Cause Of Acute Kidney Injury Research Articles

Ultrasound analysis of different forms of hemolytic uremic syndrome in children

BackgroundHemolytic uremic syndrome (HUS) is the most common cause of acute kidney injury in children. It is mainly caused by Shiga toxin-producing enterohemorrhagic Escherichia coli (EHEC; STEC-HUS) and is more rarely caused by uncontrolled complement activation (cHUS). Renal replacement therapy is frequently required and kidney function recovers in the majority of patients. Ultrasound (US) is the preferred imaging modality for the evaluation of any renal failure. The aim of this study is the evaluation of US diagnostics in both HUS types at disease onset and in the course of the disease.Materials and methodsClinical, laboratory, and US data from the digital patient records of children admitted as inpatients with a diagnosis of HUS were recruited for a monocentric, retrospective analysis. STEC-HUS and cHUS were diagnosed when, in addition to the laboratory constellation, EHEC infection and complement system activation were verified, respectively. US examinations were performed by pediatricians with certified pediatric US experience.ResultsIn total, 30 children with STEC-HUS (13/25 male; median age of disease onset 2.9 years; most prevalent EHEC serotype was O157) and cHUS (2/5 male; median age of disease onset 5.4 years; 3/5 with proven pathogenic variation) were included. Renal replacement therapy proportions were comparable in the STEC-HUS and cHUS patients (64% vs. 60%). The resistance index (RI) was elevated at disease onset in the patients with STEC-HUS and cHUS (0.88 ± 0.10 vs. 0.77 ± 0.04, p = 0.13) and was similar in the STEC-HUS subcohorts divided based on dialysis requirement (yes: 0.86 ± 0.1; no: 0.88 ± 0.1; p = 0.74). Total kidney size at disease onset displayed a positive correlation with dialysis duration (R = 0.53, p = 0.02) and was elevated in both HUS types (177% ± 56 and 167% ± 53). It was significantly higher in the STEC-HUS subcohort which required dialysis (200.7% vs. 145%, p < .029), and a regressor kidney size threshold value of 141% was indicated in the receiver operating characteristic analysis. A classification model using both US parameters sequentially might be of clinical use for predicting the need for dialysis in patients with STEC-HUS. The US parameters normalized over time.ConclusionThe US parameters of RI and total kidney size are valuable for the assessment of HUS at disease onset and during therapy, and may be helpful in the assessment of whether dialysis is required in patients with STEC-HUS.

M6A demethylase FTO transcriptionally activated by SP1 improves ischemia reperfusion-triggered acute kidney injury by activating Ambra1/ULK1-mediated autophagy.

Ischemia reperfusion (I/R) was considered as one of main causes of acute kidney injury (AKI). However, the exact mechanism remains unclear. Here, this study aimed to investigate the role and mechanism of the m6A demethylase fat mass and obesity-associated (FTO) protein in I/R-induced AKI. HK-2 cells and SD rats were utilized to establish hypoxia/reoxygenation (H/R) or I/R induced AKI models. The changes of RNAs and proteins were quantified using RT-qPCR, western blot, and immunofluorescence assays, respectively. Cell proliferation and apoptosis were assessed by CCK-8 and flow cytometry. Interactions between molecules were investigated using RIP, ChIP, Co-IP, RNA pull-down, and dual luciferase reporter assays. Global m6A quantification was evaluated by kits. TUNEL and HE staining were employed for histopathological examinations. Oxidative stress-related indicators and renal function were determined using ELISA assays. The FTO expression was downregulated in H/R-induced HK-2 cells and renal tissues from I/R-induced rats. Overexpression of FTO improved the cell viability but repressed apoptosis and oxidative stress in H/R-treated HK-2 cells, as well as enhanced renal function and alleviated kidney injury in I/R rats. Notably, the FTO overexpression significantly increased autophagy-related LC3 and ULK1 levels. When autophagy was inhibited, the protective effects of FTO in AKI were diminished. Notably, Ambra1, a crucial regulator of autophagy, was repressed in H/R-induced HK-2 cells. However, the FTO overexpression restored the Ambra1 expression by reducing m6A modification of its mRNA. SP1, acting as an upstream transcription factor, directly interacts with the FTO promoter to enhance FTO expression. Knockdown of SP1 or Ambra1 suppressed the beneficial effects of FTO upregulation on autophagy and oxidative stress injury in H/R-stimulated cells. FTO, transcriptionally activated by SP1, promoted autophagy by upregulating Ambra1/ULK1 signaling, thereby inhibiting oxidative stress and kidney injury. These findings may provide some novel insights for AKI treatment.

Early intervention in viper bites: a potential strategy to mitigate acute kidney injury and its long-term consequences

Dear Editor, By this letter we intend to highlight the close association between snake bites and acute kidney injury, as the causative snakes are common natives of Tropical regions and a common cause of death because of being poorly managed. Snake bites are a significant cause of acute kidney injury in tropical regions, particularly in Eastern Pakistan, where Russell's viper, a common cause, is prevalent. The farmlands of Sindh and Balochistan are predisposed to snake bites due to their favorable weather and vast fields. A 2020 study found 454 snakebite cases in Southern Sindh, with 6 deaths. The most common mechanisms are venom-mediated consumption coagulopathy (VMCC) and endothelial damage, leading to systemic bleeding diathesis and decreased perfusion of end organs. Long-term effects of snake bites include worsening renal conditions and progression towards end-stage renal disease. Eastern Pakistan commonly harbors Russell’s viper- a frequent cause of snakebite-associated mortality, which belongs to the Viperidae family and is famously known to produce vasculotoxic venom. (1) The farmlands of Sindh and Balochistan are predisposed to snake bites as the weather of these regions and the vast fields allow the vipers to flourish and thrive well. A study conducted in 2020, representing the population of Southern Sindh, demonstrated a total of 454 cases of snakebite in a span of 1 year, out of which 6 victims died. (2) Since the prevalence of vipers is common in the district of Sindh, the deaths could be attributable to the hemorrhagic manifestations of vipers' bites. The most significant mechanisms underlying viper bite presentations are venom-mediated consumption coagulopathy (VMCC) and endothelial damage resulting in systemic bleeding diathesis, which together contribute to decreased perfusion of end organs like the heart, kidneys, brain, or gastrointestinal system. (3) VMCC is a major contributor to acute kidney injury (AKI), a common outcome of vasculotoxic snake bites, along with enzymatic dissolution of the glomerular basement membrane (BM) by the venom metalloproteinases. (4) The hemorrhagic deterioration of the vessels leads to ischemic nephropathy, and the impaired BM allows proteinuria, hemoglobinuria, and increased creatinine, often predisposing the victim to timely dialysis. A study concluded that individuals with co-morbidities are more susceptible to developing long-term effects of snake bites like worsening renal conditions such as new-onset hypertension, dialysis dependence, and end-stage renal disease. (5) ---Continue

Non-Steroidal Anti-Inflammatory Drugs: What Is the Actual Risk of Chronic Kidney Disease? A Systematic Review and Meta-Analysis.

Non-steroidal anti-inflammatory drugs (NSAIDs) are common cause of acute kidney injury, but chronic kidney disease (CKD) risk of NSAIDs is controversial. Prior systematic reviews are outdated with some methodological flaws. We conducted this systematic review to clarify the association between chronic NSAIDs use and occurrence and/or progression of CKD. MEDLINE, Cochrane Library, Web of Science and Science direct were searched for observational and interventional studies from inception to May 2023. Qualitative synthesis was performed. The meta-analysis used pooled odds ratios (OR) and hazard ratios (HR) to estimate the association between chronic NSAID use and CKD occurrence or progression. Forty studies with a total of 1757118 participants were included in the systematic review; of them 39 studies were suitable for meta-analysis. 56% of our included studies were recent, published within the last 10 years. The meta-analysis revealed a significant association between chronic NSAIDs use and CKD occurrence and progression. The pooled odds ratio was 1.24 (95% CI: 1.11-1.39, p <0.001, I² = 91.21%), and the pooled hazard ratio was 1.50 (95% CI: 1.31-1.7, p <0.001, I² = 90.77%). The pooled hazard ratio (HR) for individuals with no CKD at baseline was 1.31 (95% CI, 1.26-1.40), while for those with preexisting CKD, the HR was significantly higher at 1.67 (95% CI, 1.38-2.02). The HR for individuals with no specific chronic disease was 1.6 (95% CI, 1.32-1.94). For populations with diabetes mellitus (DM) and/or hypertension (HTN), the HR was 1.35 (95% CI, 1.27-1.43), and for those with rheumatic disease, the HR was 1.36 (95% CI, 0.88-2.10). Long-term NSAID use increases the risk of chronic kidney disease (CKD) occurrence and progression, especially in individuals with pre-existing CKD, who have a 67% risk compared to the general population's 60%. A patient-centered approach for safe and effective pain management is crucial, with special caution for those with pre-existing CKD.

Protective effect of reduced glutathione on acute kidney injury in lung cancer patients treated with cisplatin: a retrospective cohort study

Background Cisplatin is a common cause of acute kidney injury (AKI) during chemotherapy for lung cancer, and the nephrotoxicity limits its clinical use. Reduced glutathione (GSH) is a major component of the cellular antioxidant defense system and performs important physiological functions. The aim of this study was to analyze the protective effect of GSH on AKI in lung cancer patients treated with cisplatin. Methods The clinical data were retrospectively collected from lung cancer patients treated with cisplatin at our hospital between 1 January and 31 December 2019. The patients were divided into AKI group and non-AKI group based on whether AKI occurred, and into GSH group and non-GSH group based on whether GSH was used. Univariate and multivariate logistic regressions were used to analyze the risk factors for AKI. Results A total of 1372 lung cancer patients treated with cisplatin were enrolled. Of these patients, 231 patients (16.8%) developed AKI. The incidence of AKI was lower in the GSH group compared with the non-GSH group (10.6% vs. 18%, p = 0.009). Multivariate logistic regression analysis indicated that older age (OR = 1.045, 95% CI 1.025–1.065, p < 0.001), anemia (OR = 2.436, 95% CI 1.800–3.298, p < 0.001), higher SUA levels (OR = 1.002, 95% CI 1.000–1.004, p = 0.012), higher total amount of cisplatin per cycle (OR = 1.015, 95% CI 1.004–1.025, p = 0.005), and combination with paclitaxel (OR = 2.099, 95% CI 1.435–3.070, p < 0.001) were independent risk factors for AKI in lung cancer patients treated with cisplatin, whereas GSH (OR = 0.573, 95% CI 0.353–0.931, p = 0.025) and mannitol (OR = 0.229, 95% CI 0.055–0.963, p = 0.044) reduced the risk of AKI. Conclusion GSH was an independent protective factor against AKI in lung cancer patients treated with cisplatin and could be considered for clinical use in these patients to better protect renal function.

Monte Carlo simulations of cefepime in children receiving continuous kidney replacement therapy support continuous infusions for target attainment

BackgroundSepsis is a leading cause of acute kidney injury requiring continuous kidney replacement therapy (CKRT) and CKRT can alter drug pharmacokinetics (PK). Cefepime is used commonly in critically ill children and is cleared by CKRT, yet data regarding cefepime PK and pharmacodynamic (PD) target attainment in children receiving CKRT are scarce, so we performed Monte Carlo simulations (MCS) of cefepime dosing strategies in children receiving CKRT.MethodsWe developed a CKRT “module” in the precision dosing software Edsim++. The module was added into a pediatric cefepime PK model. 1000-fold MCS were performed using six dosing strategies in patients aged 2–25 years and ≥ 10 kg with differing residual kidney function (estimated glomerular filtration rate of 5 vs 30 mL/min/1.73 m2), CKRT prescriptions, (standard-dose total effluent flow of 2500 mL/h/1.73 m2 vs high-dose of 8000 mL/h/1.73 m2), and fluid accumulation (0–30%). Probability of target attainment (PTA) was defined by percentage of patients with free concentrations exceeding bacterial minimum inhibitory concentration (MIC) for 100% of the dosing interval (100% fT > 1xMIC) and 4xMIC using an MIC of 8 mg/L for Pseudomonas aeruginosa.ResultsAssuming standard-dose dialysis and minimal kidney function, > 90% PTA was achieved for 100% fT > 1x MIC with continuous infusions (CI) of 100–150 mg/kg/day (max 4/6 g) and 4-h infusions of 50 mg/kg (max 2 g), but > 90% PTA for 100% fT > 4x MIC was only achieved by 150 mg/kg CI. Decreased PTA was seen with less frequent dosing, shorter infusions, higher-dose CKRT, and higher residual kidney function.ConclusionsOur new CKRT-module was successfully added to an existing cefepime PK model for MCS in young patients on CKRT. When targeting 100% fT > 4xMIC or using higher-dose CKRT, CI would allow for higher PTA than intermittent dosing.

The frequency, risk factors, onset time, and outcome of acute kidney injury induced by vancomycin, colistin, and liposomal amphotericin B in hospitalized patients

Introduction: Medications are among the major causes of acute kidney injury (AKI) in hospitalized patients. Objectives: This study aimed to explore the frequency, characteristics, risk factors, and clinical outcomes of AKI induced by vancomycin, colistin, and liposomal amphotericin B (L-AmB) in hospitalized patients across various wards of two educational hospitals in Shiraz, Iran. Patients and Methods: From October 2022 to May 2023, an observational cross-sectional study was conducted in both intensive care unit (ICU) and non-ICU wards of Namazi and Shahid Faghihi hospitals, Shiraz, Iran. Patients aged 18 and older, without a documented history of AKI or chronic kidney disease, scheduled to receive treatment with vancomycin, colistin, or L-AmB for at least one week, were considered eligible. Relevant data, including demographic, clinical, and laboratory findings, were collected. Results: AKI was observed in 36 (34.3%) out of 105 patients during treatment. The incidence rates of AKI were 29%, 55%, and 31.1% in vancomycin, colistin, and L-AmB recipients, respectively. The mean ± SD time to AKI onset was 5.44 ± 2.04 days (range; 3 to 13 days). Dehydration at admission significantly increased the risk of antibiotic-induced AKI (odds ratio [OR] = 3.686, 95% confidence interval [CI] = 1.226–11.081, P = 0.020). Co-administration of aminoglycosides (OR = 8.422, 95% CI = 1.846 – 38.426, P = 0.006), diuretics (OR = 3.763, 95% CI = 1.092–12.965, P = 0.036), and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (OR = 7.149, 95% CI = 1.534–33.308, P = 0.012) were also identified as independent risk factors. The in-hospital mortality rate was significantly higher in patients with AKI than in those without AKI (8.6% vs. 6.7%; P &lt; 0.044). Conclusion: AKI induced by vancomycin, colistin, and L-AmB occurred in about one-third of our study population, primarily within five days of initiating treatment. Dehydration and co-administration of nephrotoxic medications were significantly associated with AKI. Clinicians should explicitly address these factors in preventive strategies to reduce antibiotic-induced AKI in hospitalized patients.

Clinicopathological Characteristics and Kidney Outcomes in Biopsy-Confirmed Acute Interstitial Nephritis

IntroductionAcute interstitial nephritis (AIN) is a significant cause of acute kidney injury, with varying etiologies and outcomes. This study aimed to examine the causes, clinical characteristics, management, and kidney outcomes in patients with biopsy-confirmed AIN. MethodsA retrospective review was conducted on 166 patients diagnosed with AIN via kidney biopsy at Mayo Clinic between 2012 and 2023. Demographic, clinical, laboratory, and pathological data were collected. The primary outcome was kidney function recovery within the first six months. Statistical analyses included univariable and multivariable logistic regression, Kaplan-Meier survival analysis, and Cox proportional hazards modeling. ResultsMedications were the primary cause of AIN (67%), followed by autoimmune diseases (20%) and infections (6%). Within six months, 76% of patients achieved kidney recovery. Multivariable analysis indicated that moderate to severe interstitial fibrosis and tubular atrophy (IFTA) and dialysis requirement were associated with non-recovery, whereas a prebiopsy diagnosis of AIN was positively associated with kidney recovery. Drug-related AIN had higher recovery rates compared to all other causes (81% versus 66%, P = 0.04), and moderate to severe IFTA and dialysis need remained significant predictors for decreased recovery. Steroid therapy, used in 81% of patients, did not significantly influence kidney recovery in the overall cohort or in drug-induced AIN. ConclusionThis study provides insights into the characteristics and outcomes of biopsy-confirmed AIN. IFTA and dialysis requirement were significant factors associated with worse kidney outcomes. These findings may help inform clinical management and prognostication in AIN patients.

Potential nephroprotective effect of dapagliflozin against renal ischemia reperfusion injury in rats via activation of autophagy pathway and inhibition of inflammation, oxidative stress and apoptosis

Renal ischemia/reperfusion injury is a common cause of acute kidney injury (AKI), causing tissue damage, inflammation and oxidative stress. Autophagy, responsible for breakdown and recycling of cytoplasmic components. In hypoxic and ischemic renal damage, autophagy may serve as a survival strategy for the cells. Dapagliflozin has been shown to have protective effects against ischemia. Objective: The study investigates the potential nephro-protective effects of dapagliflozin on renal ischemia reperfusion injury, evaluating its antioxidant, anti-inflammatory, anti-apoptotic effects and activation of autophagy via biochemical parameters and histopathological changes in adult male rats. Material and method: In this study, twenty eight male rats weighing between 200-300g, were divided into 4 groups sham, RIRI, DMSO, Dapagliflozin pretreated groups. All groups subjected to 30 min. of ischemia then 24 h of reperfusion except sham undergo the same anesthesia and surgical procedures except for bilateral renal ischemia. Dapagliflozin 1mg/kg and DMSO was given 2 hours before the induction of ischemia. Results: The study found that blood urea and serum creatinine levels increased in RIRI and DMSO groups when compared with sham group. Renal tissue levels of IL-6, Kim-1, caspase-3, LC-3 and Akt were also elevated in RIRI while GSH levels decreased in the RIRI. Dapagliflozin group showed significant increases in GSH, LC-3 and Akt levels when compared to sham group. Dapagliflozin reduced serum urea and creatinine levels, and renal tissue levels of IL-6, Kim-1, and caspase-3 also reduced. Conclusion: Dapagliflozin significantly reduced renal damage in rat model due to its antioxidant, anti-inflammatory, anti-apoptotic, and activation autophagy.

Malate dehydrogenase-2 inhibition shields renal tubular epithelial cells from anoxia-reoxygenation injury by reducing reactive oxygen species.

Ischemia-reperfusion (I-R) injury is the most common cause of acute kidney injury. In experiments involving primary human renal proximal tubular epithelial cells (RPTECs) exposed to anoxia-reoxygenation, we explored the hypothesis that mitochondrial malate dehydrogenase-2 (MDH-2) inhibition redirects malate metabolism from the mitochondria to the cytoplasm, towards the malate-pyruvate cycle and reversed malate-aspartate shuttle. Colorimetry, fluorometry, and western blotting showed that MDH2 inhibition accelerates the malate-pyruvate cycle enhancing cytoplasmic NADPH, thereby regenerating the potent antioxidant reduced glutathione. It also reversed the malate-aspartate shuttle and potentially diminished mitochondrial reactive oxygen species (ROS) production by transferring electrons, in the form of NADH, from the mitochondria to the cytoplasm. The excessive ROS production induced by anoxia-reoxygenation led to DNA damage and protein modification, triggering DNA damage and unfolded protein response, ultimately resulting in apoptosis and senescence. Additionally, ROS induced lipid peroxidation, which may contribute to the process of ferroptosis. Inhibiting MDH-2 proved effective in mitigating ROS overproduction during anoxia-reoxygenation, thereby rescuing RPTECs from death or senescence. Thus, targeting MDH-2 holds promise as a pharmaceutical strategy against I-R injury.

The negative feedback loop of NF-κB/miR-202-5p/HMGB2 attenuates sepsis induced acute kidney injury

Sepsis represents a primary cause of acute kidney injury (AKI), yet the underlying mechanisms of septic AKI remain poorly understood. Thus, there exists an urgent need for a deeper understanding of its underlying mechanisms and the development of effective therapeutic strategies. Our study reveals a notable induction in microRNA-202-5p (miR-202-5p) levels within renal tubular cells in septic AKI both in vivo and in vitro models. Treatment of renal tubular cells with LPS induced NF-κB activation, which was linked to the induction of miR-202-5p. ChIP assays confirmed NF-κB binding to the miR-202-5p gene promoter upon LPS stimulation. Functionally, miR-202-5p mimics attenuated tubular cell death, kidney injury, and intra-renal inflammatory cytokine production, whereas inhibition of miR-202-5p conferred injurious effects in septic AKI. Notably, miR-202-5p suppressed the expression of High Mobility Group Box 2 (HMGB2) in both in vitro and in vivo septic AKI models. Luciferase microRNA target assays further validated HMGB2 as a direct target of miR-202-5p. Knockdown of HMGB2 inhibits LPS-induced NF-κB activation in septic AKI, as evidenced by HMGB2 siRNA transfection significantly inhibited the nuclear translocation of NF-κB. Together, these findings elucidate the NF-κB/miR-202-5p/HMGB2 negative feedback loop which can attenuate kidney injury by inhibiting renal inflammation in septic AKI. Our findings open new avenues for developing targeted therapies to manage septic AKI effectively.

ANKRD1 aggravates renal ischaemia‒reperfusion injury via promoting TRIM25-mediated ubiquitination of ACSL3.

Renal ischaemia‒reperfusion injury (IRI) is the primary cause of acute kidney injury (AKI). To date, effective therapies for delaying renal IRI and postponing patient survival remain absent. Ankyrin repeat domain 1 (ANKRD1) has been implicated in some pathophysiologic processes, but its role in renal IRI has not been explored. The mouse model of IRI-AKI and in vitro model were utilised to investigate the role of ANKRD1. Immunoprecipitation-mass spectrometry was performed to identify potential ANKRD1-interacting proteins. Protein‒protein interactions and protein ubiquitination were examined using immunoprecipitation and proximity ligation assay and immunoblotting, respectively. Cell viability, damage and lipid peroxidation were evaluated using biochemical and cellular techniques. First, we unveiled that ANKRD1 were significantly elevated in renal IRI models. Global knockdown of ANKRD1 in all cell types of mouse kidney by recombinant adeno-associated virus (rAAV9)-mitigated ischaemia/reperfusion-induced renal damage and failure. Silencing ANKRD1 enhanced cell viability and alleviated cell damage in human renal proximal tubule cells exposed to hypoxia reoxygenation or hydrogen peroxide, while ANKRD1 overexpression had the opposite effect. Second, we discovered that ANKRD1's detrimental function during renal IRI involves promoting lipid peroxidation and ferroptosis by directly binding to and decreasing levels of acyl-coenzyme A synthetase long-chain family member 3 (ACSL3), a key protein in lipid metabolism. Furthermore, attenuating ACSL3 in vivo through pharmaceutical approach and in vitro via RNA interference mitigated the anti-ferroptotic effect of ANKRD1 knockdown. Finally, we showed ANKRD1 facilitated post-translational degradation of ACSL3 by modulating E3 ligase tripartite motif containing 25 (TRIM25) to catalyse K63-linked ubiquitination of ACSL3, thereby amplifying lipid peroxidation and ferroptosis, exacerbating renal injury. Our study revealed a previously unknown function of ANKRD1 in renal IRI. By driving ACSL3 ubiquitination and degradation, ANKRD1 aggravates ferroptosis and ultimately exacerbates IRI-AKI, underlining ANKRD1's potential as a therapeutic target for kidney IRI. Ankyrin repeat domain 1 (ANKRD1) is rapidly activated in renal ischaemia‒reperfusion injury (IRI) models in vivo and in vitro. ANKRD1 knockdown mitigates kidney damage and preserves renal function. Ferroptosis contributes to the deteriorating function of ANKRD1 in renal IRI. ANKRD1 promotes acyl-coenzyme A synthetase long-chain family member 3 (ACSL3) degradation via the ubiquitin‒proteasome pathway. The E3 ligase tripartite motif containing 25 (TRIM25) is responsible for ANKRD1-mediated ubiquitination of ACSL3.

AST-120 alleviates renal ischemia-reperfusion injury by inhibiting HK2-mediated glycolysis

ObjectiveRenal ischemia/reperfusion injury (IRI) is a major cause of acute kidney injury (AKI), which is associated with high incidence and mortality. AST-120 is an oral carbonaceous adsorbent that can alleviate kidney damage. This study aimed to explore the effects of AST-120 on renal IRI and the molecular mechanism.MethodsA renal IRI mouse model was established and administrated AST-120, and differentially expressed genes were screened using RNA sequencing. Renal function and pathology were analyzed in mice. Hypoxia/reoxygenation (H/R) cell model was generated, and glycolysis was evaluated by detecting lactate levels and Seahorse analysis. Histone lactylation was analyzed by western blotting, and its relationship with hexokinase 2 (HK2) was assessed using chromatin immunoprecipitation.ResultsThe results showed that HK2 expression was increased after IRI, and AST-120 decreased HK2 expression. Knockout of HK2 attenuated renal IRI and inhibits glycolysis. AST-120 inhibited renal IRI in the presence of HK2 rather than HK2 absence. In proximal tubular cells, knockdown of HK2 suppressed glycolysis and H3K18 lactylation caused by H/R. H3K18 lactylation was enriched in HK2 promoter and upregulated HK2 levels. Rescue experiments revealed that lactate reversed IRI that suppressed by HK2 knockdown.ConclusionsIn conclusion, AST-120 alleviates renal IRI via suppressing HK2-mediated glycolysis, which suppresses H3K18 lactylation and further reduces HK2 levels. This study proposes a novel mechanism by which AST-120 alleviates IRI.

Three-dimensional Culture of Human Proximal Tubular Epithelial Cells for an in vitro Evaluation of Drug-induced Kidney Injury

Drug-induced kidney injury (DIKI) is the major cause of acute kidney injury (AKI). Renal proximal tubular epithelial cells (RPTECs) are the primary target sites of DIKI and express transporters involved in renal drug disposition. In the present study, we focused on three-dimensionally cultured human RPTECs (3D-RPTECs) with elevated expression of drug transporters to investigate their utility in DIKI evaluation. Intracellular ATP levels in 3D-RPTECs are reduced by tenofovir and cisplatin that are substrates of an organic anion transporter 1 and an organic cation transporter 2, respectively. In addition, 3D-RPTECs were exposed to 17 and 15 drugs that are positive and negative to RPTEC toxicity, respectively, for up to 28 d. The 20 % decreasing concentration of drugs for ATP amount (EC20) was obtained, and the ratio of EC20 values and clinical maximum concentration (Cmax) ≤100 were used as cut-off value to evaluate potential of DIKI. The sensitivities of 3D-RPTECs were 82.4 % and 88.2 % after 7 d and 28 d of drug exposure, respectively, and the specificities were 100 % and 93.3 %, respectively. The predictive performance of 3D-RPTECs was higher than that of two-dimensional cultured RPTECs and the kidney cell line HK-2. In conclusion, 3D-RPTECs are useful for in vitro evaluation of RPTEC injury by measuring intracellular ATP levels.

Is there a relationship between hyperchloremia status and the risk of developing acute kidney injury in pediatric patients with diabetic ketoacidosis?

Diabetic ketoacidosis (DKA) is a life-threatening complication of type 1 diabetes mellitus (T1DM). Prerenal acute kidney injury (AKI) is associated with profound hypovolemia and reduced renal perfusion. Results regarding hyperchloremia-associated AKI in patients with DKA are conflicting; we therefore investigated the potential relationship between hyperchloremia status and the risk of developing AKI. This single-center cohort study included 113 newly diagnosed T1DM patients with DKA admitted to the pediatric intensive care unit. Laboratory parameters, including Na, K, urea, creatinine, and chloride levels, were retrospectively reviewed at the time of presentation and at 12, 24 and 36h. AKI was defined using the eGFR according to the pediatric RIFLE classification criteria. Twenty-two (19.5%) of the 113 patients were in the AKI group. Two-way repeated-measures ANOVA showed significant (P values ≤ 0.01) time interaction effects within the groups based on the eGFR and the serum chloride, hyperchloremia, and phosphate levels. Serum chloride levels did not differ between the groups during the first 12h (p > 0.05) but were significantly greater in the AKI group than in the non-AKI group at 24h and 36h (p < 0.01). The final DKA resolution time was significantly greater in the AKI group than in the non-AKI group [22.2 (9.5) vs. 17.0 (12.0) h, respectively; p = 0.03]. However, the groups had similar lengths of hospital stay [13.0 (8.0) days vs. 12.0 (4.0) days, respectively; p = 0.17].Conclusions: Hyperchloremia may be iatrogenic rather than causative during treatment. This may worsen renal failure and prolong the recovery and treatment time for DKA patients. What is Known? • Acute kidney injury resulting from severe volume depletion is a common occurrence in diabetic ketoacidosis and typically requires significant volume replacement therapy. • In recent years, hyperchloremia has been associated with increased risks of AKI, morbidity, and mortality in some conditions, such as diabetic ketoacidosis. What is New? • The incidence of hyperchloremia increases over time during the treatment of diabetic ketoacidosis. • Hyperchloremia may be an iatrogenic element rather than a cause of acute kidney injury during the treatment of diabetic ketoacidosis.

Hydrogen sulphide reduces renal ischemia-reperfusion injury by enhancing autophagy and reducing oxidative stress.

Renal ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury. Hydrogen sulphide (H2S) exerts a protective effect in renal IRI. The present study was carried out to investigate the effects of exogenous H2S on renal IRI by regulating autophagy in mice. Mice were randomly assigned to control, IRI and NaHS (an H2S donor, 28, 56 and 100 μmol/kg) groups. Renal IRI was induced by clamping the bilateral renal pedicles with non-traumatic arterial clamp for 45 min and then reperfused for 24 h. Mice were administered intraperitoneally with NaHS 20 min prior to renal ischemia. Sham group mice underwent the same procedures without clamping. Serum and kidney tissues were harvested 24 h after reperfusion for functional, histological, oxidative stress, and autophagic determination. Compared with the control group, the concentrations of serum creatinine (Scr), blood urea nitrogen (BUN), and malondialdehyde (MDA), the protein levels of LC3II/I, Beclin-1 and P62, as well as the number of autophagosomes were significantly increased, but the activity of superoxide dismutase (SOD) was decreased after renal IRI. NaHS pre-treatment dramatically attenuated renal IRI-induced renal dysfunction, histological changes, MDA concentration and p62 expression in a dose-dependent manner. However, NaHS increased the SOD activity and the protein levels of LC3II/I and Beclin-1. These results indicate that exogenous H2S protects the kidney from IRI through enhancement of autophagy and reduction of oxidative stress. Novel H2S donors could be developed in the treatment of renal IRI.

The protective effect of 1400W against ischaemia and reperfusion injury is countered by transient medullary kidney endothelial dysregulation.

Renal ischaemia and reperfusion (I/R) is caused by a sudden temporary impairment of the blood flow. I/R is a prevalent cause of acute kidney injury. As nitric oxide generated by inducible nitric oxide synthase (iNOS) has detrimental effects during I/R, the pharmacological blockade of iNOS has been proposed as a potential strategy to prevent I/R injury. The aim of this study was to improve the understanding of 1400W (an iNOS inhibitor) on renal I/R as a pharmacological strategy against kidney disease. BALB/c mice received 30min of bilateral ischaemia, followed by 48h or 28days of reperfusion. Vehicle or 1400W (10mg/kg) was administered 30min before inducing ischaemia. We found that after 48h of reperfusion 1400W decreased the serum creatinine, blood urea nitrogen, neutrophil gelatinase-associated lipocalin and proliferating cell nuclear antigen 3 in the I/R animals. Unexpectedly, we observed mRNA upregulation of genes involved in kidney injury, cell-cycle arrest, inflammation, mesenchymal transition and endothelial activation in the renal medulla of sham animals treated with 1400W. We also explored if 1400W promoted chronic kidney dysfunction 28days after I/R and did not find significant alterations in renal function, fibrosis, blood pressure or mortality. The results provide evidence that 1400W may have adverse effects in the renal medulla. Importantly, our data point to 1400W-induced endothelial dysfunction, establishing therapeutic limitations for its use. KEY POINTS: Acute kidney injury is a global health problem associated with high morbidity and mortality. The pharmacological blockade of inducible nitric oxide synthase (iNOS) has been proposed as a potential strategy to prevent AKI induced by ischaemia and reperfusion (I/R). Our main finding is that 1400W, a selective and irreversible iNOS inhibitor with low toxicity that is proposed as a therapeutic strategy to prevent kidney I/R injury, produces aberrant gene expression in the medulla associated to tissue injury, cell cycle arrest, inflammation, mesenchymal transition and endothelial activation. The negative effect of 1400W observed in the renal medulla at 48h from drug administration, is transient as it did not translate into a chronic kidney disease condition.

Epithelial CEBPD activates fibronectin and enhances macrophage adhesion in renal ischemia-reperfusion injury

Ischemia-reperfusion injury (IRI) is a cause of acute kidney injury in patients after renal transplantation and leads to high morbidity and mortality. Damaged kidney resident cells release cytokines and chemokines, which rapidly recruit leukocytes. Fibronectin (FN-1) contributes to immune cell migration, adhesion and growth in inflamed tissues. CCAAT/enhancer-binding protein delta is responsive to inflammatory cytokines and stresses and plays functional roles in cell motility, extracellular matrix production and immune responses. We found that the expression of CCAAT/enhancer-binding protein delta was increased in renal epithelial cells in IRI mice compared with sham mice. Following IRI, the colocalization of FN-1 with the macrophage marker F4/80 was increased in renal injury model wild-type mice but was significantly attenuated in Cebpd-deficient mice. Inactivation of CEBPD can repress hypoxia-induced FN-1 expression in HK-2 cells. Moreover, the inactivation of CEBPD and FN-1 also reduces macrophage accumulation in HK-2 cells. These findings suggest that the involvement of CEBPD in macrophage accumulation through the activation of FN-1 expression and the inhibition of CEBPD can protect against renal IRI.

Time-Restricted Feeding Protects against Renal Ischemia-Reperfusion Injury in Mice.

Ischemia-reperfusion injury (IRI) in the kidneys is a major cause of acute kidney injury (AKI). Time-restricted feeding (TRF), known for its metabolic health benefits and alleviation of various chronic diseases without calorie restriction, was investigated for its potential protective effects against IRI-induced AKI. Male C57BL/6 mice underwent unilateral IRI, with their kidneys collected after two days. For two weeks before IRI induction, the TRF group had unlimited access to standard chow but within an 8-hour feeding window during the dark cycle. The study groups were Control, TRF, IRI, and TRF + IRI. In the TRF + IRI group, tubular damage scores significantly decreased compared to the IRI group. Furthermore, the TRF + IRI mice had lower levels of phosphorylated NF-κB and fewer F4/80-positive macrophages than the IRI group. Oxidative stress markers for lipids and proteins were also notably lower in the TRF + IRI group. Additionally, TUNEL-positive tubular cells and cleaved caspase-3 expression were reduced in the TRF + IRI group. Without calorie restriction, TRF mitigated renal damage by reducing inflammation, oxidative stress, and tubular apoptosis in renal IRI. This suggests that TRF could be a promising dietary strategy to prevent IRI-induced AKI.

Tissue-resident memory T cells break tolerance to renal autoantigens and orchestrate immune-mediated nephritis

Immune-mediated nephritis is a leading cause of acute kidney injury and chronic kidney disease. While the role of B cells and antibodies has been extensively investigated in the past, the advent of immune-checkpoint inhibitors has led to a reappraisal of the role of T cells in renal immunology. However, it remains elusive how T cells with specificity for renal autoantigens are activated and participate in immune-mediated nephritis. Here, we followed the fate and function of pathogen-activated autoreactive CD8 T cells that are specific for a renal autoantigen. We demonstrate that recently activated splenic CD8 T cells developed a hybrid phenotype in the context of renal autoantigen cross-presentation, combining hallmarks of activation and T cell dysfunction. While circulating memory T cells rapidly disappeared, tissue-resident memory T cells emerged and persisted within the kidney, orchestrating immune-mediated nephritis. Notably, T cells infiltrating kidneys of patients with interstitial nephritis also expressed key markers of tissue residency. This study unveils how a tissue-specific immune response can dissociate from its systemic counterpart driving a compartmentalized immune response in the kidneys of mice and man. Consequently, targeting tissue-resident memory T cells emerges as a promising strategy to control immune-mediated kidney disease.