Biomarkers Of Acute Kidney Injury Research Articles

Proficient Novel Biomarkers Guide Early Detection of Acute Kidney Injury: A Review

The definition of acute kidney injury (AKI), despite improvements in criteria, continues to be based on the level of serum creatinine and urinary output that do not specifically indicate tubular function or injury, or glomerular function or injury that is not significant enough to warrant acute hospitalization of the patient. Finding novel biomarkers of AKI has become a major focus nowadays in nephrology to overcome the further complications of end stage renal disease (ESRD). Many compounds, such as KIM 1, IL 18, NGAL, uromodulin, calprotectin, vanin 1, galactin 3, platelet-derived growth factor (PDGF), urinary Na+/H+ exchanger isoform 3 (NHE3), retinol binding protein (RBP) and Cystatin C, are released from the renal tubules and thus any alterations in tubular function can be detected by measuring these parameters in urine. Additionally, glomerular injury can be detected by measuring immunoglobulin G, nephrin, podocalyxin, podocin, transferrin, netrin-1, pyruvate kinase M2, etc. in urine. These novel biomarkers will be useful for timing the initial insult and assessing the duration of AKI. According to available research, these biomarkers could be applied to assess the onset of AKI, distinguishing between kidney injury and dysfunction, directing the management of AKI, and enhancing disease diagnosis. Therefore, we intend to present recent developments in our understanding of significant biomarkers implicated in various aspects of renal damage. Numerous biomarkers are implicated in various pathophysiological processes that follow renal injury, and can improve prognosis and risk classification.

What Promotes Acute Kidney Injury in Patients with Myocardial Infarction and Multivessel Coronary Artery Disease-Contrast Media, Hydration Status or Something Else?

Multivessel coronary artery disease (MVCAD) is found in approximately 50% of patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI). Although we have data showing the benefits of revascularization of significant non-culprit coronary lesions in patients with AMI, the optimal timing of angioplasty remains unclear. The most common reason for postponing subsequent percutaneous treatment is the fear of contrast-induced acute kidney injury (CI-AKI). Acute kidney injury (AKI) is common in patients with AMI undergoing PCI, and its etiology appears to be complex and incompletely understood. In this review, we discuss the definition, pathophysiology and risk factors of AKI in patients with AMI undergoing PCI. We present the impact of AKI on the course of hospitalization and distant prognosis of patients with AMI. Special attention was paid to the phenomenon of AKI in patients undergoing multivessel revascularization. We analyze the correlation between increased exposure to contrast medium (CM) and the risk of AKI in patients with AMI to provide information useful in the decision-making process about the optimal timing of revascularization of non-culprit lesions. In addition, we present diagnostic tools in the form of new biomarkers of AKI and discuss ways to prevent and mitigate the course of AKI.

Urinary interleukin-18 as a biomarker of Acute Kidney Injury in the Critically Ill Patients

Urinary interleukin-18 as a biomarker of Acute Kidney Injury in the Critically Ill Patients

Role of neutrophil gelatinase-associated lipocalin (NGAL) as a acute prerenal kidney injury marker: Exploring factors associated with its postoperative levels in hypotension-controlled otorhinolaryngology surgery

Introduction: Acute kidney injury (AKI) is a sudden decrease in kidney function due to damage within seven days or less, thus inducing an early stress response that can be promptly detected by biomarkers, such as Neutrophil Gelatinase-Associated Lipocalin (NGAL). The aim of this study was to analyse the role of NGAL level as a biomarker of postoperative prerenal AKI in patients who underwent otorhinolaryngology surgery with controlled hypotension. Methods: A prospective study was conducted among patients that underwent otorhinolaryngology surgery with controlled hypotension. Patients were selected with purposive sampling. NGAL level was measured using enzyme-linked immunosorbent assay (ELISA) from venous blood collected 1-hour pre- and 2-hour post-surgery. NGAL levels were compared between preoperative and postoperative states. Wilcoxon and Spearman test were used to determine the correlation between NGAL levels and parameters of AKI. Results: A total of 30 patients underwent a varies of otorhinolaryngology surgeries were recruited in this study. Our data suggested no significant different between the level of NGAL during preoperative and postoperative (184.73±120.09 ng/mL vs 175.80±129.97 ng/mL). Pre-operative laboratory parameters of AKI such as blood urea nitrogen (BUN), serum creatine (SCr), BUN/SCr ratio, and GFR had no correlation with postoperative NGAL level. In addition, systolic blood pressure, diastolic blood pressure, MAP, heart rate, EtCO2, duration of surgery and the duration of controlled hypotension had no correlation with postoperative NGAL. Conclusion: NGAL levels have nonsignificant role as biomarker of incidence of postoperative prerenal AKI in patients who receiving otorhinolaryngology surgery with controlled hypotension. However, further study with the bigger sample size is warrant to confirm the findings of this study.

In situ detection of alkaline phosphatase in a cisplatin-induced acute kidney injury model with a fluorescent/photoacoustic bimodal molecular probe.

Kidneys play an important part in drug metabolism and excretion. High local concentration of drugs or drug allergies often cause acute kidney injury (AKI). Identification of effective biomarkers of initial stage AKI and constructing activable molecular probes with excellent detection properties for early evaluation of AKI are necessary, yet remain significant challenges. Alkaline phosphatase (ALP), a key hydrolyzing protease, exists in the epithelial cells of the kidney and is discharged into the urine following kidney injury. However, no studies have revealed its level in drug-induced AKI. Existing ALP fluorescent molecular probes are not suitable for testing and imaging of ALP in the AKI model. Drug-induced AKI is accompanied by oxidative stress, and many studies have indicated that a large increase in reactive oxygen species (ROS) occur in the AKI model. Thus, the probe used for imaging of AKI must be chemically stable in the presence of ROS. However, most existing near-infrared fluorescent (NIRF) ALP probes are not stable in the presence of ROS in the AKI model. Hence, we built a chemically stable molecular sensor (CS-ALP) to map ALP level in cisplatin-induced AKI. This novel probe is not destroyed by ROS generated in the AKI model, thus allowing high-fidelity imaging. In the presence of ALP, the CS-ALP probe generates a new absorbance peak at 685nm and a fluorescent emission peak at 716nm that could be used to "turn on" photoacoustic (PA) and NIRF imaging of ALP in AKI. Levels of CS-ALP build up rapidly in the kidney, and CS-ALP has been successfully applied in NIRF/PA bimodal in vivo imaging. Through the NIRF/PA bimodal imaging results, we demonstrate that upregulated expression of ALP occurs in the early stages of AKI and continues with injury progression.

Renal Endothelial Cell-Targeted Extracellular Vesicles Protect the Kidney from Ischemic Injury.

Endothelial cell injury plays a critical part in ischemic acute kidney injury (AKI) and participates in the progression of AKI. Targeting renal endothelial cell therapy may ameliorate vascular injury and further improve the prognosis of ischemic AKI. Here, P-selectin as a biomarker of ischemic AKI in endothelial cells is identified and P-selectin binding peptide (PBP)-engineered extracellular vesicles (PBP-EVs) with imaging and therapeutic functions are developed. The results show that PBP-EVs exhibit a selective targeting tendency to injured kidneys, while providing spatiotemporal information for the early diagnosis of AKI by quantifying the expression of P-selectin in the kidneys by molecular imaging. Meanwhile, PBP-EVs reveal superior nephroprotective functions in the promotion of renal repair and inhibition of fibrosis by alleviating inflammatory infiltration, improving reparative angiogenesis, and ameliorating maladaptive repair of the renal parenchyma. In conclusion, PBP-EVs, as an ischemic AKI theranostic system that is designed in this study, provide a spatiotemporal diagnosis in the early stages of AKI to help guide personalized therapy and exhibit superior nephroprotective effects, offering proof-of-concept data to design EV-based theranostic strategies to promote renal recovery and further improve long-term outcomes following AKI.

No safe renal warm ischemia time-The molecular network characteristics and pathological features of mild to severe ischemia reperfusion kidney injury.

Ischemic acute kidney injury (AKI) has always been a hot and difficult research topic in the field of renal diseases. This study aims to illustrate the safe warm ischemia time of kidney and the molecular network characteristics and pathological features of mild to severe ischemia reperfusion kidney injury. We established varying degrees of renal injury due to different ischemia time (0min, 16min, 18min, 20min, 22min, 24min, 26min, 28min, and 30min) on unilateral (left kidney) ischemia-reperfusion injury and contralateral (right kidney) resection (uIRIx) mouse model. Mice were sacrificed 24h after uIRIx, blood samples were harvested to detect serum creatinine (Scr), and kidney tissue samples were harvested to perform Periodic Acid-Schiff (PAS) staining and RNA-Seq. Differentially expressed genes (DEGs) were identificated, time-dependent gene expression patterns and functional enrichment analysis were further performed. Finally, qPCR was performed to validated RNA-Seq results. Our results indicated that there was no absolute safe renal warm ischemia time, and every minute of ischemia increases kidney damage. Warm ischemia 26min or above in mice makes severe kidney injury, renal pathology and SCr were both significantly changed. Warm ischemia between 18 and 26min makes mild kidney injury, with changes in pathology and renal molecular expression, while SCr did not change. No obvious pathological changes but significant differences in molecular expression were found less than 16min warm ischemia. There are two key time intervals in the process of renal ischemia injury, 0min-16min (short-term) and 26min-28min (long-term). Gene expression of immune-related pathways were most significantly down-regulated in short-term ischemia, while metabolism-related pathways were the mainly enriched pathway in long-term ischemia. Taken together, this study provides novel insights into safe renal artery occlusion time in partial nephrectomy, and is of great value for elucidating molecular network characteristics and pathological features of mild to severe ischemia reperfusion kidney injury, and key genes related to metabolism and immune found in this study also provide potential diagnostic and therapeutic biomarkers for AKI.

Validation of Neutrophil gelatinase associated lipocalin (NGAL), a urinary biomarker for Acute Kidney Injury and the positive interference from high leukocyturia samples

Abstract Acute kidney injury (AKI) is a sudden and serious kidney damage condition that affects more than 1.2 million people every year. KIDNEY DISEASE IMPROVING GLOBAL OUTCOMES (KDIGO) guidelines currently suggest measuring the increase of serum creatinine as a diagnostic marker for AKI. However, the elevation of serum creatinine levels can take up to seven days or when >50% kidney function is lost. Neutrophil gelatinase-associated lipocalin (NGAL) has been identified as an early biomarker for tubular injury, which can be detected in the urine of AKI patients in as early as three hours. In the current study, we evaluated the performance of BioPorto’s (Hellerup, Denmark) NGAL assay, which uses particle enhanced turbidimetry immunoassay (PETIA) technology on the Roche (Indianapolis, USA) cobas c502 chemistry analyzer. Linearity was determined using linearity material from BioPorto and also verified by serial dilutions of a high NGAL patient sample. The limit of quantitation was determined by running urine samples with values of 20 ng/mL, 25 ng/mL, and 35 ng/mL, respectively in duplicate for 10 days. Within-run precisions were determined by running urine two samples containing 100 ng/mL and 400 ng/mL NGAL 20 times and between–run precisions were determined by running the same samples 2 times a day for 10 days. To determine the accuracy of the NGAL method on cobas 502, 40 samples were used to compare results with those measured on Siemens Atellica using the BioPorto’s NGAL assay. Reference interval was verified in 40 urine samples collected from healthy donors. A urine dipstick test was performed to confirm the normal urine samples did not contain leukocyte esterase activity. Since NGAL is also present in neutrophils, we evaluated the effect of leukocytes in urine with the NGAL assay. Results showed the sample with 75 leukocytes/µL had an NGAL of 68 ng/mL and the sample with 500 leukocytes/µL has an NGAL of 222 ng/mL. The linearity range was determined to be 0 - 3000 ng/mL with a limit of quantification of 26 ng/mL. The within-run precision mean and CV% are 121 ng/mL, 4.3% for Level 1 and 401 ng/mL, 1.8% for Level 2. Between-run precisions mean and CV% are 106 ng/mL, 4.8% for Level 1 and 399 ng/mL, 2.6% Level 2. Method comparison had a slope of 0.90 and an intercept of 32.9. The reference interval was determined to be <50 ng/mL and Leukocytes in urine did cause false-positive NGAL results.

Novel biomarkers of acute kidney injury in chronic liver disease: Where do we stand after a decade of research?

Acute kidney injury (AKI) is a frequently encountered complication in decompensated chronic liver disease (CLD) with an estimated prevalence of 20%-50% among hospitalized patients. AKI often heralds the onset of a downhill course in the natural history of CLD. Serum creatinine has several limitations as a stand-alone marker of AKI in patients with decompensated CLD. The concept of hepatorenal syndrome, the prototype of AKI in decompensated CLD, has evolved tremendously over recent years. There is emerging evidence of an additional "structural" component in the pathophysiology of hepatorenal syndrome-AKI, which was previously identified as a purely "functional" form of renal impairment. Lacunae in the existent biochemical arsenal for diagnosis and prognosis of AKI have fueled enthusiastic research in the field of novel biomarkers of kidney injury in patients with cirrhosis. The advent of these biomarkers provides a crucial window of opportunity to improve the diagnosis and clinical outcomes of this vulnerable cohort of patients. This review summarizes the dynamic concept of renal dysfunction in CLD and the available literature on the role of novel biomarkers of AKI in assessing renal function, identifying AKI subtypes, and predicting prognosis. There is special emphasis on the renal tubular injury marker, neutrophil gelatinase-associated lipocalin, the most exhaustively studied biomarker of AKI in the CLD population.

Abstract 125: Kidney-specific Biomarkers For Predicting Acute Kidney Injury Following Cardiac Arrest

Introduction: Acute kidney injury (AKI) is a common complication following cardiac arrest (CA) and is associated with poor outcomes. Early detection of AKI is crucial; serum creatinine (sCR) is the most commonly used indicator of AKI, despite low sensitivity and specificity for early detection of AKI. Hypothesis: Kidney-specific serum biomarkers neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and cystatin-C could better predict post-CA AKI than sCR. Methods: Adult CA patients who had kidney-specific biomarkers of AKI collected shortly after return of spontaneous circulation (ROSC) as part of four randomized trials and one observational study were included. Patients with Kidney Disease Improving Global Outcome (KDIGO) stage III AKI or end-stage renal disease, or renal replacement therapy at the time of enrollment were excluded. The association between renal biomarker levels (sCR, NGAL, KIM-1, cystatin-C) shortly after ROSC and the development of KDIGO stage III AKI within 7 days of enrollment were assessed as well as their predictive value of future AKI development. Results: Of 155 patients, 46 (29.7%) developed stage III AKI within 7 days, and 98 (63.2%) died prior to hospital discharge. Patients who developed stage III AKI, compared to those who did not, had higher median levels of sCR (1.4 mg/dL [IQR: 1.2, 1.9] vs. 1.2 [IQR: 1.0, 1.5]; p=0.001), NGAL (868,208 pg/mL [IQR: 412,547.1, 1,341,597] vs. 298,928.3 [IQR: 170,786.6, 594,389.7], p<0.001). and cystatin-C (1,649,202 pg/mL [IQR: 1,184,788, 2,440,583] vs. 1,132,955 [IQR: 795,323.7, 1,580,415]; p<0.001). There was no difference in KIM-1 between groups (150.6 pg/mL [IQR: 150.8, 288.4] vs. 158.9 [IQR: 78.8, 284.7]; p=0.351). There was no significant difference between biomarkers in their ability to predict development of stage III AKI (NGAL AUC=0.75 [95%CI: 0.67-0.83], cystatin-C AUC=0.71 [95%CI: 0.62-0.79], KIM-1 AUC=0.55 [95%CI: 0.45-0.65], sCR AUC=0.67 [95%CI: 0.57-0.76], p>0.05 for all). Both NGAL and cystatin-C performed better than KIM-1 (p<0.01). Conclusion: In post-CA patients, sCR, NGAL, and cystatin-C (but not KIM-1) measured shortly after ROSC were higher in patients who subsequently developed AKI. No biomarker was statistically superior to sCR. Comparison was limited by the small number of patients who developed AKI.

A universal predictive and mechanistic urinary peptide signature in acute kidney injury

BackgroundThe delayed diagnosis of acute kidney injury (AKI) episodes and the lack of specificity of current single AKI biomarkers hamper its management. Urinary peptidome analysis may help to identify early molecular changes in AKI and grasp its complexity to identify potential targetable molecular pathways.MethodsIn derivation and validation cohorts totalizing 1170 major cardiac bypass surgery patients and in an external cohort of 1569 intensive care unit (ICU) patients, a peptide-based score predictive of AKI (7-day KDIGO classification) was developed, validated, and compared to the reference biomarker urinary NGAL and NephroCheck and clinical scores.ResultsA set of 204 urinary peptides derived from 48 proteins related to hemolysis, inflammation, immune cells trafficking, innate immunity, and cell growth and survival was identified and validated for the early discrimination (< 4 h) of patients according to their risk to develop AKI (OR 6.13 [3.96–9.59], p < 0.001) outperforming reference biomarkers (urinary NGAL and [IGFBP7].[TIMP2] product) and clinical scores. In an external cohort of 1569 ICU patients, performances of the signature were similar (OR 5.92 [4.73–7.45], p < 0.001), and it was also associated with the in-hospital mortality (OR 2.62 [2.05–3.38], p < 0.001).ConclusionsAn overarching AKI physiopathology-driven urinary peptide signature shows significant promise for identifying, at an early stage, patients who will progress to AKI and thus to develop tailored treatments for this frequent and life-threatening condition. Performance of the urine peptide signature is as high as or higher than that of single biomarkers but adds mechanistic information that may help to discriminate sub-phenotypes of AKI offering new therapeutic avenues.

Effect of up to 30-days of storage at different temperatures on detection of feline kidney injury molecule-1 in urine

BackgroundIn humans, kidney injury molecule-1 (KIM-1) is a biomarker of acute kidney injury that can be quantified in urine. Preliminary investigation in cats with experimentally induced acute kidney injury showed that KIM-1 urine concentration correlated with kidney injury histopathology scores. A lateral flow assay (LFA) has recently become available for patient-side feline KIM-1 measurement. In vitro parameters of the assay have not yet been determined. The objectives of this study were to determine detection of KIM-1 in urine stored at different temperatures over time, to establish the linear range of the LFA, and to assess the intra-assay repeatability of measurements. ResultsTen urine samples with a range of KIM-1 concentrations were stored at room temperature (22o C), 4o C or -20o C, and tested with the LFA on days 0, 1, 2, 3, 7, 14, and 30. The concentration of KIM-1 in samples was not significantly different from the day 0 value, except one sample that had been stored for 30 days at room temperature yielded a significantly higher value. The assay results had a correlation coefficient of 0.922. The mean coefficient of variation for all samples was 15.7%. The slope of the curve of expected versus measured values in samples diluted two-fold nine times was 0.908, and results were linear over all dilutions.ConclusionsThe LFA for feline KIM-1 yields consistent results from stored urine samples. These characteristics will allow for KIM-1 to be measured retrospectively if immediate testing is not feasible. Within assay precision was high, and linearity over 9 logs of dilution suggests suitability for a range of subclinical and clinical kidney injuries.

Assessment of Urinary Exosomal NHE3 as a Biomarker of Acute Kidney Injury.

The diagnosis of acute kidney injury (AKI) traditionally depends on the serum creatinine (Scr) and urine output, which lack sufficient sensitivity and specificity. Using urinary exosomes as a biomarker has unique advantages. To assess whether urinary exosomal Na+/H+ exchanger isoform 3 (NHE3) protein could serve as a biomarker of AKI, we constructed four AKI rat models: cisplatin (7.5 mg/kg) injected intraperitoneally (IP), furosemide (20 mg/kg, IP) with a low-NaCl (0.03%) diet, a low-NaCl (0.03%) diet with candesartan (1 mg/kg, IP) and bilateral ischemia and reperfusion (I/R) injury for 40 min. Additionally, we assessed six sepsis-associated AKI patients and six healthy volunteers. Urinary exosomes were extracted by ultracentrifugation, and the NHE3 protein abundance was tested by immunoblotting for all the AKI rats and human subjects. The isolated cup-shaped particles with an average diameter of 70 nm and enrichment in CD63 were identified as exosomes. NHE3 abundance was six times higher in exosomes than in the whole urine. In cisplatin-induced AKI rats, urinary exosomal NHE3 was increased on day 2, one day earlier than the increases in Scr and blood urea nitrogen (BUN). In additional rats, urinary exosomal NHE3 decreased along with the decline in Scr after EPO pretreatment. In volume-depletion AKI induced by furosemide injection with a low-NaCl diet, the urinary exosomal NHE3 expression was higher than that in the control. Under a low-NaCl diet with candesartan-related AKI, the urinary exosomal NHE3 was elevated on day 5, earlier than Scr. In I/R-injury AKI, the urinary exosomal NHE3 was also raised compared with that in the control. In humans, the urinary exosomal NHE3 level was also elevated in sepsis-associated AKI patients in comparison with that in the healthy volunteers. The urinary exosomal NHE3 was increased in multiple AKI; it may be used as a diagnostic biomarker of AKI.

Update on prognosis driven classification of pediatric AKI.

Acute kidney injury (AKI) affects a large proportion of hospitalized children and increases morbidity and mortality in this population. Initially thought to be a self-limiting condition with uniformly good prognosis, we now know that AKI can persist and progress to acute kidney disease (AKD) and chronic kidney disease (CKD). AKI is presently categorized by stage of injury defined by increase in creatinine, decrease in eGFR, or decrease in urine output. These commonly used biomarkers of acute kidney injury do not change until the injury is well established and are unable to detect early stage of the disease when intervention is likely to reverse injury. The kidneys have the ability to compensate and return serum creatinine to a normal or baseline level despite nephron loss in the setting of AKI possibly masking persistent dysfunction. Though these definitions are important, classifying children by their propensity for progression to AKD and CKD and defining these risk strata by other factors besides creatinine may allow for better prognosis driven discussion, expectation setting, and care for our patients. In order to develop a classification strategy, we must first be able to recognize children who are at risk for AKD and CKD based on modifiable and non-modifiable factors as well as early biomarkers that identify their risk of persistent injury. Prevention of initial injury, prompt evaluation and treatment if injury occurs, and mitigating further injury during the recovery period may be important factors in decreasing risk of AKD and CKD after AKI. This review will cover presently used definitions of AKI, AKD, and CKD, recent findings in epidemiology and risk factors for AKI to AKD to CKD progression, novel biomarkers for early identification of AKI and AKI that may progress to CKD and future directions for improving outcome in children with AKI.

Plasma Circulating Tumor Necrosis Factor Receptors at Multiple Time Points Can Predict the Outcome of Severe Acute Kidney Injury

Introduction: This prospective cohort study investigated the clinical role of circulating tumor necrosis factor receptor (cTNFR) levels as prognostic biomarkers in severe acute kidney injury (AKI) patients requiring continuous renal replacement therapy (CRRT). Methods: We enrolled 136 patients from 7 hospitals participating in the VENUS (VolumE maNagement Under body composition monitoring in critically ill patientS on CRRT) trial from July 2017 to October 2019. The levels of cTNFR1 and cTNFR2 were measured using plasma samples collected on days 0 (D0), 2 (D2), and 7 (D7). Patients were divided into high- and low-cTNFR groups based on their receptor concentrations. Results: D0 concentrations of cTNFR1 and cTNFR2 were positively correlated with one another (R2 = 0.37, p < 0.001). The high-cTNFR1 group displayed a higher in-hospital mortality rate than the low-TNFR1 group (p = 0.002). Moreover, the mortality rate was significantly higher in the high-TNFR1 group than in the low-TNFR1 group after adjusting for age, sex, and acute physiology, and chronic health evaluation II scores (hazard ratio 1.82, 95% confidence interval 1.09–3.03, p = 0.025). D2 and D7 cTNFR1 levels were also associated with in-hospital mortality; contrastingly, cTNFR2 levels were not associated with this outcome. Additionally, patients were divided into three groups according to the change in cTNFR levels from D0 to D2 (ΔcTNFR). Those in the highest ΔcTNFR tertile had a higher mortality rate than the remaining patients (p = 0.033 for ΔcTNFR1; p = 0.025 for ΔcTNFR2). Patients who underwent AKI-to-chronic kidney disease transition had higher concentrations of cTNFR1 (p = 0.014). Discussion/Conclusion: Plasma cTNFR1 concentrations at CRRT initiation and changes in cTNFR1 and 2 levels immediately following CRRT initiation are significant biomarkers for predicting the outcomes of patients with severe AKI.

Identification of RPS7 as the Biomarker of Ferroptosis in Acute Kidney Injury.

Objective This paper aims to explore novel ferroptosis-related biomarkers for acute kidney injury (AKI). Methods Various bioinformatic methods, such as differential expression analysis, functional annotation analysis, machine learning, and chemical-gene network analysis, were used in this study. Furthermore, the expression and proferroptotic role of RPS7 were validated with further bioinformatics analysis and biochemical experiments. Results GSE30718 dataset and GSE139061 dataset were used, and the differentially expressed genes (DEGs) were screened. The DEGs were overlapped with ferroptosis-related genes and genes associated with AKI, which led to the identification of four candidate genes. Machine learning and ROC curve analysis were conducted, and RPS7 and TRIB3 were selected for diagnostic model analysis and functional analysis. Finally, the upregulation of RSP7 in cisplatin-induced AKI was validated in cisplatin-induced AKI, and its proferroptotic role was confirmed in cisplatin-treated proximal tubular cells. Conclusion Our results indicated that RPS7 might present as a novel ferroptosis-related biomarker for AKI, and it derived ferroptosis to accentuate cisplatin-induced AKI.

Activating Transcription Factor 3 Based Early Alarm Model of Acute Kidney Injury after Cardiopulmonary Bypass in Adults.

Acute kidney injury (AKI) is a common complication after cardiopulmonary bypass (CPB) for cardiac surgery, and there is no effective treatment. This study was aimed at constructing an early warning model of AKI after CPB in adults and investigating the performance of this model. Patients who underwent CPB in the Department of Cardiac Surgery, Shanghai Tenth People's Hospital, from January 2018 to December 2019 were recruited into the present study. Blood and urine samples were collected preoperatively (0 h) and 2 h, 6 h, 12 h, 24 h, and 48 h after surgery, and the creatinine and activating transcription factor 3 (ATF3) were detected. According to the diagnostic criteria of AKI, patients were divided into the AKI group and the non-AKI group, and the risk factors for AKI after CPB were screened. The receiver operating characteristic (ROC) curve analysis was used to identify the optimal biomarkers for the establishment of early warning model of AKI after CPB. Finally, the performance of this model was further verified. A total of 83 patients were included in this study, 42 of whom developed AKI after surgery. After CPB, the serum and urine levels of creatinine and ATF3 increased to different degrees, and the increase in urine ATF3 was the most obvious in the AKI group. The area under ROC (AUC) of urine ATF3 at 12 h after surgery was 0.691 (95% CI: 0.576-0.807). When ATF3 was higher than 1216 pg/mL, the sensitivity and specificity of ATF3 in the diagnosis of AKI were 0.43 and 0.85, respectively. The height, conjugated bilirubin on the surgery day, urine ATF3 12 h after surgery, and serum creatinine 24 h after surgery were independent risk factors for postoperative AKI. Urine ATF3 and other factors were used to establish AKI warning model after CPB, which showed good fitting and accuracy. In conclusion, ATF3 is an early biomarker of post-CPB AKI. Addition of urine ATF3 to AKI risk factors can improve the accuracy of early AKI prediction.

Increased urinary B2-microglobulin is associated with poor prognosis of upper tract urothelial carcinoma

BackgroundKidney tubular damage markers are biomarkers of acute or chronic kidney injury. Hypothetically, upper tract urothelial cancer (UTUC), which induces obstructive uropathy or direct invasion of the renal parenchyma, may also induce increased excretion of urinary tubular damage proteins. Therefore, this study aimed to investigate the use of tubular damage biomarker as prognostic markers for UTUC.MethodsThe records of 417 surgically resected patients with UTUC were obtained from the Seoul National University Prospectively Enrolled Registry for urothelial cancer-upper tract urothelial cancer (SUPER-UC-UTUC) between January 2016 and December 2020. Patients with non-urothelial cancer or without urinary tubular injury marker measurement were excluded, and finally, 296 patients were finally included. B2-microglobulin (B2-MG) was an injury marker, and a value higher than 0.3 was considered abnormally elevated, according to previous studies.ResultsThe mean age was 70.9 years, and the male sex was predominant (n = 211, 71.3%). The incidences of renal pelvis and ureter cancer were similar (50.7% vs. 49.3%). Most patients had high-grade diseases (n = 254, 88.8%). The high urine B2-MG group was older, had decreased renal function, and had a higher pathologic T stage than did the low group. Multivariate Cox regression analysis of disease-free survival (DFS), open surgical method (Hazard ratio (HR) 1.52, p = 0.027), large tumor size (HR 1.06, p = 0.017), tumor multifocality (HR 1.90, p = 0.038), lymphovascular invasion (HR 2.19, p < 0.001), and high urine B2-MG (HR 1.57, p = 0.021) were significantly associated with shortened metastasis-free survival (MFS). Kaplan–Meier curve analysis revealed short DFS (median survival 15.5 months vs. unattained, log-rank p = 0.001) and MFS (unattained median survival in both groups, log-rank p = 0.003) for the high urine B2-MG group compared to the low urine B2-MG group.ConclusionPatients with UTUC presenting with increased pre-operative urine B2-MG levels were associated with disease recurrence and metastasis. This biomarker may aid in performing pre-operative risk stratification and in assessing the individual prognosis of patients with UTUC.

Chuan Huang Fang combining reduced glutathione in treating acute kidney injury (grades 1-2) on chronic kidney disease (stages 2-4): A multicenter randomized controlled clinical trial.

Lack of effective drugs for acute kidney injury (AKI) grades 1–2 is a crucial challenge in clinic. Our previously single-center clinical studies indicated Chuan Huang Fang (CHF) might have nephroprotection in AKI on chronic kidney disease (CKD) (A on C) patients by preventing oxidant damage and inhibiting inflammation. Reduced glutathione (RG) has recently been shown to increase the clinical effectiveness of high-flux hemodialysis among patients with severe AKI. In this multicenter randomized controlled clinical study, we designed a new protocol to assess the efficacy and safety of CHF combining RG in patients with A on C. We also explored therapeutic mechanisms from renal fibrosis biomarkers. 98 participants were randomly and equally divided into the RG and RG + CHF subgroups. The RG and RG + CHF groups received general treatments with RG and a combination of RG and CHF, respectively. The therapy lasted for 2 weeks. In this study, the primary assessment result was a difference in the slope of serum creatinine (Scr) over the course of 2 weeks. The secondary evaluation outcomes were alterations in blood urea nitrogen (BUN), uric acid (UA), estimated glomerular filtration rate (eGFR), urinary AKI biomarkers, renal fibrosis biomarkers (transforming growth factor-β 1 (TGF-β 1), connective tissue growth factor (CTGF)), and traditional Chinese medicine (TCM) symptoms. Furthermore, vital signs and adverse events (AEs) were observed. Both groups had a slower renal function decline after treatment than before treatment. Compared with RG group, more reductions of Scr, BUN, UA, and better improvement of eGFR were observed in RG + CHF group (p < 0.05). Additionally, the levels of urinary AKI biomarkers, renal fibrosis biomarkers, and TCM syndromes were decreased in RG + CHF group versus RG group (p < 0.05). No significant between-group differences were observed of AEs. We thus concluded this novel therapy of CHF combining RG might be a useful method for treating A on C patients.

Proenkephalin A119-159 As A Biomarker of Acute Kidney Injury in ICU Patients with Sepsis

Proenkephalin A119-159 As A Biomarker of Acute Kidney Injury in ICU Patients with Sepsis