Acute kidney injury (AKI) is associated with high morbidity and mortality rates, primarily due to the lack of effective therapeutic options for kidney repair. To restore the biological function of injured kidney, there is a need to protect renal tubular epithelial cells (RTECs) and regulate M1 macrophages, responsible for progress of AKI. Herein, based on metabolic glycoengineering-mediated click chemistry, we prepare the engineered extracellular vesicles (pSEVs), derived from PEGylated hyaluronic acid (HA)-modified mesenchymal stem cells. Owing to their cell-protective and anti-inflammatory properties, pSEVs effectively prevent the apoptosis of RTECs and inhibit the polarization of macrophages into an inflammatory phenotype in vitro. When systemically administered into the cisplatin-induced AKI animal model, pSEVs selectively accumulate in injured kidneys via HA-mediated binding to CD44 and toll-like receptor4 which are over-expressed on RTECs and M1 macrophages, respectively. This targeted delivery efficiently alleviates AKI-related symptoms, as evidenced by delayed kidney weight reduction, and decreased levels of creatinine, blood urea nitrogen, and neutrophil gelatinase-associated lipocalin. Overall, pSEVs show potent anti-inflammatory effects and specific targeting to injured kidneys, presenting a considerable potential as the therapeutics for AKI.

Renal inflammatory diseases are a group of severe conditions marked by significant morbidity and mortality. Extracellular vesicles (EVs), as facilitators of intercellular communication, have been recognized as pivotal regulators of renal inflammatory diseases, significantly contributing to these conditions by modulating immune responses among other mechanisms. This review highlights the intricate mechanisms through which EVs modulate macrophage-kidney cell interactions by regulating macrophages, the principal immune cells within the renal milieu. This regulation subsequently influences the pathophysiology of renal inflammatory diseases such as acute kidney injury and chronic kidney disease. Furthermore, understanding these mechanisms offers novel opportunities to alleviate the severe consequences associated with renal inflammatory diseases. In addition, we summarize the therapeutic landscape based on EV-mediated macrophage regulatory mechanisms, highlighting the potential of EVs as biomarkers and therapeutic targets as well as the challenges and limitations of translating therapies into clinical practice.

Background/Objectives: Anethole, a terpenoid with several pharmacologic effects, is the major constituent of the essential oil of Croton zehntneri (EOCz), Pax & K. Hoffm, Euphorbiaceae. Due to the mild renal toxicity associated with high doses of EOCz, its potential therapeutic effects on several diseases, and the fact that its chemical composition consists of 80% anethole, the renal effects of anethole in mice were investigated. Methods: Mice were randomly divided into eight groups, dosed daily as follows: Group 1-CTRL (control; vehicle only); Groups 2-A100, 3-A1252x, and 4-A250 (dosed with 100, 125 twice daily, and 250 mg/kg, per os anethole); Group 5-SUBAKI (i.p. albumin to induce hyperproteinemia and proteinuria; subclinical acute kidney injury); and Groups 6-SUBAKI+A100, 7-SUBAKI+A1252x, and 8-SUBAKI+A250 (per os anethole + i.p. albumin). Results: The A1252x and A250 groups significantly increased urinary proteinuria and interstitial inflammation (p < 0.001, for these groups). SUBAKI+A100, SUBAKI+A1252x, and SUBAKI+A250 showed a neither protective nor additive effect in the proteinuria induced by anethole and by administered albumin. The anethole-induced proteinuria was spontaneously reversible in approximately 4 weeks. In vitro experiments showed that anethole (300 µg/mL) inhibits albumin uptake from the culture medium by tubular cells. Conclusions: Anethole at high doses bears renal acute toxicity that, although mild and spontaneously fully reversible, must be taken into consideration in a cost-benefit analysis.

AimTo investigate the prognostic implication (mortality at 3 months) of acute kidney injury (AKI) in acute ischemic stroke treated with mechanical thrombectomy (MT).Material and MethodsA literature search was performed using PubMed/OVID/Cochran's CENTRAL database (time frame: inception to January 2023). Study characteristics, patient status, clinical outcomes, AKI incidence, and sample size were recorded. The exclusion criteria were non-English literature, no human subjects, and <10 patients as the sample size. Studies were assessed using the MINORS/GRADE system. Meta-analysis and meta-regression with a random-effects model were performed.Results3314 studies were retrieved. After applying the exclusion criteria, the final population included of 18/3314 studies (0.5%). Among them, only 6/18 (33.3%) studies reported results in two separate groups (AKI vs non-AKI), allowing for inference statistics for a total population of 3229 (538.6 ± 403.7). The I^2 was 34.6 and Q's Cochrane was 7.80. The pooled odds ratio (OR) for mortality at 3 months in patients with AKI was 5.8 (95% confidence interval [95% CI] 95% CI 3.62 to 9.52). Leave-one-out meta-analysis showed no significant sources of heterogeneity. In the meta-regression, diabetes prevalence was associated with a higher mortality rate (OR 1.14, 95% CI 1.03 to 1.28), and lower age and a small amount of contrast media were negatively correlated (0.91 [95% CI 0.83 to 0.99] and OR 0.97 [95% CI 0.94 to 1.00], respectively).ConclusionAKI was significantly associated with the mortality rate in MT-treated stroke patients (OR 5.8 [95% CI 3.62 to 9.36]).

Acute kidney injury (AKI) is a common complication of sepsis due to a myriad of contributing factors and leads to significant morbidity and mortality in critically ill patients. Prompt identification and management are vital to reverse and/or prevent the worsening of AKI. When renal function is severely compromised, there may be a need for dialytic therapy to meet the metabolic needs of patients. This article will review the definition of AKI, epidemiology, risk factors, and pathophysiology of AKI in sepsis, along with both non-dialytic and dialytic treatment strategies. We will also review landmark trials in fluid resuscitation in sepsis.

Acute kidney injury (AKI) is a frequent clinical complication lacking early diagnostic tests and effective treatments. Novel biomarkers have shown promise for enabling earlier detection, risk stratification, and guiding management of AKI. We conducted a systematic review to synthesize evidence on the efficacy of novel biomarkers for AKI detection and management. Database searches yielded 17 relevant studies which were critically appraised. Key themes were biomarker efficacy in predicting AKI risk and severity before functional changes; potential to improve clinical management through earlier diagnosis, prognostic enrichment, and guiding interventions; emerging roles as therapeutic targets and prognostic tools; and ongoing challenges requiring further validation. Overall, novel biomarkers like neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and cell cycle arrest markers ([TIMP-2] •[IGFBP7]) demonstrate capability for very early AKI prediction and accurate risk stratification. Their incorporation has potential to facilitate timely targeted interventions and personalized management. However, factors influencing biomarker performance, optimal cutoffs, cost-effectiveness, and impact on patient outcomes require robust validation across diverse settings before widespread implementation. Addressing these limitations through ongoing research can help translate novel biomarkers into improved detection, prognosis, and management of AKI in clinical practice.

Macroautophagy/autophagy activation in renal tubular epithelial cells protects against acute kidney injury (AKI). However, the role of immune cell autophagy, such as that involving macrophages, in AKI remains unclear. In this study, we discovered that macrophage autophagy was an adaptive response during AKI as mice with macrophage-specific autophagy deficiency (atg5-/-) exhibited higher serum creatinine, more severe renal tubule injury, increased infiltration of ADGRE1/F4/80+ macrophages, and elevated expression of inflammatory factors compared to WT mice during AKI induced by either LPS or unilateral ischemia-reperfusion. This was further supported by adoptive transfer of atg5-/- macrophages, but not WT macrophages, to cause more severe AKI in clodronate liposomes-induced macrophage depletion mice. Similar results were also obtained in vitro that bone marrow-derived macrophages (BMDMs) lacking Atg5 largely increased pro-inflammatory cytokine expression in response to LPS and IFNG. Mechanistically, we uncovered that atg5 deletion significantly upregulated the protein expression of TARM1 (T cell-interacting, activating receptor on myeloid cells 1), whereas inhibition of TARM1 suppressed LPS- and IFNG-induced inflammatory responses in atg5-/- RAW 264.7 macrophages. The E3 ubiquitin ligases MARCHF1 and MARCHF8 ubiquitinated TARM1 and promoted its degradation in an autophagy-dependent manner, whereas silencing or mutation of the functional domains of MARCHF1 and MARCHF8 abolished TARM1 degradation. Furthermore, we found that ubiquitinated TARM1 was internalized from plasma membrane into endosomes, and then recruited by the ubiquitin-binding autophagy receptors TAX1BP1 and SQSTM1 into the autophagy-lysosome pathway for degradation. In conclusion, macrophage autophagy protects against AKI by inhibiting renal inflammation through the MARCHF1- and MARCHF8-mediated degradation of TARM1.Abbreviations: AKI, acute kidney injury; ATG, autophagy related; Baf, bafilomycin A1; BMDMs, bone marrow-derived macrophages; CCL2/MCP-1, C-C motif chemokine ligand 2; CHX, cycloheximide; CQ, chloroquine; IFNG, interferon gamma; IL, interleukin; IR, ischemia-reperfusion; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; LPS, lipopolysaccharide; MARCHF, membrane associated ring-CH-type finger; NC, negative control; NFKB, nuclear factor of kappa light polypeptide gene enhancer in B cells; NLRP3, NLR family, pyrin domain containing 3; NOS2, nitric oxide synthase 2, inducible; Rap, rapamycin; Wort, wortmannin; RT-qPCR, real-time quantitative polymerase chain reaction; Scr, serum creatinine; SEM, standard error of mean; siRNA, small interfering RNA; SYK, spleen tyrosine kinase; TARM1, T cell-interacting, activating receptor on myeloid cells 1; TAX1BP1, Tax1 (human T cell leukemia virus type I) binding protein 1; TECs, tubule epithelial cells; TNF, tumor necrosis factor; WT, wild type.

Acute kidney injury (AKI) is prevalent in critically ill patients and is associated with an increased risk of in-hospital mortality. Nephrology consultation may be protective, but this has rarely been evaluated in South Korea.

This multicenter retrospective study was based on the electronic medical records (EMRs) of two third-affiliated hospitals. We extracted the records of patients admitted to intensive care units (ICUs) between 2011 and 2020, and retrospectively detected AKI using the modified serum creatinine criteria of the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. The AKI diagnosis date was defined as the first day of a significant change in serum creatinine level (≥0.3 mg/dL) within 48 hours. Nephrology consultation status was retrieved from the EMRs.

In total, 2,461 AKI patients were included; the median age was 65 years (interquartile range [IQR], 56-75 years), 1,459 (59.3%) were male, and 1,065 (43.3%) were of AKI stage 3. During a median of 5 days (IQR, 3-11 days) of ICU admission, nephrology consultations were provided to 512 patients (20.8%). Patients who received such consultations were older, had more comorbidities, and more commonly required dialysis. In a multivariable model, nephrology consultation reduced the risk of in-hospital mortality by 30% (hazard ratio, 0.71; 95% confidence interval, 0.57-0.88). Other factors significant for in-hospital mortality were older age, a higher sequential organ failure assessment (SOFA) score, sepsis, diabetes, hypertension, heart disease, and cancer.

For AKI patients in ICUs, nephrology consultation reduced the risk of in-hospital mortality, particularly among those with multiple comorbidities. Therefore, nephrology consultation should not be omitted during ICU care.

Podocyte injury is a major biomarker of primary glomerular disease that leads to massive proteinuria and kidney failure. Ginsenoside Rk1, a substance derived from ginseng, has several pharmacological activities, such as anti-apoptotic, anti-inflammatory, and antioxidant effects. In this study, our goal is to investigate the roles and mechanisms of ginsenoside Rk1 in podocyte injury and acute kidney injury (AKI). C57BL/6 mice were intraperitoneally injected with 10 mg/kg LPS to mimic AKI-like conditions in vivo. One hour after the LPS challenge, ginsenoside Rk1 (10 mg/kg or 20 mg/kg) or vehicle was orally administered into mice every 6 h until sacrifice at 24 h. Renal functions were assessed by measuring blood urea nitrogen and creatinine. Renal histological changes were examined by hematoxylin and eosin staining. The production of proinflammatory cytokines in kidney tissues was evaluated by RT-qPCR and western blotting. A conditionally immortalized mouse MPC-5 podocyte cell line was treated with LPS and ginsenoside Rk1. Viability and apoptosis of MPC-5 cells were estimated by CCK-8 and flow cytometry. Western blotting was also conducted to measure the protein levels of apoptosis-related and pathway-related genes. The results of abovementioned experiments revealed that Ginsenoside Rk1 ameliorated LPS-stimulated podocyte apoptosis in vitro and relieved renal dysfunctions and inflammatory response in LPS-induced AKI mice. Mechanistically, ginsenoside Rk1 inactivated the JAK2/STAT3 and NF-κB pathways in LPS-treated podocytes and mice. In conclusion, this study shows that Ginsenoside Rk1 attenuates LPS-induced renal dysfunctions and inflammatory response in mice and LPS-induced podocyte apoptosis in vitro through inactivating the NF-κB and JAK2/STAT3 pathways.

This study aimed to examine the impact of APS on acute kidney injury induced by rhabdomyolysis (RIAKI), exploring its association with macrophage M1 polarization and elucidating the underlying mechanisms.

C57BL/6J mice were randomly assigned to one of three groups: a normal control group, a RIAKI model group, and an APS treatment group. Techniques such as flow cytometry and immunofluorescence were employed to demonstrate that APS can inhibit the transition of renal macrophages to the M1 phenotype in RIAKI. Furthermore, the raw264.7 macrophage cell line was chosen and induced into the M1 phenotype to further examine the impact of APS on this model and elucidate the underlying mechanism.

Administration of APS led to a significant decrease in UREA levels by 25.2% and CREA levels by 60.9% within the model group. Also, APS exhibited an inhibitory effect on the infiltration of M1 macrophages and the cGAS-STING pathway in kidneys within the RIAKI, subsequently leading to decreased serum concentrations of IL-1β, IL-6 and TNF-α by 44.5%, 12.9%, and 10.3%, respectively, consistent with the results of in vitro experiments. Furthermore, APS exhibited an anti-apoptotic effect on MPC5 cells when co-cultured with M1 macrophages.

Astragalus polysaccharide (APS) potentially mitigated rhabdomyolysis-induced renal damage by impeding the M1 polarization of macrophages. This inherent mechanism might involve the suppression of the cGAS-STING pathway activation within macrophages. Furthermore, APS could endow protective effects on podocytes through the inhibition of apoptosis.

Anticoagulation for continuous renal replacement therapy (CRRT) can be performed using systemic anticoagulation or regional citrate anticoagulation (RCA). The 2012 Kidney Disease Improving Global Outcomes guidelines support the use of RCA as the first-line strategy in patients requiring CRRT, with and without bleeding risk. Implementing RCA in the intensive care unit (ICU) implies involving all medical and nursing staff. The primary objective of this study was to report and describe the various anticoagulation strategies for CRRT in French ICUs. The secondary objectives were to determine the rate of RCA use and to identify the factors limiting its implementation.

An online questionnaire containing 40 questions was sent to attending physicians and fellows practicing in French ICUs between May and September 2021. The questionnaire was sent via several networks: mailing list from the French Society of Anesthesia and Intensive Care Medicine and mailing lists of RRT manufacturers.

A total of 597 responses were analyzed. RCA was used by most of the participants for patients with (81%) and without (80%) increased bleeding risk. The preferred CRRT modality of the participants while using RCA was continuous veno-venous hemodialysis (48%). The clinical situations frequently reported as an absolute contraindication to RCA were uncontrolled shock associated with liver failure and drug poisoning impairing citrate metabolism (62% and 52%, respectively). In case of a higher risk of citrate accumulation, most participants claimed to perform closer biological monitoring (57%) or to modify the CRRT protocol (61%). Among the participants who did not prescribe RCA as a first-line strategy, the main factors limiting its implementation were the lack of nurse (50%) or physician (34%) training.

RCA is the main anticoagulation strategy prescribed for CRRT in France. Providing medical and nursing staff easy access to training may facilitate the understanding and use of RCA as the first-line anticoagulation strategy for CRRT.

Acute kidney injury (AKI) is widely recognized as a precursor to the onset or rapid progression of chronic kidney disease (CKD). However, there is currently no effective treatment available for AKI, underscoring the urgent need for the development of new strategies to improve kidney function. Human placental mesenchymal stromal cells (hpMSCs) were isolated from donor placentas, cultured, and characterized with regard to yield, viability, flow cytometry, and potency. To mimic AKI and its progression to CKD in a rat model, a dedicated sensitive non-clinical bilateral kidney ischemia-reperfusion injury (IRI) model was utilized. The experimental group received 3 × 105 hpMSCs into each kidney, while the control group received IRI and saline and the untreated group received IRI only. Urine, serum, and kidney tissue samples were collected over a period of 28 days. The hpMSCs exhibited consistent yields, viability, and expression of mesenchymal lineage markers, and were also shown to suppress T cell proliferation in a dose-dependent manner. To ensure optimal donor selection, manufacturing optimization, and rigorous quality control, the rigorous Good Manufacturing Practice (GMP) conditions were utilized. The results indicated that hpMSCs increased rat survival rates and improved kidney function by decreasing serum creatinine, urea, potassium, and fractionated potassium levels. Furthermore, the study demonstrated that hpMSCs can prevent the initial stages of kidney structural fibrosis and improve kidney function in the early stages by mitigating late interstitial fibrosis and tubular atrophy. Additionally, a robust manufacturing process with consistent technical parameters was established.

The biology of the cyclin-dependent kinase-like (CDKL) kinase family remains enigmatic. Contrary to their nomenclature, CDKLs do not rely on cyclins for activation and are not involved in cell cycle regulation. Instead, they share structural similarities with mitogen-activated protein kinases and glycogen synthase kinase-3, although their specific functions and associated signaling pathways are still unknown. Previous studies have shown that the activation of CDKL5 kinase contributes to the development of acute kidney injury (AKI) by suppressing the protective SOX9-dependent transcriptional program in tubular epithelial cells. In the current study, we measured the functional activity of all five CDKL kinases and discovered that, in addition to CDKL5, CDKL1 is also activated in tubular epithelial cells during AKI. To explore the role of CDKL1, we generated a germline knockout mouse that exhibited no abnormalities under normal conditions. Notably, when these mice were challenged with bilateral ischemia-reperfusion and rhabdomyolysis, they were found to be protected from AKI. Further mechanistic investigations revealed that CDKL1 phosphorylates and destabilizes SOX11, contributing to tubular dysfunction. In summary, this study has unveiled a previously unknown CDKL1-SOX11 axis that drives tubular dysfunction during AKI.NEW & NOTEWORTHY Identifying and targeting pathogenic protein kinases holds potential for drug discovery in treating acute kidney injury. Our study, using novel germline knockout mice, revealed that Cdkl1 kinase deficiency does not affect mouse viability but provides protection against acute kidney injury. This underscores the importance of Cdkl1 kinase in kidney injury and supports the development of targeted small-molecule inhibitors as potential therapeutics.

Background: Nosocomial infections are a worldwide healthcare issue, especially in intensive care units (ICUs), and they had a prevalence of 21.1% in 2023 in Spain. Numerous predisposing risk factors have been identified, with the most relevant being invasive techniques, including renal replacement therapies (RRTs). Several outstanding strategies have been published that prevent or reduce their incidence, including the nationwide ZERO in Spain, which consists of structured guidelines to be implemented to tackle this problem. One of these strategies, which is defined as 'highly recommended' in these projects, is selective digestive decontamination (SDD). The main aim of this study is to compare the incidences of ICU-acquired infections, including those due to multidrug-resistant bacteria (MDRB), in two cohorts of RRT with or without SDD. Methods: We conducted a multicenter, prospective, observational study at two tertiary hospitals in Spain. In total, 140 patients treated with RRT were recruited based on their exposure to SDD. Surveillance microbiological samples and nosocomial infection risk factors were obtained. Infection rates per 1000 days of exposure and the MDRB incidence density ratio were determined. Results: SDD statistically significantly reduced RRT-associated nosocomial infections (OR: 0.10, 95% CI: (0.04-0.26)) and the MDRB incidence density ratio (IDR: 0.156, 95% CI = 0.048-0.506). However, mechanical ventilation (OR: 7.91, 95% CI: (2.54-24.66)) and peripheral vascular disease (OR: 3.17, 95% CI: (1.33-7.56)) were significantly associated with increases in infections. Conclusions: Our results favor the use of SDD in ICU patients with renal failure undergoing CRRT as a tool for infection control.

Pyroptosis is a form of pro-inflammatory programmed cell death and it represents a potential therapeutic target for alleviating drug-induced acute kidney injury (AKI). However, there is a lack of effective and kidney-targeted pyroptosis inhibitors for AKI treatment so far. Herein, we report a pharmacologically active carbonized nanoinhibitor (P-RCDs) derived from 3,4',5-trihydroxystilbene that can preferentially accumulate in the kidneys and ameliorate chemotherapeutic drug-induced AKI by inhibiting pyroptosis. In particular, such a carbonized nanoformulation enables the transfer of desired pyroptosis inhibitory activity as well as the radical eliminating activity to the nanoscale, endowing P-RCDs with a favorable kidney-targeting ability. In cisplatin-induced AKI mice, P-RCDs can not only pharmacologically inhibit GSDME-mediated pyroptosis in renal cells with high efficacy, but also exhibit high antioxidative activity that protects the kidneys from oxidative injury. The present study proposes a feasible but efficacious strategy to construct versatile carbonized nanomedicine for targeted delivery of the desired pharmacological activities.

Acute kidney injury (AKI) is associated with increased complications after total hip arthroplasty (THA) and total knee arthroplasty (TKA). The purpose of this study was to determine the risk factors for AKI after THA and TKA and evaluate if preoperative use of antihypertensive drugs is a risk factor for AKI.

A retrospective review of 7406 primary TKAs and THAs (4532 hips and 2874 knees) from 2013 to 2019 was performed. The following preoperative variables were obtained from medical records: medications, chemistry 7 panel, Elixhauser comorbidities, and demographic factors. AKI was defined as an increase in serum creatinine by 26.4 μmol·L-1. Multivariate analysis was performed to identify the risk factors.

The overall incidence of postoperative AKI was 6.2% (n = 459). Risk factors for postoperative AKI were found to be: chronic kidney disease (odds ratio [OR] = 7.09; 95% confidence interval [CI]: 4.8-9.4), diabetes (OR: 5.03; 95% CI: 2.8-6.06), ≥3 antihypertensive drugs (OR: 4.2; 95% CI: 2.1-6.2), preoperative use of an angiotensin receptor blockers or angiotensin-converting enzyme inhibitors (OR: 3.8; 95% CI: 2.2-5.9), perioperative vancomycin (OR: 2.7; 95% CI: 1.8-4.6), and body mass index >40 kg/m2 (OR: 1.9; 95% CI: 1.3-3.06).

We have identified several modifiable risk factors for AKI that can be optimized prior to an elective THA or TKA. The use of certain antihypertensive agents namely angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and multidrug antihypertensive regimens were found to significantly increase the risk of AKI. Therefore, perioperative management of patients undergoing joint replacement should include medical comanagement with a focus on careful management of antihypertensives.

Kidney damage can result from various factors, leading to structural and functional changes in the kidney. Acute kidney injury (AKI) refers to a sudden decline in kidney function, while chronic kidney disease involves a gradual deterioration lasting more than 3 months. Mechanisms of renal injury include impaired microcirculation, inflammation, and oxidative stress. Cysteinyl-leukotrienes (CysLTs) are inflammatory substances contributing to tissue damage. Montelukast, a leukotriene receptor antagonist, has shown potential renoprotective effects in experimental models of kidney injury.

The authors conducted a scoping review using PubMed, Scopus, and Web of Science databases to identify relevant studies investigating the impact of montelukast on renal diseases. Articles published until 2022 were included and evaluated for quality. Data extraction and analysis were performed based on predetermined inclusion criteria.

The scoping review included 30 studies from 8 countries. Montelukast demonstrated therapeutic effects in various experimental models of nephrotoxicity and AKI induced by agents such as cisplatin, lipopolysaccharide, diclofenac, amikacin, Escherichia coli, cyclosporine, methotrexate, cobalt-60 gamma radiation, doxorubicin, and cadmium. Studies involving human subjects with nephrotic syndrome, pyelonephritis, and other renal diseases also reported positive outcomes with montelukast treatment. Montelukast exhibited anti-inflammatory, anti-apoptotic, antioxidant, and neutrophil-inhibiting properties, leading to improved kidney function and histopathological changes.

Montelukast shows promise as a renoprotective medication, particularly in early-stage kidney injury. Its ability to mitigate inflammation, oxidative stress, and neutrophil infiltration contributes to its therapeutic effects. Further research is needed to explore the clinical applications and mechanisms underlying the renoprotective action of montelukast.

Current classification for acute kidney injury (AKI) in critically ill patients with sepsis relies only on its severity-measured by maximum creatinine which overlooks inherent complexities and longitudinal evaluation of this heterogenous syndrome. The role of classification of AKI based on early creatinine trajectories is unclear.

This retrospective study identified patients with Sepsis-3 who developed AKI within 48-h of intensive care unit admission using Medical Information Mart for Intensive Care-IV database. We used latent class mixed modelling to identify early creatinine trajectory-based classes of AKI in critically ill patients with sepsis. Our primary outcome was development of acute kidney disease (AKD). Secondary outcomes were composite of AKD or all-cause in-hospital mortality by day 7, and AKD or all-cause in-hospital mortality by hospital discharge. We used multivariable regression to assess impact of creatinine trajectory-based classification on outcomes, and eICU database for external validation.

Among 4197 patients with AKI in critically ill patients with sepsis, we identified eight creatinine trajectory-based classes with distinct characteristics. Compared to the class with transient AKI, the class that showed severe AKI with mild improvement but persistence had highest adjusted risks for developing AKD (OR 5.16; 95% CI 2.87-9.24) and composite 7-day outcome (HR 4.51; 95% CI 2.69-7.56). The class that demonstrated late mild AKI with persistence and worsening had highest risks for developing composite hospital discharge outcome (HR 2.04; 95% CI 1.41-2.94). These associations were similar on external validation.

These 8 classes of AKI in critically ill patients with sepsis, stratified by early creatinine trajectories, were good predictors for key outcomes in patients with AKI in critically ill patients with sepsis independent of their AKI staging.

Acute kidney injury (AKI) is a common and severe complication in patients treated at an Intensive Care Unit (ICU). The pathogenesis of AKI has been reported to involve hypoperfusion, diminished oxygenation, systemic inflammation, and damage by increased intracellular iron concentration. Hepcidin, a regulator of iron metabolism, has been shown to be associated with sepsis and septic shock, conditions that can result in AKI. Heparin binding protein (HBP) has been reported to be associated with sepsis and AKI. The aim of the present study was to compare serum hepcidin and heparin binding protein (HBP) levels in relation to AKI in patients admitted to the ICU.

One hundred and forty patients with community acquired illness admitted to the ICU within 24 hours after first arrival to the hospital were included in the study. Eighty five of these patients were diagnosed with sepsis and 55 with other severe non-septic conditions. Logistic and linear regression models were created to evaluate possible correlations between circulating hepcidin and heparin-binding protein (HBP), stage 2-3 AKI, peak serum creatinine levels, and the need for renal replacement therapy (RRT).

During the 7-day study period, 52% of the 85 sepsis and 33% of the 55 non-sepsis patients had been diagnosed with AKI stage 2-3 already at inclusion. The need for RRT was 20% and 15%, respectively, in the groups. Hepcidin levels at admission were significantly higher in the sepsis group compared to the non-sepsis group but these levels did not significantly correlate to the development of stage 2-3 AKI in the sepsis group (p = 0.189) nor in the non-sepsis group (p = 0.910). No significant correlation between hepcidin and peak creatinine levels, nor with the need for RRT was observed. Stage 2-3 AKI correlated, as expected, significantly with HBP levels at admission in both groups (Odds Ratio 1.008 (CI 1.003-1.014, p = 0.005), the need for RRT, as well as with peak creatinine in septic patients.

Initial serum hepcidin, and HBP levels in patients admitted to the ICU are biomarkers for septic shock but in contrast to HBP, hepcidin does not portend progression of disease into AKI or a later need for RRT. Since hepcidin is a key regulator of iron metabolism our present data do not support a decisive role of initial iron levels in the progression of septic shock into AKI.

Acute kidney injury (AKI) is characterized by an abrupt decline of excretory kidney function. The incidence of AKI has increased in the past decades. Patients diagnosed with AKI often undergo diverse clinical trajectories, such as early or late recovery, relapses, and even a potential transition from AKI to chronic kidney disease (CKD). Although recent clinical studies have demonstrated a strong association between AKI and progression of CKD, our understanding of the complex relationship between AKI and CKD is still evolving. No cohort study has succeeded in painting a comprehensive picture of these multi-faceted pathways. To address this lack of understanding, the idea of acute kidney disease (AKD) has recently been proposed. This presents a new perspective to pinpoint a period of heightened vulnerability following AKI, during which a patient could witness a substantial decline in glomerular filtration rate, ultimately leading to CKD transition. Although AKI is included in a range of kidney conditions collectively known as AKD, spanning from mild and self-limiting to severe and persistent, AKD can also occur without a rapid onset usually seen in AKI, such as when kidney dysfunction slowly evolves. In the present review, we summarize the most recent findings about AKD, explore the current state of biomarker discovery related to AKD, discuss the latest insights into pathophysiological underpinnings of AKI to CKD transition, and reflect on therapeutic challenges and opportunities that lie ahead.

Sepsis and acute kidney injury (AKI) are two major public health concerns that contribute significantly to illness and death worldwide. Early diagnosis and prompt treatment are essential for achieving the best possible outcomes. To date, there are no specific clinical, imaging, or biochemical indicators available to diagnose sepsis, and diagnosis of AKI based on the KDIGO criterion has limitations. To improve the diagnostic process for sepsis and AKI, it is essential to continually evolve our understanding of these conditions. Delays in diagnosis and appropriate treatment can have serious consequences. Sepsis and AKI often occur together, and patients with kidney dysfunction are more prone to developing sepsis. Therefore, identifying potential biomarkers for both conditions is crucial. In this review, we talk about the main biomarkers that evolve the diagnostic of sepsis and AKI, namely neutrophil gelatinase-associated lipocalin (NGAL), proenkephalin (PENK), and cell-free DNA.

Acute kidney injury (AKI) is a common complication after surgery and the more complex the surgery, the greater the risk. During surgery, patients are exposed to a combination of factors all of which are associated with the development of AKI. These include hypotension and hypovolaemia, sepsis, systemic inflammation, the use of nephrotoxic agents, tissue injury, the infusion of blood or blood products, ischaemia, oxidative stress and reperfusion injury. Given the risks of AKI, it would seem logical to conclude that early identification of patients at risk of AKI would translate into benefit. The conventional markers of AKI, namely serum creatinine and urine output are the mainstay of defining chronic kidney disease but are less suited to the acute phase. Such concerns are compounded in surgical patients given they often have significantly reduced mobility, suboptimal levels of nutrition and reduced muscle bulk. Many patients may also have misleadingly low serum creatinine and high urine output due to aggressive fluid resuscitation, particularly in intensive care units. Over the last two decades, considerable information has accrued with regard to the performance of what was termed "novel" biomarkers of AKI, and here, we discuss the most examined molecules and performance in surgical settings. We also discuss the application of biomarkers to guide patients' postoperative care.

Sesamol is a natural antioxidant known for its potent antioxidant and free radical scavenging properties. This study aimed to explore the therapeutic effects and underlying mechanisms of sesamol in the development of renal ischemia-reperfusion injury (IRI) in mice.

C57BL/6J wild-type mice were divided into 3 groups: IR group, treated with normal saline after undergoing the IRI procedure; Sesamol + IR group, treated with 30 mg/kg/d of sesamol after the IRI procedure; and Sham group, treated with normal saline but not subjected to the IRI process. Renal IRI was induced by performing a right kidney nephrectomy and subjecting the left kidney to 30-minute ischemia, followed by 24-hour reperfusion. Kidney tissues and serum were collected 24 hours post-IRI to assess the impact of sesamol on renal function after IRI. Serum creatinine and blood urea nitrogen levels were assessed, and renal cell apoptosis was detected through terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. The levels of interleukin 1β and interleukin 18 in kidney tissues, as well as indicators of oxidative stress, were also measured. Furthermore, Nrf2-deficient mice were used to examine the protective function of the nuclear factor erythroid 2-related factor 2 (Nrf2)/hemeoxygenase-1 (HO-1) and NAD(P)H dehydrogenase quinone 1 (NQO1) signaling pathways induced by sesamol, as determined by western blot assay.

Sesamol demonstrated significant improvement in renal function, along with reductions in renal tubular injury, cell necrosis, and apoptosis in mice. It also effectively lowered key inflammatory mediator levels. Sesamol exhibited antioxidant properties by reducing malondialdehyde levels and enhancing superoxide dismutase activities 24 hours after IRI. Western blot assay revealed increased Nrf2, HO-1, and NQO-1 protein levels with sesamol treatment. Notably, Nrf2-deficient mice did not exhibit the beneficial effects of sesamol.

This study demonstrates that sesamol effectively alleviates renal IRI by enhancing antioxidant defenses and reducing inflammation potentially through the Nrf2/HO-1 and NQO1 signaling pathways.

Incidence of acute kidney injury (AKI) remained relatively stable over the last decade and the adjusted risks for it and mortality are similar across different continents and regions. Also, the mortality of septic-AKI can reach 70% in critically-ill patients. These sole facts can give rise to a question: is there something we do not understand yet? Currently, there are no specific therapies for septic AKI and the treatment aims only to maintain the mean arterial pressure over 65mmHg by ensuring a good fluid resuscitation and by using vasopressors, along with antibiotics. On the other hand, there is an increased concern about the different hemodynamic changes in septic AKI versus other forms and the link between the gut microbiome and the severity of septic AKI. Fortunately, progress has been made in the form of administration of pre- and probiotics, short chain fatty acids (SCFA), especially acetate, and also broad-spectrum antibiotics or selective decontaminants of the digestive tract in a successful attempt to modulate the microbial flora and to decrease both the severity of AKI and mortality. In conclusion, septic-AKI is a severe form of kidney injury, with particular hemodynamic changes and with a strong link between the kidney and the gut microbiome. By modulating the immune response we could not only treat but also prevent severe forms. The most difficult part is to categorize patients and to better understand the key mechanisms of inflammation and cellular adaptation to the injury, as these mechanisms can serve in the future as target therapies.

This study aims to develop and validate a prognostic nomogram that accurately predicts the short-term survival rate of cirrhotic patients with acute kidney damage (AKI) upon ICU admission. For this purpose, we examined the admission data of 3060 cirrhosis patients with AKI from 2008 to 2019 in the MIMIC-IV database. All included patients were randomly assigned to derivation and validation cohorts in a 7:3 ratio. The derivation cohort used the least absolute shrinkage and selection operator (LASSO) regression model to identify independent predictors of AKI. A prognostic nomogram was constructed via multivariate logistic regression analysis in the derivation cohort and subsequently verified in the validation cohort. Nomogram's discrimination, calibration, and clinical utility were evaluated using the C-index, calibration plot, and decision curve analysis (DCA). A total of 2138 patients were enrolled in the derivation cohort, with a median follow-up period of 15 days, a median survival time of 41 days, and a death rate of 568 patients (26.6%). The cumulative survival rates at 15 and 30 days were 75.8% and 57.5%, respectively. The results of the multivariate analysis indicated that advanced AKI stage, use of vasoactive drugs, advanced age, lower levels of ALB, lower mean sBp, longer INR, and longer PT were all independent risk factors that significantly influenced the all-cause mortality of cirrhosis patients with AKI (all p < 0.01). The C-indices for the derivation and the validation cohorts were 0.821 (95% CI 0.800-0.842) and 0.831 (95% CI 0.810-0.852), respectively. The model's calibration plot demonstrated high consistency between predicted and actual probabilities. Furthermore, the DCA showed that the nomogram was clinically valuable. Therefore, the developed and internally validated prognostic nomogram exhibited favorable discrimination, calibration, and clinical utility in forecasting the 15-day and 30-day survival rates of cirrhosis patients with AKI upon admission to the ICU.

Rhabdomyolysis is a severe clinical syndrome associated to acute kidney injury (AKI) and chronic kidney disease (CKD). TWEAK/Fn14 signaling axis regulates renal inflammation and tubular cell death. However, the functional role of TWEAK/Fn14 in rhabdomyolysis remains unknown.

Rhabdomyolysis was induced in wild-type, TWEAK- and Fn14-deficient mice or mice treated with TWEAK blocking antibody. Renal injury, inflammation, fibrosis and cell death were assessed. Additionally, we performed in vivo and in vitro studies to explore the possible signalling pathways involved in Fn14 regulation.

Fn14 renal expression was increased in mice with rhabdomyolysis, correlating with decline of renal function. Mechanistically, myoglobin (Mb) induced Fn14 expression via ERK and p38 pathway, whereas Nrf2 activation diminished Mb-mediated Fn14 upregulation in cultured renal cells. TWEAK or Fn14 genetic depletion ameliorated rhabdomyolysis-associated loss of renal function, histological damage, tubular cell death, inflammation, and expression of both tubular and endothelial injury markers. Deficiency of TWEAK or Fn14 also decreased long-term renal inflammation and fibrosis in mice with rhabdomyolysis. Finally, pharmacological treatment with a blocking TWEAK antibody diminished the expression of acute renal injury markers and cell death and lessened residual kidney fibrosis and chronic inflammation in rhabdomyolysis.

TWEAK/Fn14 axis participates in the pathogenesis of rhabdomyolysis-AKI and subsequent AKI-CKD transition. Blockade of this signaling pathway may represent a promising therapeutic strategy for reducing rhabdomyolysis-mediated renal injury.

Spanish Ministry of Science and Innovation, ISCIII and Junta de Andalucía.

Acute kidney injury (AKI) is caused by a sudden loss of renal function, resulting in the build-up of waste products and a significant increase in mortality and morbidity. It is commonly diagnosed in critically ill patients, with its occurrence estimated at up to 50% in patients hospitalized in the intensive critical unit. Despite ongoing efforts, the death rate associated with AKI has remained high over the past half-century. Thus, it is critical to investigate novel therapy options for preventing the epidemic. Many studies have found that inflammation and Toll-like receptor-4 (TLR-4) activation have a significant role in the pathogenesis of AKI. Noteworthy, challenges in the search for efficient pharmacological therapy for AKI have arisen due to the multifaceted origin and complexity of the clinical history of people with the disease. This article focuses on kidney injury's epidemiology, risk factors, and pathophysiological processes. Specifically, it focuses on the role of TLRs especially type 4 in disease development.

The incidence, patient features, risk factors and outcomes of surgery-associated postoperative acute kidney injury (PO-AKI) across different countries and health care systems is unclear.

We conducted an international prospective, observational, multi-center study in 30 countries in patients undergoing major surgery (> 2-h duration and postoperative intensive care unit (ICU) or high dependency unit admission). The primary endpoint was the occurrence of PO-AKI within 72 h of surgery defined by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Secondary endpoints included PO-AKI severity and duration, use of renal replacement therapy (RRT), mortality, and ICU and hospital length of stay.

We studied 10,568 patients and 1945 (18.4%) developed PO-AKI (1236 (63.5%) KDIGO stage 1500 (25.7%) KDIGO stage 2209 (10.7%) KDIGO stage 3). In 33.8% PO-AKI was persistent, and 170/1945 (8.7%) of patients with PO-AKI received RRT in the ICU. Patients with PO-AKI had greater ICU (6.3% vs. 0.7%) and hospital (8.6% vs. 1.4%) mortality, and longer ICU (median 2 (Q1-Q3, 1-3) days vs. 3 (Q1-Q3, 1-6) days) and hospital length of stay (median 14 (Q1-Q3, 9-24) days vs. 10 (Q1-Q3, 7-17) days). Risk factors for PO-AKI included older age, comorbidities (hypertension, diabetes, chronic kidney disease), type, duration and urgency of surgery as well as intraoperative vasopressors, and aminoglycosides administration.

In a comprehensive multinational study, approximately one in five patients develop PO-AKI after major surgery. Increasing severity of PO-AKI is associated with a progressive increase in adverse outcomes. Our findings indicate that PO-AKI represents a significant burden for health care worldwide.

Acute kidney injury (AKI) is a common syndrome characterized by a sudden reduction in kidney function. It is strongly associated with high mortality and longer, more expensive hospital stays. As AKI often presents silently, a lack of recognition can prevent recommended standards of care. Over the last decade or more, electronic alerts (eAlerts) for AKI have been studied and implemented to address this. This review will summarize the major randomized trials in this area.

A number of randomized trials now exist that study the effectiveness of AKI eAlerts in isolation or as part of more complex interventions. Varying results arise from differences in study design, healthcare system in which the eAlert is introduced, nature of alert, supporting interventions, implementation plan, stated aim (prevention or treatment of established AKI) and choice of outcome measures.

Current randomized trial evidence does not show any benefit of eAlerts on mortality. However, variously reported reductions in AKI incidence, AKI progression and AKI duration support a conclusion that strategies incorporating eAlerts can meaningfully benefit delivery of AKI care. Future work should consider how best eAlerts can be utilised, targeted and implemented.

Coronaviral disease 2019 (COVID-19) is a recent pandemic disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, there are still cases of COVID-19 around the world that can develop into persistent symptoms after discharge. The constellation of symptoms, termed long COVID, persists for months and can lead to various diseases such as lung inflammation and cardiovascular disease, which may lead to considerable financial burden and possible risk to human health. Moreover, the molecular mechanisms underlying the post-pandemic syndrome of COVID-19 remain unclear. In this study, we aimed to explore the molecular mechanism, disease association, and possible health risks in convalescent COVID-19 patients. Gene expression data from a human convalescent COVID-19 data set was compared with a data set from healthy normal individuals in order to identify differentially expressed genes (DEGs). To determine biological function and potential pathway alterations, the GO and KEGG databases were used to analyze the DEGs. Disease association, tissue, and organ-specific analyses were used to identify possible health effects. A total of 250 DEGs were identified between healthy and convalescent COVID-19 subjects. The biological function alterations identified revealed cytokine interactions and increased inflammation through NF-κB1, RELA, JUN, STAT3, and SP1. Interestingly, the most significant pathways were cytokine-cytokine receptor interaction, altered lipid metabolism, and atherosclerosis that play a crucial role in convalescent COVID-19. In addition, we also found pneumonitis, dermatitis, and autoimmune diseases. Based on our study, convalescent COVID-19 is associated with inflammation in a variety of organs that could lead to autoimmune and inflammatory diseases, as well as atherosclerosis. These findings are a first step toward fully exploring the disease mechanisms in depth to understand the relationship between post-COVID-19 infection and potential health risks. This is necessary for the development of appropriate strategies for the prevention and treatment of long COVID.

Acute kidney injury is a common complication of COVID-19, frequently fuelled by a complex interplay of factors. These include tubular injury and three primary drivers of cardiocirculatory instability: heart-lung interaction abnormalities, myocardial damage, and disturbances in fluid balance. Further complicating this dynamic, renal vulnerability to a "second-hit" injury, like a SARS-CoV-2 infection, is heightened by advanced age, chronic kidney disease, cardiovascular diseases, and diabetes mellitus. Moreover, the influence of chronic treatment protocols, which may constrain the compensatory intrarenal hemodynamic mechanisms, warrants equal consideration. COVID-19-associated acute kidney injury not only escalates mortality rates but also significantly affects long-term kidney function recovery, particularly in severe instances. Thus, the imperative lies in developing and applying therapeutic strategies capable of warding off acute kidney injury and decelerating the transition into chronic kidney disease after an acute event. This narrative review aims to proffer a flexible diagnostic and therapeutic strategy that recognizes the multi-faceted nature of COVID-19-associated acute kidney injury in critically ill patients and underlines the crucial role of a tailored, overarching hemodynamic and respiratory framework in managing this complex clinical condition.

Decreased kidney function is associated with increased risk of cardiovascular events and mortality, and heart failure (HF) is a wellknown risk factor for renal dysfunction. Acute kidney injury (AKI) in patients with HF often is attributed to prerenal factors, such as renal hypoperfusion and ischemia as a result of decreased cardiac output. Another such factor is reduction of absolute or relative circulating blood volume, with the decrease in renal blood flow leading to renal hypoxia followed by a decrease in the glomerular filtration rate. However, renal congestion is increasingly being recognized as a potential cause of AKI in patients with HF. Increased central venous pressure and renal venous pressure lead to increased renal interstitial hydrostatic pressure and a reduction of the glomerular filtration rate. Both decreased kidney function and renal congestion have been shown to be important prognostic factors of HF, and adequate control of congestion is important for improving kidney function. Loop and thiazide diuretics are recommended as standard therapies to reduce volume overload. However, these agents are associated with worsening renal function even though they are effective for improving congestive symptoms. There is growing interest in tolvaptan, which can improve renal congestion by increasing excretion of free water and decreasing the required dose of loop diuretic, thereby improving kidney function. This review summarizes renal hemodynamics, the pathogenesis of AKI due to renal ischemia and renal congestion, and diagnosis and treatment options for renal congestion.

Acute kidney injury (AKI) is a common complication in critically ill patients with sepsis and is often associated with a poor prognosis. We aimed to construct and validate an interpretable prognostic prediction model for patients with sepsis-associated AKI (S-AKI) using machine learning (ML) methods.

Data on the training cohort were collected from the Medical Information Mart for Intensive Care IV database version 2.2 to build the model, and data of patients were extracted from Hangzhou First People's Hospital Affiliated to Zhejiang University School of Medicine for external validation of model. Predictors of mortality were identified using Recursive Feature Elimination (RFE). Then, random forest, extreme gradient boosting (XGBoost), multilayer perceptron classifier, support vector classifier, and logistic regression were used to establish a prognosis prediction model for 7, 14, and 28 days after intensive care unit (ICU) admission, respectively. Prediction performance was assessed using the receiver operating characteristic (ROC) curve and decision curve analysis (DCA). SHapley Additive exPlanations (SHAP) were used to interpret the ML models.

In total, 2599 patients with S-AKI were included in the analysis. Forty variables were selected for the model development. According to the areas under the ROC curve (AUC) and DCA results for the training cohort, XGBoost model exhibited excellent performance with F1 Score of 0.847, 0.715, 0.765 and AUC (95% CI) of 0.91 (0.90, 0.92), 0.78 (0.76, 0.80), and 0.83 (0.81, 0.85) in 7 days, 14 days and 28 days group, respectively. It also demonstrated excellent discrimination in the external validation cohort. Its AUC (95% CI) was 0.81 (0.79, 0.83), 0.75 (0.73, 0.77), 0.79 (0.77, 0.81) in 7 days, 14 days and 28 days group, respectively. SHAP-based summary plot and force plot were used to interpret the XGBoost model globally and locally.

ML is a reliable tool for predicting the prognosis of patients with S-AKI. SHAP methods were used to explain intrinsic information of the XGBoost model, which may prove clinically useful and help clinicians tailor precise management.

Chemotherapeutic drug-induced acute kidney injury (AKI) involves pathologically increased labile iron species in the kidneys that mediate the excessive generation of reactive oxygen species (ROS) to induce ferroptosis and apoptosis, subsequently driving renal dysfunction. Herein, we report renal clearable quantum dot-drug conjugates (QDCs) composed of carbon quantum dot (CDs), deferoxamine (DFO), and poly(ethylene glycol) (PEG) for attenuating chemotherapeutic drug-induced AKI. The CDs component in QDCs can not only provide DFO with high renal specificity to effectively remove the pathological labile iron species in the kidneys to block the source of ROS generation but also exert high antioxidative effects to avoid renal oxidative damage caused by the ROS that have been overproduced. In cisplatin-induced AKI mice, QDCs can inhibit ferroptosis and apoptosis with high efficacy for AKI treatment. This study will provide a new paradigm to realize enhanced therapeutic efficacy for AKI by simultaneously removing the pathological labile iron species and eliminating overproduced ROS in the kidneys to achieve the goal of addressing both symptoms and root causes.

Kidneys are complex organs, and reproducing their function and physiology in a laboratory setting remains difficult. During drug development, potential compounds may exhibit unexpected nephrotoxic effects, which imposes a significant financial burden on pharmaceutical companies. As a result, there is an ongoing need for more accurate model systems. The use of renal organoids to simulate responses to nephrotoxic insults has the potential to bridge the gap between preclinical drug efficacy studies in cell cultures and animal models, and the stages of clinical trials in humans. Here we established an accessible fluorescent whole-mount approach for nuclear and membrane staining to first provide an overview of the organoid histology. Furthermore, we investigated the potential of renal organoids to model responses to drug toxicity. For this purpose, organoids were treated with the chemotherapeutic agent doxorubicin for 48 h. When cell viability was assessed biochemically, the organoids demonstrated a significant, dose-dependent decline in response to the treatment. Confocal microscopy revealed visible tubular disintegration and a loss of cellular boundaries at high drug concentrations. This observation was further reinforced by a dose-dependent decrease of the nuclear area in the analyzed images. In contrast to other approaches, in this study, we provide a straightforward experimental framework for drug toxicity assessment in renal organoids that may be used in early research stages to assist screen for potential adverse effects of compounds.

We aimed to analyze the optimal timing of enteral nutrition (EN) in the treatment of sepsis and its effect on sepsis-associated acute kidney injury (SA-AKI.).

The MIMIC-III database was employed to identify patients with sepsis who had received EN. With AKI as the primary outcome variable, receiver operating characteristic (ROC) curves were utilized to calculate the optimal cut-off time of early EN (EEN). Propensity score matching (PSM) was employed to control confounding effects. Logistic regressions and propensity score-based inverse probability of treatment weighting were utilized to assess the robustness of our findings. Comparisons within the EEN group were performed.

2364 patients were included in our study. With 53 hours after intensive care units (ICU) admission as the cut-off time of EEN according to the ROC curve, 1212 patients were assigned to the EEN group and the other 1152 to the delayed EN group. The risk of SA-AKI was reduced in the EEN group (odds ratio 0.319, 95% confidence interval 0.245-0.413, p<0.001). The EEN patients received fewer volumes (mL) of intravenous fluid (IVF) during their ICU stay (3750 mL vs. 5513.23 mL, p<0.001). The mediating effect of IVF was significant (p<0.001 for the average causal mediation effect). No significant differences were found within the EEN group (0-48 hours vs. 48-53 hours), except that patients initiating EN within 48 hours spent fewer days in ICU and hospital.

EEN is associated with decreased risk of SA-AKI, and this beneficial effect may be proportionally mediated by IVF volume.

Proton pump inhibitors (PPIs) are widely prescribed in medical practice for the treatment of several gastrointestinal disorders. Previous epidemiology studies have reported the association between PPI use and the risk of AKI, although the magnitude of the association between PPIs and the risk of acute kidney injury (AKI) remains uncertain. Therefore, we conducted a meta-analysis to determine the relationship between PPI therapy and the risk of AKI. We systematically searched for relevant articles published before January 2023 on PubMed, Scopus, and Web of Science. In addition, we conducted a manual search of the bibliographies of potential articles. Two independent reviewers examined the appropriateness of all studies for inclusion. We pooled studies that compared the risk of AKI with PPI against their control using a random effect model. The search criteria based on PRISMA guidelines yielded 568 articles. Twelve observational studies included 2,492,125 individuals. The pooled adjusted RR demonstrated a significant positive association between PPI therapy and the risk of AKI (adjusted RR 1.75, 95% CI: 1.40-2.19, p < 0.001), and it was consistent across subgroups. A visual presentation of the funnel plot and Egger's regression test showed no evidence of publication bias. Our meta-analysis indicated that persons using PPIs exhibited an increased risk of AKI. North American individuals had a higher risk of AKI compared to Asian and European individuals. However, the pooled effect from observational studies cannot clarify whether the observed association is a causal effect or the result of some unmeasured confounding factors. Hence, the biological mechanisms underlying this association are still unclear and require further research.

Necroinflammation plays an important role in disease settings such as acute kidney injury (AKI). We and others have elucidated that prostaglandins, which are critically involved in inflammation, may activate E-prostanoid 3 receptor (EP3) at low concentrations. However, how EP3 blockade interacts with regulated cell death and affects AKI remains unknown. In this study, AKI was induced by ischemia-reperfusion (30 minutes/24 hours) in Ep3 knockout (Ep3-/-), bone marrow chimeric, myeloid conditional EP3 knockout and corresponding control mice. The production of prostaglandins E2 and I2 was markedly increased after ischemia-reperfusion, and either abrogation or antagonism of EP3 ameliorated the injury. EP3 deficiency curbed inflammatory cytokine release, neutrophil infiltration and serum high-mobility group box 1 levels, but additional TLR4 inhibition with TAK-242 did not offer further protection against the injury and inflammation. The protection of Ep3-/- was predominantly mediated by suppressing Mixed Lineage Kinase domain-Like-dependent necroptosis, resulting from the inhibition of cytokine generation and the switching of cell death modality from necroptosis to apoptosis through caspase-8 up-regulation, in part due to the restraint of IL-6/JAK2/STAT3 signaling. EP3 deficiency failed to further alleviate the injury when necroptosis was inhibited. Ep3-/- in bone marrow-derived cells, particularly that in myeloid cells, protected kidneys to the same extent as that of global EP3 deletion. Thus, our results demonstrate that EP3 deficiency especially that on myeloid cells, ameliorates ischemic AKI via curbing inflammation and breaking the auto-amplification loop of necroinflammation. Hence, EP3 may be a promising target for the prevention and/or treatment of AKI.

Sepsis-induced acute kidney injury (AKI) is a singularly grievous and life-threatening syndrome. Its pathogenesis is closely related to inflammatory response, apoptosis, oxidative stress, and ferroptosis. Cation transport regulator-like protein 1 (CHAC1), as a proapoptic factor, may be involved in apoptosis, oxidative stress, and ferroptosis. This study aimed to explore the role of CHAC1 in the lipopolysaccharide (LPS)-induced the human renal proximal tubular epithelial (HK-2) cells.

HK-2 cells were challenged with LPS to construct a model of sepsis-induced AKI in vitro. The role of CHAC1 in the LPS-induced HK-2 cells was explored using Western blot assay, cell counting kit-8 (CCK-8), flow cytometry, and colorimetric assays. Additionally, N-acetyl cysteine (NAC) was incubated with HK-2 cells to define deeply the relation between oxidative stress and apoptosis or ferroptosis.

The expression of CHAC1 was enhanced in the kidney tissues of mice with sepsis--induced multiple organ dysfunction syndrome (MODS), through the Gene Expression Omnibus database (GSE60088 microarray dataset), and in the LPS-induced HK-2 cells. The cell viability was significantly reduced by LPS treatment, which was at least partly restored by the transfection of siCHAC1#1 and siCHAC1#2 but not siNC. In addition, down-regulation of CHAC1 counteracted the LPS-induced reactive oxygen species level and malonaldehyde concentrations while restored the LPS-induced glutathione concentrations. Meanwhile, interference of CHAC1 neutralized LPS-induced apoptosis rate, and the relative level of cleaved poly(ADP-ribose) polymerase (PARP)/PARP, and cleaved caspase-3/caspase-3. In addition, silencing of CHAC1 recovered the LPS-induced enhanced protein level of glutathione peroxidase 4 (GPx4) whereas antagonized the LPS-induced relative protein level of ACSL4 and that of iron. Moreover, application of NAC inverted the effect of CHAC1 on apoptosis and ferroptosis in HK-2 cells.

CHAC1 exacerbated ferroptosis and apoptosis by enhancing oxidative stress in LPS-induced HK-2 cells.

Nanozymes are artificial enzymes with high catalytic activity, low cost, and good biocompatibility, and have received ever-increasing attention in recent years. Various inorganic and organic nanoparticles have been found to exhibit enzyme-like activities and are used as nanozymes for diverse biomedical applications ranging from tumor imaging and therapeutics to detection. However, their further clinical applications are hindered by the potential toxicity and long-term retention of nanomaterials in vivo. Clarifying the catalytic mechanism of nanozymes and identifying the key factors responsible for their behavior can guide the design of nanozyme structure, enlighten the ways to improve their enzyme-like activities, and minimize the dosage of nanozymes, leading to reduced toxicity to the human body for a real biomedical application prospect. In particular, inflammation occurring in numerous diseases is closely related to reactive oxygen species, and the active oxygen scavenging ability of nanozymes potentially exerts excellent therapeutic effects on inflammatory diseases. In this review, we systematically summarize the structure-activity relationship of nanozymes, including regulation strategies for size and morphology, surface structure, and composition. Based on the structure-activity mechanisms, a series of chemically designed nanozymes developed to target various inflammatory diseases are briefly summarized.