cell ◽

White Blood Cells ◽

Cecal Ligation ◽

Kidney Injury ◽

Lung Dysfunction ◽

Sepsis Score ◽

Cardiovascular Evaluation ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns

Abstract Sepsis has no proven pharmacologic treatment other than appropriate antibiotic agents, fluids, vasopressors as needed, and possibly corticosteroids. It is generally initiated mainly by the simultaneous recognition by various components of the innate immune system of either pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). In the current study, we employed the murine cecal ligation and puncture (CLP) model for sepsis to evaluate the effect of post-CLP infusion of apoptotic cells (Allocetra-OTS) on a CLP severe sepsis model. Cardiovascular evaluation, acute kidney injury (AKI), acute liver injury (ALI), and hematological and metabolic function were evaluated. Cytokine and chemokine profiles were measured by Multiplex ELISA and mitochondrial function, and glycolysis by Seahorse. The Murine Sepsis Score (MSS) was used for disease severity definition. CLP mice had low blood pressure, poor cardiac output, and lung dysfunction, as well as AKI, ALI, and thrombocytopenia, which correlated with the MSS and corresponded to a cytokine/chemokine storm. Apoptotic cell administration markedly improved the cytokine and chemokine storm and restored the impaired mitochondrial and glycolytic function in white blood cells leading to increased survival, from 6 to 60% (P < 0.0001), together with a significant improvement in organ dysfunction. We conclude that the deleterious immune response in CLP-induced sepsis can be successfully modified by apoptotic cell infusion.

Download Full-text

Histone H3 Cleavage in Severe COVID-19 ICU Patients

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.694186 ◽

2021 ◽

Vol 11 ◽

Author(s):

Joram Huckriede ◽

Femke de Vries ◽

Michael Hultström ◽

Kanin Wichapong ◽

Chris Reutelingsperger ◽

...

Keyword(s):

Inflammatory Diseases ◽

Secondary Infection ◽

Treatment Options ◽

Histone H3 ◽

Kidney Injury ◽

Neutrophil Extracellular Trap ◽

Icu Patients ◽

Extracellular Histones ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns

The severity of coronavirus disease 19 (COVID-19) is associated with neutrophil extracellular trap (NET) formation. During NET formation, cytotoxic extracellular histones are released, the presence of which is linked to the initiation and progression of several acute inflammatory diseases. Here we study the presence and evolution of extracellular histone H3 and several other neutrophil-related molecules and damage-associated molecular patterns (DAMPs) in the plasma of 117 COVID-19-positive ICU patients. We demonstrate that at ICU admission the levels of histone H3, MPO, and DNA-MPO complex were all significantly increased in COVID-19-positive patients compared to control samples. Furthermore, in a subset of 54 patients, the levels of each marker remained increased after 4+ days compared to admission. Histone H3 was found in 28% of the patients on admission to the ICU and in 50% of the patients during their stay at the ICU. Notably, in 47% of histone-positive patients, we observed proteolysis of histone in their plasma. The overall presence of histone H3 during ICU stay was associated with thromboembolic events and secondary infection, and non-cleaved histone H3 was associated with the need for vasoactive treatment, invasive ventilation, and the development of acute kidney injury. Our data support the validity of treatments that aim to reduce NET formation and additionally underscore that more targeted therapies focused on the neutralization of histones should be considered as treatment options for severe COVID-19 patients.

Download Full-text

Recombinant human soluble thrombomodulin is associated with attenuation of sepsis-induced renal impairment by inhibition of extracellular histone release

10.1101/780403 ◽

2019 ◽

Author(s):

Masayuki Akatsuka ◽

Yoshiki Masuda ◽

Hiroomi Tatsumi ◽

Michiaki Yamakage

Keyword(s):

Histone H3 ◽

Cecal Ligation ◽

Kidney Injury ◽

Treated Group ◽

Cecal Ligation And Puncture ◽

Soluble Thrombomodulin ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns ◽

Vehicle Treated Group ◽

Recombinant Human Soluble Thrombomodulin

AbstractMultiple organ dysfunction induced by sepsis often involves kidney injury. Extracellular histones released in response to damage-associated molecular patterns are known to facilitate sepsis-induced organ dysfunction. Recombinant human soluble thrombomodulin (rhTM) and its lectin-like domain (D1) exert anti-inflammatory effects and neutralize damage-associated molecular patterns. However, the effects of rhTM and D1 on extracellular histone H3 levels and kidney injury remain poorly understood. Our purpose was to investigate the association between extracellular histone H3 levels and kidney injury, and to clarify the effects of rhTM and D1 on extracellular histone H3 levels, kidney injury, and survival in sepsis-induced rats. Rats in whom sepsis was induced via cecal ligation and puncture were used in this study. Histone H3 levels, histopathology of the kidneys, and the survival rate of rats at 24 h after cecal ligation and puncture were investigated. Histone H3 levels increased over time following cecal ligation and puncture. Histopathological analyses indicated that the distribution of degeneration foci among tubular epithelial cells of the kidney and levels of histone H3 increased simultaneously. Administration of rhTM and D1 significantly reduced histone H3 levels compared with that in the vehicle-treated group and improved kidney injury. The survival rates of rats in rhTM- and D1-treated groups were significantly higher than that in the vehicle-treated group. The results of this study indicated that rhTM and its D1 similarly reduce elevated histone H3 levels, thereby reducing acute kidney injury. Our findings also proposed that rhTM and D1 show potential as new treatment strategies for sepsis combined with acute kidney injury.

Download Full-text