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International Journal of Molecular... Jun 2023Neutrophil gelatinase-associated lipocalin (NGAL) is a 25-kDa protein that is secreted mostly by immune cells such as neutrophils, macrophages, and dendritic cells. Its... (Review)
Review
Neutrophil gelatinase-associated lipocalin (NGAL) is a 25-kDa protein that is secreted mostly by immune cells such as neutrophils, macrophages, and dendritic cells. Its production is stimulated in response to inflammation. The concentrations of NGAL can be measured in plasma, urine, and biological fluids such as peritoneal effluent. NGAL is known mainly as a biomarker of acute kidney injury and is released after tubular damage and during renal regeneration processes. NGAL is also elevated in chronic kidney disease and dialysis patients. It may play a role as a predictor of the progression of renal function decreases with complications and mortality due to kidney failure. NGAL is also useful in the diagnostic processes of cardiovascular diseases. It is highly expressed in injured heart tissue and atherosclerostic plaque; its serum concentrations correlate with the severity of heart failure and coronary artery disease. NGAL increases inflammatory states and its levels rise in arterial hypertension, obesity, diabetes, and metabolic complications such as insulin resistance, and is also involved in carcinogenesis. In this review, we present the current knowledge on NGAL and its involvement in different pathologies, especially its role in renal and cardiovascular diseases.
Topics: Humans; Lipocalin-2; Cardiovascular Diseases; Renal Dialysis; Kidney; Renal Insufficiency, Chronic; Acute Kidney Injury; Biomarkers
PubMed: 37445650
DOI: 10.3390/ijms241310470 -
Critical Care (London, England) Sep 2023Approximately 20% of patients with acute brain injury (ABI) also experience acute kidney injury (AKI), which worsens their outcomes. The metabolic and inflammatory... (Review)
Review
Approximately 20% of patients with acute brain injury (ABI) also experience acute kidney injury (AKI), which worsens their outcomes. The metabolic and inflammatory changes associated with AKI likely contribute to prolonged brain injury and edema. As a result, recognizing its presence is important for effectively managing ABI and its sequelae. This review discusses the occurrence and effects of AKI in critically ill adults with neurological conditions, outlines potential mechanisms connecting AKI and ABI progression, and highlights AKI management principles. Tailored approaches include optimizing blood pressure, managing intracranial pressure, adjusting medication dosages, and assessing the type of administered fluids. Preventive measures include avoiding nephrotoxic drugs, improving hemodynamic and fluid balance, and addressing coexisting AKI syndromes. ABI patients undergoing renal replacement therapy (RRT) are more susceptible to neurological complications. RRT can negatively impact cerebral blood flow, intracranial pressure, and brain tissue oxygenation, with effects tied to specific RRT methods. Continuous RRT is favored for better hemodynamic stability and lower risk of dialysis disequilibrium syndrome. Potential RRT modifications for ABI patients include adjusted dialysate and blood flow rates, osmotherapy, and alternate anticoagulation methods. Future research should explore whether these strategies enhance outcomes and if using novel AKI biomarkers can mitigate AKI-related complications in ABI patients.
Topics: Adult; Humans; Acute Kidney Injury; Continuous Renal Replacement Therapy; Brain Injuries; Brain; Blood Pressure
PubMed: 37661277
DOI: 10.1186/s13054-023-04632-1 -
Clinical and Molecular Hepatology Oct 2023Hepatorenal syndrome (HRS), a progressive but potentially reversible deterioration of kidney function, remains a major complication in patients with advanced cirrhosis,... (Review)
Review
Hepatorenal syndrome (HRS), a progressive but potentially reversible deterioration of kidney function, remains a major complication in patients with advanced cirrhosis, often leading to death before liver transplantation (LT). Recent updates in the pathophysiology, definition, and classification of HRS have led to a complete revision of the nomenclature and diagnostic criteria for HRS type 1, which was renamed HRS-acute kidney injury (AKI). HRS is characterized by severe impairment of kidney function due to increased splanchnic blood flow, activation of several vasoconstriction factors, severe vasoconstriction of the renal arteries in the absence of kidney histologic abnormalities, nitric oxide dysfunction, and systemic inflammation. Diagnosis of HRS remains a challenge because of the lack of specific diagnostic biomarkers that accurately distinguishes structural from functional AKI, and mainly involves the differential diagnosis from other forms of AKI, particularly acute tubular necrosis. The optimal treatment of HRS is LT. While awaiting LT, treatment options include vasoconstrictor drugs to counteract splanchnic arterial vasodilation and plasma volume expansion by intravenous albumin infusion. In patients with HRS unresponsive to pharmacological treatment and with conventional indications for kidney replacement therapy (KRT), such as volume overload, uremia, or electrolyte imbalances, KRT may be applied as a bridging therapy to transplantation. Other interventions, such as transjugular intrahepatic portosystemic shunt, and artificial liver support systems have a very limited role in improving outcomes in HRS. Although recently developed novel therapies have potential to improve outcomes of patients with HRS, further studies are warranted to validate the efficacy of these novel agents.
Topics: Humans; Hepatorenal Syndrome; Liver Cirrhosis; Liver Transplantation; Vasoconstrictor Agents; Acute Kidney Injury
PubMed: 37050843
DOI: 10.3350/cmh.2023.0024 -
Journal of Advanced Research Dec 2023Crush syndrome (CS) is a kind of traumatic and ischemic injury that seriously threatens life after prolonged compression. It is characterized by systemic inflammatory... (Review)
Review
BACKGROUND
Crush syndrome (CS) is a kind of traumatic and ischemic injury that seriously threatens life after prolonged compression. It is characterized by systemic inflammatory reaction, myoglobinuria, hyperkalemia and acute kidney injury (AKI). Especially AKI, it is the leading cause of death from CS. There are various cell death forms in AKI, among which ferroptosis is a typical form of cell death. However, the role of ferroptosis has not been fully revealed in CS-AKI.
AIM OF REVIEW
This review aimed to summarize the evidence of ferroptosis in CS-AKI and its related molecular mechanism, discuss the therapeutic significance of ferroptosis in CS-AKI, and open up new ideas for the treatment of CS-AKI.
KEY SCIENTIFIC CONCEPTS OF REVIEW
One of the main pathological manifestations of CS-AKI is renal tubular epithelial cell dysfunction and cell death, which has been attributed to massive deposition of myoglobin. Large amounts of myoglobin released from damaged muscle deposited in the renal tubules, impeding the normal renal tubules function and directly damaging the tubules with oxidative stress and elevated iron levels. Lipid peroxidation damage and iron overload are the distinguishing features of ferroptosis. Moreover, high levels of pro-inflammatory cytokines and damage-associated molecule pattern molecules (HMGB1, double-strand DNA, and macrophage extracellular trap) in renal tissue have been shown to promote ferroptosis. However, how ferroptosis occurs in CS-AKI and whether it can be a therapeutic target remains unclear. In our current work, we systematically reviewed the occurrence and underlying mechanism of ferroptosis in CS-AKI.
Topics: Humans; Acute Kidney Injury; Cell Death; Crush Syndrome; Ferroptosis; Myoglobin
PubMed: 36702249
DOI: 10.1016/j.jare.2023.01.016 -
Cardiovascular Diabetology Aug 2023Insulin resistance (IR) can be effectively assessed using the dependable surrogate biomarker triglyceride-glucose (TyG) index. In various critical care contexts, like...
Association between the triglyceride glucose (TyG) index and the risk of acute kidney injury in critically ill patients with heart failure: analysis of the MIMIC-IV database.
BACKGROUND
Insulin resistance (IR) can be effectively assessed using the dependable surrogate biomarker triglyceride-glucose (TyG) index. In various critical care contexts, like contrast-induced acute kidney injury (AKI), an elevated TyG index has demonstrated a robust correlation with the incidence of AKI. Nonetheless, the potential of the TyG index to predict AKI in critically ill patients with heart failure (HF) remains uncertain.
METHODS
A cohort of participants was non-consecutively selected from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database and divided into quartiles based on their TyG index values. The incidence of AKI was the primary outcome. The secondary endpoint was in-hospital mortality within both the whole study population and the subset of AKI patients. The use of the renal replacement therapy (RRT) which represented the progression of AKI severity was also included as a secondary endpoint representing renal outcome. A restricted cubic splines model and Cox proportional hazards models were utilized to evaluate the association of TyG index with the risk of AKI in patients with HF in a critical condition. Kaplan-Meier survival analysis was employed to estimate primary and secondary endpoint disparities across groups differentiated by their TyG index.
RESULTS
This study included a total of 1,393 patients, with 59% being male. The incidence of AKI was 82.8%. Cox proportional hazards analyses revealed a significant association between TyG index and the incidence of AKI in critically ill patients with HF. The restricted cubic splines model illustrated the linear relationship between higher TyG index and increased risk of AKI in this specific patient population. Furthermore, the Kaplan-Meier survival analyses unveiled statistically significant differences in the use of RRT across the subset of AKI patients based on the quartiles of the TyG index.
CONCLUSIONS
The results highlight the TyG index as a robust and independent predictor of the incidence of AKI and poor renal outcome in patients with HF in a critical condition. However, further confirmation of causality necessitates larger prospective studies.
Topics: Humans; Male; Female; Critical Illness; Prospective Studies; Acute Kidney Injury; Heart Failure; Critical Care; Glucose
PubMed: 37653418
DOI: 10.1186/s12933-023-01971-9 -
Intensive Care Medicine Sep 2023The Acute Disease Quality Initiative (ADQI) Workgroup recently released a consensus definition of sepsis-associated acute kidney injury (SA-AKI), combining Sepsis-3 and... (Observational Study)
Observational Study
Sepsis-associated acute kidney injury in the intensive care unit: incidence, patient characteristics, timing, trajectory, treatment, and associated outcomes. A multicenter, observational study.
PURPOSE
The Acute Disease Quality Initiative (ADQI) Workgroup recently released a consensus definition of sepsis-associated acute kidney injury (SA-AKI), combining Sepsis-3 and Kidney Disease Improving Global Outcomes (KDIGO) AKI criteria. This study aims to describe the epidemiology of SA-AKI.
METHODS
This is a retrospective cohort study carried out in 12 intensive care units (ICUs) from 2015 to 2021. We studied the incidence, patient characteristics, timing, trajectory, treatment, and associated outcomes of SA-AKI based on the ADQI definition.
RESULTS
Out of 84,528 admissions, 13,451 met the SA-AKI criteria with its incidence peaking at 18% in 2021. SA-AKI patients were typically admitted from home via the emergency department (ED) with a median time to SA-AKI diagnosis of 1 day (interquartile range (IQR) 1-1) from ICU admission. At diagnosis, most SA-AKI patients (54%) had a stage 1 AKI, mostly due to the low urinary output (UO) criterion only (65%). Compared to diagnosis by creatinine alone, or by both UO and creatinine criteria, patients diagnosed by UO alone had lower renal replacement therapy (RRT) requirements (2.8% vs 18% vs 50%; p < 0.001), which was consistent across all stages of AKI. SA-AKI hospital mortality was 18% and SA-AKI was independently associated with increased mortality. In SA-AKI, diagnosis by low UO only, compared to creatinine alone or to both UO and creatinine criteria, carried an odds ratio of 0.34 (95% confidence interval (CI) 0.32-0.36) for mortality.
CONCLUSION
SA-AKI occurs in 1 in 6 ICU patients, is diagnosed on day 1 and carries significant morbidity and mortality risk with patients mostly admitted from home via the ED. However, most SA-AKI is stage 1 and mostly due to low UO, which carries much lower risk than diagnosis by other criteria.
Topics: Humans; Retrospective Studies; Incidence; Creatinine; Intensive Care Units; Acute Kidney Injury; Sepsis
PubMed: 37432520
DOI: 10.1007/s00134-023-07138-0 -
Theranostics 2023Cisplatin is a widely used anti-tumor agent but its use is frequently limited by nephrotoxicity. Transient receptor potential melastatin 2 (TRPM2) is a non-selective...
Cisplatin is a widely used anti-tumor agent but its use is frequently limited by nephrotoxicity. Transient receptor potential melastatin 2 (TRPM2) is a non-selective cation channel which is generally viewed as a sensor of oxidative stress, and increasing evidence supports its link with autophagy, a critical process for organelle homeostasis. Cisplatin-induced cell injury and mitochondrial damage were both assessed in WT and knockout mice and primary cells. RNA sequencing, immunofluorescence staining, immunoblotting and flowcytometry were applied to interpret the mechanism of TRPM2 in cisplatin nephrotoxicity. Knockout of TRPM2 exacerbates renal dysfunction, tubular injury and cell apoptosis in a model of acute kidney injury (AKI) induced by treatment with cisplatin. Cisplatin-caused tubular mitochondrial damage is aggravated in TRPM2-deficient mice and cells and, conversely, alleviated by treatment with Mito-TEMPO, a mitochondrial ROS scavenger. TRPM2 deficiency hinders cisplatin-induced autophagy via blockage of Ca influx and subsequent up-regulation of AKT-mTOR signaling. Consistently, cisplatin-induced tubular mitochondrial damage, cell apoptosis and renal dysfunction in TRPM2-deficient mice are mitigated by treatment with a mTOR inhibitor. Our results suggest that the TRPM2 channel plays a protective role in cisplatin-induced AKI via modulating the Ca-AKT-mTOR signaling pathway and autophagy, providing novel insights into the pathogenesis of kidney injury.
Topics: Animals; Mice; Mice, Knockout; Cisplatin; Proto-Oncogene Proteins c-akt; TRPM Cation Channels; Acute Kidney Injury; Autophagy
PubMed: 37649595
DOI: 10.7150/thno.84655 -
Biomedicine & Pharmacotherapy =... Oct 2023Ferroptosis is an important pathological process in acute kidney injury (AKI) which could lead to chronic kidney disease (CKD) and end-stage renal disease (ESRD). As an...
Ferroptosis is an important pathological process in acute kidney injury (AKI) which could lead to chronic kidney disease (CKD) and end-stage renal disease (ESRD). As an active ingredient of Chinese medicine Tripterygium wilfordii, celastrol has been reported to alleviate inflammation and preclinical studies have confirmed its anticancer effect. In the present study, we investigated the renal protective effects of celastrol against cisplatin induced AKI. Mice were administrated cisplatin by intraperitoneal injection and we found that celastrol reduced serum levels of BUN and creatinine, inhibited renal dysfunction, inflammation and oxidative stress. In addition, renal iron accumulation and ferroptosis were significantly reduced by celastrol treatment. Further mechanistic analyses suggested that Nrf2 is essential for celastrol upregulated GPX4 to alleviate ferroptosis and reduction of LDH release, intracellular iron accumulation and lipid peroxidation. These findings expand the potential uses of celastrol for treatment of various kinds of AKI associated with ferroptosis.
Topics: Animals; Mice; NF-E2-Related Factor 2; Ferroptosis; Cisplatin; Acute Kidney Injury; Inflammation; Iron
PubMed: 37598476
DOI: 10.1016/j.biopha.2023.115333 -
Redox Biology Sep 2023Cisplatin is one of the major causes of acute kidney injury (AKI) in clinical practice, and ferroptosis is an essential form of cell death in cisplatin-induced AKI...
Cisplatin is one of the major causes of acute kidney injury (AKI) in clinical practice, and ferroptosis is an essential form of cell death in cisplatin-induced AKI (CP-AKI). WW domain binding protein-2 (WBP2), a molecular chaperon, is involved in the progression of various malignancies, but its role in renal injuries has not been investigated. Our present study employed bioinformatics analysis to identify WBP2 as a potential modulator of AKI and ferroptosis. Preliminary laboratory investigations showed that WBP2, highly expressed in renal proximal tubular cells, was downregulated in CP-AKI. Further studies demonstrated that WBP2 decelerated ferroptosis to alleviate CP-AKI. Mechanistically, WBP2 interacted with glutathione peroxidase 4 (GPX4, a key detoxicating enzyme for ferroptosis) via its PPXY1 motif to inhibit ferroptosis. Furthermore, the in-depth investigations revealed that WBP2 competed with heat shock cognate protein 70 (HSC70) for the binding with the KEFRQ-like motifs of GPX4, leading to the deceleration of chaperon-mediated autophagy of GPX4. All in all, this study indicated the beneficial effect of WBP2 in CP-AKI and its relevance with ferroptosis, thus providing a novel insight into the modulation of ferroptosis in cisplatin-related nephropathy.
Topics: Humans; Cisplatin; Ferroptosis; Acute Kidney Injury; Kidney; Cell Death; HSP70 Heat-Shock Proteins; Trans-Activators
PubMed: 37516014
DOI: 10.1016/j.redox.2023.102826 -
Europace : European Pacing,... Dec 2023Pulsed field ablation (PFA) has been proposed as a novel alternative to radiofrequency (RF) and cryoablation in the treatment of atrial fibrillation (AF). Following the...
AIMS
Pulsed field ablation (PFA) has been proposed as a novel alternative to radiofrequency (RF) and cryoablation in the treatment of atrial fibrillation (AF). Following the occurrence of two cases of acute kidney injury (AKI) secondary to haemolysis after a PFA procedure, we evaluated haemolysis in a cohort of consecutive patients.
METHODS AND RESULTS
Two cases of AKI occurred in last May and June 2023. AKI was secondary to acute and severe haemolysis after a PFA procedure. From June 2023, a total of 68 consecutive patients (64.3 ± 10.5 years) undergoing AF ablation with PFA were enrolled in the study. All patients had a blood sample the day after the procedure for the assessment of haemolysis indicators. The pentaspline PFA catheter was used with a total number of median applications of 64 (54; 76). Nineteen patients (28%) showed significantly depleted haptoglobin levels (<0.04 g/L). A significant inverse correlation was found between the plasma level of haptoglobin and the total number of applications. Two groups were compared: the haemolysis+ group (haptoglobin < 0.04 g/L) vs. the haemolysis- group. The total number of applications was significantly higher in the haemolysis+ group vs the haemolysis - group respectively 75 (62; 127) vs 62 (54; 71) P = 0.011. More than 70 applications seem to have better sensitivity and specificity to predict haemolysis.
CONCLUSION
Intravascular haemolysis can occur after certain procedures of PFA. Acute kidney injury is a phenomenon that appears to be very rare after a PFA procedure. However, caution must be exercised in the number of applications to avoid severe haemolysis.
Topics: Humans; Atrial Fibrillation; Hemolysis; Haptoglobins; Acute Kidney Injury; Catheter Ablation; Pulmonary Veins; Treatment Outcome
PubMed: 38175788
DOI: 10.1093/europace/euad371