Acute kidney injury (AKI) is a common clinically critical syndrome in hospitalized patients with high morbidity and mortality. At present, the mechanism of AKI has not been fully elucidated, and no therapeutic drugs exist. As known, glycolytic product lactate is a key metabolite in physiological and pathological processes. The kidney is an important gluconeogenic organ, where lactate is the primary substrate of renal gluconeogenesis in physiological conditions. During AKI, altered glycolysis and gluconeogenesis in kidneys significantly disturb the lactate metabolic balance, which exert impacts on the severity and prognosis of AKI. Additionally, lactate-derived posttranslational modification, namely lactylation, is novel to AKI as it could regulate gene transcription of metabolic enzymes involved in glycolysis or Warburg effect. Protein lactylation widely exists in human tissues and may severely affect non-histone functions. Moreover, the strategies of intervening lactate metabolic pathways are expected to bring a new dawn for the treatment of AKI. This review focused on renal lactate metabolism, especially in proximal renal tubules after AKI, and updated recent advances of lactylation modification, which may help to explore potential therapeutic targets against AKI.
Humans ; Acute Kidney Injury/metabolism* ; Lactic Acid/metabolism* ; Animals ; Glycolysis/physiology* ; Gluconeogenesis/physiology* ; Kidney/metabolism*

Acute kidney injury (AKI) affects more than 20% of hospitalized patients and is a significant contributor to morbidity and mortality, primarily due to ischemia-reperfusion injury (IRI), which is one of the leading causes of AKI. IRI not only exacerbates the immediate impact of AKI but also facilitates its progression to chronic kidney disease (CKD) and, in cases of preexisting CKD, to end-stage renal disease (ESRD). One of the critical pathological processes associated with IRI-AKI is cellular senescence, characterized by an irreversible arrest in the cell cycle, morphological and chromatin organization changes, altered transcriptional and metabolic profiles, and the development of a hypersecretory phenotype known as the senescence-associated secretory phenotype (SASP). The SASP amplifies senescence signals in surrounding normal cells through senescence-related pathways, contributing to tissue damage, fibrosis, and chronic inflammation. This review provides an overview of the defining features of senescent cells and explores the fundamental mechanisms underlying senescent cell generation following IRI. We elucidate the pivotal roles of cellular senescence in the transition from IRI-AKI to chronic kidney injury. Furthermore, we discuss emerging therapies targeting cellular senescence, including senolytics and senomorphics, which have shown promising results in both preclinical and clinical settings. These therapies position cellular senescence as a crucial target for the treatment of IRI in the kidneys. Additionally, advancements in single-cell sequencing technology and artificial intelligence-assisted drug screening are expected to accelerate the discovery of novel senescent biomarkers and synotherapeutics, paving the way for optimized and personalized therapeutic interventions.
Humans ; Cellular Senescence/physiology* ; Reperfusion Injury/pathology* ; Acute Kidney Injury/pathology* ; Animals ; Kidney/metabolism* ; Senescence-Associated Secretory Phenotype/physiology*

OBJECTIVES: To investigate the clinical sub-phenotype (SP) of pediatric acute kidney injury (AKI) and their association with clinical outcomes. METHODS: General status and initial values of laboratory markers within 24 hours after admission to the pediatric intensive care unit (PICU) were recorded for children with AKI in the derivation cohort (n=650) and the validation cohort (n=177). In the derivation cohort, a least absolute shrinkage and selection operator (LASSO) regression analysis was used to identify death-related indicators, and a two-step cluster analysis was employed to obtain the clinical SP of AKI. A logistic regression analysis was used to develop a parsimonious classifier model with simplified metrics, and the area under the curve (AUC) was used to assess the value of this model. This model was then applied to the validation cohort and the combined derivation and validation cohort. The association between SPs and clinical outcomes was analyzed with all children with AKI as subjects. RESULTS: In the derivation cohort, two clinical SPs of AKI (SP1 and SP2) were identified by the two-step cluster analysis using the 20 variables screened by LASSO regression, namely SP_d1 group (n=536) and SP_d2 group (n=114). The simplified classifier model containing eight variables (P<0.05) had an AUC of 0.965 in identifying the two clinical SPs of AKI (P<0.001). The validation cohort was clustered into SP_v1 group (n=156) and SP_v2 group (n=21), and the combined derivation and validation cohort was clustered into SP1 group (n=694) and SP2 group (n=133). After adjustment for confounding factors, compared with the SP1 group, the SP2 group had significantly higher incidence rates of multiple organ dysfunction syndrome and death during the PICU stay (P<0.001), and SP2 was significantly associated with the risk of death within 28 days after admission to the PICU (P<0.001). CONCLUSIONS This study establishes a parsimonious classifier model and identifies two clinical SPs of AKI with different clinical features and outcomes.The SP2 group has more severe disease and worse clinical prognosis.
Humans ; Acute Kidney Injury/diagnosis* ; Prognosis ; Male ; Female ; Child ; Child, Preschool ; Phenotype ; Infant ; Logistic Models ; Adolescent

Renal ischemia-reperfusion injury (IRI) is a major contributor to acute kidney injury (AKI), leading to substantial morbidity and mortality. Spexin (SPX), a 14-amino acid endogenous peptide involved in metabolic regulation and immune modulation, has not yet been studied in the context of chronic treatment and renal IRI. This study evaluated the effects of exogenous SPX on renal function, histopathological changes, and molecular pathways in both IRI-induced injured and healthy kidneys. Twenty-eight male BALB/c mice were divided into four groups: control, SPX, IRI, and SPX+IRI. IRI was induced by 30 minutes of bilateral renal ischemia followed by 6 hours of reperfusion. Renal injury markers, histopathological changes, inflammatory mediators, apoptotic markers, and fibrosis-related proteins were analyzed. SPX significantly exacerbated IRI-induced kidney injury by activating the Wnt/β-catenin signaling pathway and promoting the upregulation of pro-inflammatory, pro-apoptotic, and pro-fibrotic mediators. It is noteworthy that SPX exerted more severe deleterious nephrotoxic effects in the healthy kidney compared to those observed in the IRI-induced injured kidney. These findings indicate that chronic treatment with SPX administration may have intrinsic pro-inflammatory, pro-apoptotic and fibrotic properties, raising concerns about its therapeutic potential. Further research is needed to clarify its physiological role and therapeutic implications in kidney diseases.
Animals ; Reperfusion Injury/chemically induced* ; Male ; Mice, Inbred BALB C ; Mice ; Acute Kidney Injury/metabolism* ; Kidney/blood supply* ; Peptide Hormones/adverse effects* ; Apoptosis/drug effects* ; Wnt Signaling Pathway/drug effects* ; Disease Models, Animal

OBJECTIVE: To investigate the effects of using different filters in continuous renal replacement therapy (CRRT) on the mortality, inflammatory mediator level and hemodynamics in patients with sepsis-associated acute kidney injury (SA-AKI). METHODS: A prospective study was conducted. The patients with SA-AKI undergoing first CRRT admitted to the critical care medicine department of General Hospital of Ningxia Medical University from August 2022 to October 2023 were enrolled as the study objects, and they were divided into observation group and control group by random number table method. All patients received routine treatment including anti-infection, optimized volume management and organ function support. On this basis, the observation group was treated with oXiris filter for CRRT, while the control group was treated with ordinary filter for CRRT, and the first treatment time was ≥ 36 hours. General data of the two groups were collected and compared. At the same time, the inflammatory indicators [high-sensitivity C-reactive protein (hs-CRP), procalcitonin (PCT), interleukin-6 (IL-6)], sequential organ failure assessment (SOFA) score, mean arterial pressure (MAP), blood lactic acid (Lac), noradrenaline dosage and other related indicators were collected before CRRT treatment and 24 hours and 48 hours after treatment, and the 7-day and 28-day mortality of patients were recorded. RESULTS: Finally, 65 patients were enrolled, including 30 in the observation group and 35 in the control group. There were no significant differences in baseline data including age, gender, acute kidney injury (AKI) stage and infection source between the two groups. The 7-day mortality of observation group was significantly lower than that of control group [16.7% (5/30) vs. 42.9% (15/35), P < 0.05]. There was no significant difference in 28-day mortality between the observation group and the control group [36.7% (11/30) vs. 54.3% (19/35), P > 0.05]. There were no significant differences in inflammation indicators, SOFA score, MAP, Lac and norepinephrine dosage before treatment between the two groups. After 24-hour and 48-hour treatment, the hemodynamics of the two groups were stable compared with before treatment, the inflammatory indicators, SOFA score, Lac and norepinephrine dosage were reduced to varying degrees, and MAP was significantly increased. In the observation group, hs-CRP, PCT, IL-6, SOFA score, MAP, and norepinephrine dosage showed statistical significance at 24 hours after treatment as compared with before treatment [hs-CRP (mg/L): 125.0 (105.0, 171.2) vs. 280.5 (213.2, 313.8), PCT (μg/L): 51.0 (20.0, 62.8) vs. 71.0 (10.8, 100.0), IL-6 (ng/L): 1 762.2 (300.8, 4 327.5) vs. 4 447.5 (630.4, 5 000.0), SOFA score: 13.0 (12.0, 14.0) vs. 16.0 (15.0, 17.0), MAP (mmHg, 1 mmHg ≈ 0.133 kPa): 79.00±12.87 vs. 65.20±11.70, norepinephrine dosage (μg×kg^-1×min^-1): 0.82±0.33 vs. 1.63±0.51, all P < 0.05]. In the control group, PCT and MAP showed statistical significance after 48 hours of treatment as compared with before treatment. Compared with the control group, hs-CRP, SOFA score and norepinephrine dosage after 48 hours of treatment in the observation group were significantly decreased [hs-CRP (mg/L): 87.2 (74.2, 126.0) vs. 157.0 (88.0, 200.0), SOFA score: 11.0 (10.0, 12.0) vs. 12.0 (10.0, 14.0), norepinephrine dosage (μg×kg^-1×min^-1): 0.51±0.37 vs. 0.81±0.58, all P < 0.05], MAP was significantly increased (mmHg: 82.00±8.71 vs. 77.77±7.80, P < 0.05). CONCLUSION In the treatment of CRRT, oXiris filter can reduce the short-term mortality of SA-AKI patients, lower inflammatory mediators levels and improve hemodynamics, showing therapeutic advantages over conventional filters.
Humans ; Acute Kidney Injury/etiology* ; Sepsis/therapy* ; Prospective Studies ; Interleukin-6 ; Continuous Renal Replacement Therapy/methods* ; C-Reactive Protein ; Male ; Female ; Middle Aged ; Hemodynamics ; Procalcitonin ; Aged

Sepsis is a life-threatening organ dysfunction syndrome caused by a dysregulated host response to infection. Septic acute kidney injury (SAKI) is one of the most common complications of sepsis, and the occurrence of acute kidney injury (AKI) indicates that the patient's condition is critical with a poor prognosis. The traditional view holds that the main mechanism of SAKI is the reduction of renal blood flow, inadequate renal perfusion, inflammatory response, and microcirculatory dysfunction caused by sepsis, which subsequently leads to ischemia and necrosis of renal tubular cells. Recent research findings indicate that processes such as autophagy and other forms of programmed cell death play an increasingly important role. Autophagy is a programmed intracellular degradation process and is a form of programmed cell death. Cells degrade their cytoplasmic components via lysosomes, breaking down and recycling intracellular constituents to meet their metabolic needs, maintain intracellular homeostasis, and renew organelles. During SAKI, autophagy plays a crucial protective role through various mechanisms, including regulating inflammation and immune responses, clearing damaged organelles, and maintaining stability in the intracellular environment. In recent years, the role of autophagy in the pathogenesis and treatment of SAKI has received widespread attention. Research has confirmed that various intracellular signaling pathways and signaling molecules targeting autophagy [such as mammalian target of rapamycin (mTOR) signaling pathway, AMP-activated protein kinase (AMPK) signaling pathway, nuclear factor-κB (NF-κB) signaling pathway, and Sirtuins (SIRT), autophagy associated factor Beclin-1, and Toll-like receptor (TLR)] are involved in the development of SAKI. Due to the complex pathogenesis of SAKI, current treatment strategies include fluid management, infection control, maintenance of internal environment balance, and renal replacement therapy; however, the mortality remains high. In recent years, it has been found that autophagy plays a critical protective role in sepsis-mediated AKI. As a result, an increasing number of drugs are being developed to alleviate SAKI by regulating autophagy. This article reviews the latest advances in the role of autophagy in the pathogenesis and treatment of SAKI, with the aim of providing insights for the development of new drugs for SAKI patients.
Humans ; Acute Kidney Injury/etiology* ; Autophagy ; Sepsis/complications* ; Signal Transduction

OBJECTIVE: To investigate the predictive value of inflammatory indicator and serum cystatin C (Cys C) for the prognosis of patients with sepsis-associated acute kidney injury (SA-AKI). METHODS: A prospective observational study was conducted. Patients with SA-AKI admitted to the intensive care unit (ICU) of the General Hospital of Ningxia Medical University from January 2022 to December 2023 were selected as the study subjects. General patient data, sequential organ failure assessment (SOFA), acute physiology and chronic health evaluation II (APACHE II), inflammatory indicator, and serum Cys C levels were collected. The 28-day survival status of the patients was observed. A multivariate Logistic regression model was used to analyze the risk factors affecting the poor prognosis of SA-AKI patients. Receiver operator characteristic curve (ROC curve) was plotted to evaluate the predictive efficacy of each risk factor for the prognosis of SA-AKI patients. RESULTS: A total of 111 SA-AKI patients were included, with 65 patients (58.6%) in the survival group and 46 patients (41.4%) in the death group. The SOFA score, APACHE II score, interleukin-6 (IL-6), procalcitonin (PCT), hypersensitive C-reactive protein (hs-CRP), and serum Cys C levels in the death group were significantly higher than those in the survival group [SOFA score: 15.00 (14.00, 17.25) vs. 14.00 (11.00, 16.00), APACHE II score: 26.00 (23.75, 28.00) vs. 23.00 (18.50, 28.00), IL-6 (ng/L): 3 731.00±1 573.61 vs. 2 087.93±1 702.88, PCT (μg/L): 78.19±30.35 vs. 43.56±35.37, hs-CRP (mg/L): 266.50 (183.75, 326.75) vs. 210.00 (188.00, 273.00), serum Cys C (mg/L): 2.01±0.61 vs. 1.62±0.50, all P < 0.05]. Multivariate Logistic regression analysis showed that SOFA score [odds ratio (OR) = 1.273, 95% confidence interval (95%CI) was 1.012-1.600, P = 0.039], IL-6 (OR = 1.000, 95%CI was 1.000-1.001, P = 0.043), PCT (OR = 1.018, 95%CI was 1.002-1.035, P = 0.030), and Cys C (OR = 4.139, 95%CI was 1.727-9.919, P = 0.001) were independent risk factors affecting the 28-day prognosis of SA-AKI patients. ROC curve analysis showed that the area under the curve (AUC) of SOFA score, IL-6, PCT, and Cys C in predicting the 28-day prognosis of SA-AKI patients were 0.682 (95%CI was 0.582-0.782, P = 0.001), 0.753 (95%CI was 0.662-0.843, P < 0.001), 0.765 (95%CI was 0.677-0.854, P < 0.001), and 0.690 (95%CI was 0.583-0.798, P = 0.001), respectively. The combined predictive value of these four indicators for the prognosis of SA-AKI patients were superior to that of any single indicator, with an AUC of 0.847 (95%CI was 0.778-0.916, P < 0.001), a sensitivity of 95.7%, and a specificity of 56.9%. CONCLUSION The combination of SOFA score, IL-6, PCT, and Cys C provides a reliable predictive value for the prognosis of SA-AKI patients.
Humans ; Acute Kidney Injury/mortality* ; APACHE ; C-Reactive Protein ; Cystatin C/blood* ; Interleukin-6/blood* ; Logistic Models ; Predictive Value of Tests ; Procalcitonin/blood* ; Prognosis ; Prospective Studies ; Risk Factors ; ROC Curve ; Sepsis/mortality*

OBJECTIVE: To assess the impact of albumin (Alb) administration on the prognosis of patients with acute kidney injury (AKI). METHODS: Clinical data of AKI patients in the intensive care unit (ICU) were retrospectively analyzed from the American Medical Information Mart of Intensive Care-IV (MIMIC-IV), including demographic data, acute physiology score (APS), comorbidities, vital signs, laboratory indicators, treatment status, ICU length of stay, and outcome indicators. The main outcome measure is ICU mortality. AKI patients were divided into Alb infusion group and Alb non infusion group based on whether they received Alb treatment. Multiple imputation was used to process missing data and eliminate variables that missing more than 30%. To ensure the stability of the results, propensity score matching (PSM) and inverse probability weighting (IPW) were used to correct the results. Using Kaplan-Meier survival curve and Cox proportional hazards regression model to evaluate the effect of Alb infusion on ICU survival rate in AKI patients. Perform subgroup analysis based on patient age, gender, and comorbidities to evaluate the prognostic effects of Alb on different patient subgroups. RESULTS: A total of 6 390 AKI patients were included, including 1 721 in the Alb infusion group and 4 669 in the Alb non infusion group. After adjusting for key covariates in the Cox regression model, compared with the Alb non infusion group, patients in the Alb infusion group were significantly younger in age, with APS III score, proportion of vasoactive drugs and continuous renal replacement therapy (CRRT) use, sepsis proportion, heart rate, respiratory frequency, aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine (Cr), lactic acid (Lac), and arterial partial pressure of carbon dioxide (PaCO₂) levels significantly higher. The proportion of hypertension, myocardial infarction, and congestive heart failure, as well as blood pressure, urine output, platelet count (PLT), and Alb levels were significantly lower. The results of univariate and multivariate Cox regression analysis on the raw data showed that the risk of death in the Alb infusion group was significantly lower than that in the Alb non infusion group [hazard ratio (HR) = 0.69, 95% confidence interval (95%CI) was 0.60-0.80, all P < 0.05]. The results after propensity score matching (PSM) and inverse probability weighting (IPW) processing are consistent with the original data trend (both P < 0.05). The Kaplan-Meier survival curve showed that the cumulative survival rate during ICU stay in the Alb infusion group was significantly higher than that in the Alb non infusion group (24.48% vs. 12.17%, Log-Rank test: χ² = 74.26, P < 0.05). Subgroup analysis shows that Alb infusion has a more significant survival benefit for AKI patients who use vasoactive drugs, have concurrent sepsis, and do not have liver disease. CONCLUSION Albumin infusion can decrease the ICU mortality of AKI patients.
Humans ; Retrospective Studies ; Acute Kidney Injury/mortality* ; Prognosis ; Male ; Female ; Middle Aged ; Aged ; Intensive Care Units ; Albumins/therapeutic use* ; Proportional Hazards Models ; Adult ; Databases, Factual

OBJECTIVE: To investigate the relationship between mean perfusion pressure (MPP) and the risk of sepsis-associated acute kidney injury (SA-AKI) and its prognosis, and to determine the optimal cut-off value of MPP for predicting SA-AKI. METHODS: A retrospective cohort study was conducted. The clinical data of adult patients with sepsis were collected from the Medical Information Mart for Intensive Care-IV 2.2 (MIMIC-IV 2.2) database. The patients were divided into two groups based on the occurrence of SA-AKI. Baseline characteristics, vital signs, comorbidities, laboratory indicators within 24 hours of intensive care unit (ICU) admission, and clinical outcome indicators were collected. Mean MPP was calculated using the average values of mean arterial pressure (MAP) and central venous pressure (CVP), MPP = MAP-CVP. Cox regression models were constructed, relevant confounding factors were adjusted, and multivariate Logistic regression analysis was used to investigate the associations between MPP and the risk of SA-AKI as well as ICU death. The predictive value of MPP for SA-AKI was evaluated using receiver operator characteristic curve (ROC curve) analysis, and the optimal cut-off value was determined. RESULTS: A total of 6 009 patients were ultimately enrolled in the analysis. Among them, SA-AKI occurred in 4 755 patients (79.13%), while 1 254 patients (20.87%) did not develop SA-AKI. Compared with the non-SA-AKI group, the MPP in the SA-AKI group was significantly lowered [mmHg (1 mmHg≈0.133 kPa): 62.00 (57.00, 68.00) vs. 65.00 (60.00, 70.00), P < 0.01], and the ICU mortality was significantly increased [11.82% (562/4 755) vs. 1.59% (20/1 254), P < 0.01]. Three Cox regression models were constructed: model 1 was unadjusted; model 2 was adjusted for gender, age, height, weight and race; model 3 was adjusted for gender, age, height, weight, race, heart rate, respiratory rate, body temperature, hemoglobin, platelet count, white blood cell count, anion gap, HCO₃^-, blood urea nitrogen, serum creatinine, Cl^-, Na⁺, K⁺, fibrinogen, international normalized ratio, blood lactic acid, pH value, arterial partial pressure of oxygen, arterial partial pressure of carbon dioxide, sequential organ failure assessment score, Charlson comorbidity index score, use of vasopressors, mechanical ventilation, and urine output. Multivariate Logistic regression analysis showed that when MPP was treated as a continuous variable, there was a negative correlation between MPP and the risk of SA-AKI in model 1 and model 2 [model 1: odds ratio (OR) = 0.967, 95% confidence interval (95%CI) was 0.961-0.974, P < 0.001; model 2: OR = 0.981, 95%CI was 0.974-0.988, P < 0.001], and also a negative correlation between MPP and the risk of ICU death (model 1: OR = 0.955, 95%CI was 0.945-0.965, P < 0.001; model 2: OR = 0.956, 95%CI was 0.946-0.966, P < 0.001). However, in model 3, there was no significant correlation between MPP and either SA-AKI risk or ICU death risk. when MPP was used as a multi-categorical variable, in model 1 and model 2, referring to MPP ≤ 58 mmHg, when 59 mmHg ≤ MPP ≤ 68 mmHg, as MPP increased, the risk of SA-AKI progressively decreased (OR value was 0.411-0.638, all P < 0.001), and the risk of ICU death also gradually decreased (OR value was 0.334-0.477, all P < 0.001). ROC curve showed that MPP had a certain predictive value for SA-AKI occurrence [area under the ROC curve (AUC) = 0.598, 95%CI was 0.404-0.746], and the optimal cut-off value was 60.5 mmHg. CONCLUSION MPP was significantly associated with the risk of SA-AKI, with an optimal cut-off value of 60.5 mmHg, and also demonstrated a significant correlation with the risk of ICU death.
Humans ; Acute Kidney Injury/physiopathology* ; Retrospective Studies ; Sepsis/physiopathology* ; Middle Aged ; Prognosis ; Male ; Female ; Aged ; Risk Factors ; Intensive Care Units ; Adult ; Logistic Models ; Proportional Hazards Models

Peroxisome proliferator activated receptor-α (PPAR-α) is significantly expressed in various tissues such as the liver, kidney, myocardium, and skeletal muscle, which plays a central role in the development of various diseases by regulating key physiological processes such as energy homeostasis, redox balance, inflammatory response, and ferroptosis. As an important metabolic and excretory organ of the body, renal dysfunction can lead to water and electrolyte imbalance, toxin accumulation, and multiple system complications. The causes of kidney injury are complex and diverse, including acute injury factors (such as ischemia/reperfusion, nephrotoxic drugs, septic shock, and immune glomerulopathy), as well as chronic progressive causes [such as metabolic disease-related nephropathy, hypertensive nephropathy (HN)], and risk factors such as alcohol abuse, obesity, and aging. This review briefly describes the structure, function, and activity regulation mechanism of PPAR-α, systematically elucidates the molecular regulatory network of PPAR-α in the pathological process of kidney injury including acute kidney injury (AKI) such as renal ischemia/reperfusion injury (IRI), drug-induced AKI, sepsis-associated acute kidney injury (SA-AKI), glomerulonephritis, chronic kidney disease (CKD) such as diabetic nephropathy (DN), HN, and other kidney injury, and summarizes the mechanisms related to PPAR-α regulation of kidney injury, including regulation of metabolism, antioxidation, anti-inflammation, anti-fibrosis, and anti-ferroptosis. This review also evaluates PPAR-α's medical value as a novel therapeutic target, and aims to provide theoretical basis for the development of kidney protection strategies based on PPAR-α targeted intervention.
Humans ; PPAR alpha/metabolism* ; Acute Kidney Injury/therapy* ; Animals ; Kidney/metabolism*