Treatment Of Acute Kidney Injury Research Articles

Relationship between ideal cardiovascular health score and perioperative acute kidney injury: A case-control study.

Maintaining ideal cardiovascular health scores (CHS) may indirectly contribute to reducing the risk of perioperative acute kidney injury (AKI), which has never been explored previously. In this study, we aimed to explore the relationship between CHS and AKI and provide new ideas for AKI prevention and treatment. We examined the effects of CHS on the occurrence of AKI among 2783 participants from the Kailuan study, who received general anesthesia during noncardiac surgery from 2016 to 2020. The odds ratios (ORs) and 95% confidence intervals (95% CIs) for AKI were calculated by using the logistic regression. Among 2783 participants 187 were diagnosed with perioperative AKI. We found an inverse relationship between the CHS scores and the risk of AKI. Participants with CHS score ≥ 10 had 57% decreased risk of AKI (OR = 0.43, 95% CI = 0.23, 0.79), compared with participants with CHS score ≤ 7, especially in men (OR = 0.39, 95% CI: 0.20, 0.76). In addition, participants who never smoked, exercised frequently, and had normal blood pressure had decreased risk of AKI, with corresponding ORs (95% CIs) of 0.66 (0.47, 0.91), 0.73 (0.60, 0.92), and 0.46 (0.28, 0.75), respectively. CHS was strongly associated with the risk of perioperative AKI, and higher CHS scores were associated with a lower risk of AKI. Further research is needed to explore the long-term effects of achieving and maintaining an ideal CHS on AKI risk.

Clinical characteristics and outcomes of acute kidney injury in patients with severe fever with thrombocytopenia syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging zoonosis caused by a novel bunyavirus. Until recently, the SFTS related acute kidney injury (AKI) was largely unexplored. This study aimed to investigate the clinical characteristics and outcomes of AKI in patients with SFTS. The non-AKI and AKI groups were compared in terms of general characteristics, clinical features, laboratory parameters and cumulative survival rate. The independent risk factors for in-hospital mortality in patients with SFTS were analyzed by multivariate logistic regression to identify the population with poor prognosis. A total of 208 consecutive patients diagnosed with SFTS were enrolled, including 153 (73.6%) patients in the non-AKI group and 55 (26.4%) patients in the AKI group. Compared with patients without AKI, patients with AKI were older and had a higher frequency of diabetes. Among these laboratory parameters, platelet count, albumin and fibrinogen levels of patients with AKI were identified to be significantly lower than those of patients without AKI, while ALT, AST, ALP, triglyceride, LDH, BUN, uric acid, creatine, Cys-C, β2-MG, potassium, AMY, lipase, CK-MB, TnI, BNP, APTT, thrombin time, D-dimer, CRP, IL-6, PCT and ESR levels were significantly higher in patients with AKI. A higher SFTS viral load was also detected in the AKI patients than in the non-AKI patients. The cumulative survival rates of patients at AKI stage 2 or 3 were significantly lower than those of patients without AKI or at AKI stage 1. However, there was no significant difference in the cumulative survival rates between patients without AKI and those with stage 1 AKI. Univariate and multivariate binary logistic regression analyses demonstrated that stage 2 or 3 AKI was an independent risk factor for in-hospital mortality in patients with SFTS. AKI is associated with poor outcomes in patients with SFTS, especially patients at AKI stage 2 or 3, who generally have high mortality. Our findings support the importance of early identification and timely treatment of AKI in patients with SFTS.

Ferrostatin-1 post-treatment attenuates acute kidney injury in mice by inhibiting ferritin production and regulating iron uptake-related proteins.

Acute kidney injury (AKI) is a common and serious medical condition with high morbidity and mortality. Recent research has highlighted ferroptosis, a novel form of programmed cell death, as a potential therapeutic target in mitigating renal tubular injury in AKI. Ferrostatin-1, a specific ferroptosis inhibitor, has been demonstrated to prevent renal injury through ferroptosis inhibition. Utilizing a murine AKI model, we investigated the effects of Ferrostatin-1 by administering it post-injury. Through high-throughput sequencing and pathological analysis, we focused on the critical role of ferroptosis-related pathways in the treatment. Ferrostatin-1 post-conditioning effectively mitigated oxidative damage and reduced iron content associated with AKI. Additionally, critical ferroptosis-related proteins, such as GPX4, SLC7A11, NRF2, and FTH1, exhibited increased expression levels. In vitro, Ferrostatin-1 treatment of HK-2 cells significantly diminished lipid peroxidation and iron accumulation. Furthermore, Ferrostatin-1 was found to downregulate the PI3K signalling pathway. Ferrostatin-1 acted as a potential ferroptosis inhibitor with the capacity to enhance antioxidant defences. This study suggests that Ferrostatin-1 could serve as a promising novel strategy for improving the treatment of AKI and promoting recovery from the condition.

An Exploratory Review on the Potential of Artificial Intelligence for Early Detection of Acute Kidney Injury in Preterm Neonates.

A preterm birth is a live birth that occurs before 37 completed weeks of pregnancy. Approximately 15 million babies are born preterm annually worldwide, indicating a global preterm birth rate of about 11%. Up to 50% of premature neonates in the gestational age (GA) group of <29 weeks' gestation will develop acute kidney injury (AKI) in the neonatal period; this is associated with high mortality and morbidity. There are currently no proven treatments for established AKI, and no effective predictive tool exists. We propose that the development of advanced artificial intelligence algorithms with neural networks can assist clinicians in accurately predicting AKI. Clinicians can use pathology investigations in combination with the non-invasive monitoring of renal tissue oxygenation (rSO2) and renal fractional tissue oxygenation extraction (rFTOE) using near-infrared spectroscopy (NIRS) and the renal resistive index (RRI) to develop an effective prediction algorithm. This algorithm would potentially create a therapeutic window during which the treating clinicians can identify modifiable risk factors and implement the necessary steps to prevent the onset and reduce the duration of AKI.

Hyperoside ameliorates cisplatin-induced acute kidney injury by regulating the expression and function of Oat1

Cisplatin is a widely used chemotherapeutic agent to treat solid tumours in clinics. However, cisplatin-induced acute kidney injury (AKI) limits its clinical application. This study investigated the effect of hyperoside (a flavonol glycoside compound) on regulating AKI. The model of cisplatin-induced AKI was established, and hyperoside was preadministered to investigate its effect on improving kidney injury. Hyperoside ameliorated renal pathological damage, reduced the accumulation of SCr, BUN, Kim-1 and indoxyl sulphate in vivo, increased the excretion of indoxyl sulphate into the urine, and upregulated the expression of renal organic anion transporter 1 (Oat1). Moreover, evaluation of rat kidney slices demonstrated that hyperoside promoted the uptake of PAH (p-aminohippurate, the Oat1 substrate), which was confirmed by transient over-expression of OAT1 in HEK-293T cells. Additionally, hyperoside upregulated the mRNA expression of Oat1 upstream regulators hepatocyte nuclear factor-1α (HNF-1α) and pregnane X receptor (PXR). These findings indicated hyperoside could protect against cisplatin-induced AKI by promoting indoxyl sulphate excretion through regulating the expression and function of Oat1, suggesting hyperoside may offer a potential tactic for cisplatin-induced AKI treatment.

KDM2B regulates inflammation and oxidative stress of sepsis via targeting NF-κB and AP-1 pathways.

The kidney is an easily affected organ with sepsis which is a main underlying cause of acute kidney injury (AKI). Histone-modifying lysine-specific demethylase 2B (KDM2B) is involved in numerous pathological processes, such as cell senescence and tumor development. However, the role of KDM2B in sepsis-induced AKI is unclear. To investigate the role of KDM2B on cell viability, inflammation and oxidative stress of sepsis-associated AKI, and the involved signaling pathways. An AKI model in vitro was established through lipopolysaccharide (LPS)-induction in HK-2 cells. Western blots were performed to evaluate the expression of KDM2B, cyclooxygenase 2 (COX2), inducible nitric oxide synthase (iNOS), p65, c-Jun and c-Fos, as well as p65 phosphorylation. Cell viability was measured using CCK-8 kit. ELISA was performed to analyze the production of layered double hydroxide (LDH), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-18, vascular cell adhesion molecule-1 (VCAM-1), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), and H2 O2 . The qPCR was used to evaluate the transcription level of TNF-α, IL-1β, IL-18, and VCAM-1. KDM2B knockdown alleviated LPS-induced cytotoxicity, decreased LDH release, and improved cell viability. KDM2B knockdown reduced concentration of inflammation-related molecules including TNF-α, IL-1β, IL-18, and VCAM-1, and inhibited their transcription. Moreover, KDM2B knockdown promoted the quantity of SOD and GSH, while declined the production of MDA, H2 O2 , COX2, and iNOS. Further, KDM2B played a role in LPS-induced HK-2 cell injury by activating nuclear factor κB (NF-κB) and activator protein 1 (AP-1) pathways. KDM2B knockdown reduced cytotoxicity, inflammation and oxidative stress in LPS-induced AKI via inhibiting NF-κB and AP-1 pathways, indicating KDM2B may be a promising therapeutic target for the treatment of sepsis-associated AKI.

Liensinine pretreatment reduces inflammation, oxidative stress, apoptosis, and autophagy to alleviate sepsis acute kidney injury.

Liensinine is mainly derived from alkaloids extracted and isolated from lotus seeds (Nelumbo nucifera Gaertn). It possesses anti-inflammatory, and antioxidant, according to contemporary pharmacological investigations. However, the effects and therapeutic mechanisms of liensinine on acute kidney injury (AKI) models of sepsis are unclear. To gain insight into these mechanisms, we established a sepsis kidney injury model by LPS injection of mice treated with liensinine, and stimulation of HK-2 with LPS in vitro and treated with liensinine and inhibitors of p38 MAPK, JNK MAPK. We first found that liensinine significantly reduced kidney injury in sepsis mice, while suppressing excessive inflammatory responses, restoring renal oxidative stress-related biomarkers, reducing increased apoptosis in TUNEL-positive cells and excessive autophagy, and that this process was accompanied by an increase in JNK/ p38-ATF 2 axis. In vitro experiments further demonstrated that lensinine reduced the expression of KIM-1, NGAL, inhibited pro- and anti-inflammatory secretion disorders, regulated the activation of the JNK/p38-ATF 2 axis, and reduced the accumulation of ROS, as well as the reduction of apoptotic cells detected by flow cytometry, and that this process played the same role as that of p38 MAPK, JNK MAPK inhibitors. We speculate that liensinine and p38 MAPK, JNK MAPK inhibitors may act on the same targets and could be involved in the mechanism of alleviating sepsis kidney injury in part through modulation of the JNK/p38-ATF 2 axis. Our study demonstrates that lensinine is a potential drug and thus provides a potential avenue for the treatment of AKI.

Delivering drugs to tubular cells and organelles: the application of nanodrugs in acute kidney injury.

Acute kidney injury (AKI) is a common clinical syndrome with limited treatment options and high mortality rates. Proximal tubular epithelial cells (PTECs) play a key role in AKI progression. Subcellular dysfunctions, including mitochondrial, nuclear, endoplasmic reticulum and lysosomal dysfunctions, are extensively studied in PTECs. These studies have led to the development of potential therapeutic drugs. However, clinical development of those drugs faces challenges such as low solubility, short circulation time and severe systemic side effects. Nanotechnology provides a promising solution by improving drug properties through nanocrystallization and enabling targeted delivery to specific sites. This review summarizes advancements and limitations of nanoparticle-based drug-delivery systems in targeting PTECs and subcellular organelles, particularly mitochondria, for AKI treatment.

CTRP3 attenuates inflammation, oxidative and cell death in cisplatin induced HK-2 cells.

Cisplatin has been widely studied and found to be a highly effective anti-tumor drug. It has several side effects, including acute kidney injury (AKI). Cisplatin-induced AKI can be primarily attributed to oxidative stress, inflammation, and apoptosis. The CTRP3 adipokine is a new adipokine that exhibits antioxidant, anti-inflammatory, and antiapoptotic properties. Despite this, the role of CTRP3 in AKI remain unclear. In cisplatin-induced AKI models, our findings demonstrated that CTRP3 expression was decreased in human proximal tubule epithelial cells (HK-2). In the in vitro experiments, HK-2 cells were first transfected with an overexpression plasmid of CTRP3 (pcDNA-CTRP3) or a small interfering RNA for CTRP3 (si-CTRP3) and induced by cisplatin; and cell oxidative stress, inflammation, proliferation, and apoptosis were found to be present. Overexpressing CTRP3 inhibited oxidative stress through decreasing malondialdehyde (MDA) levels and increasing the activity of SOD and CAT. The mRNA levels of SOD1 and SOD2 were increased in response to CTRP3 overexpression. Additionally, CTRP3 decreased TNF-α and MCP-1 levels. Moreover, CTRP3 overexpression increased cisplatin-induced cell activity and decreased cell apoptosis, as indicated by the elevated numbers of EdU positive cells and decreased numbers of apoptotic cells. Consistent with these results, the overexpression of CTRP3 effectively elevated the mRNA levels of Bcl-2 and reduced the mRNA levels of Bax. In contrast, inhibition of CTRP3 expression by si-CTRP3 reversed the cisplatin-induced indices. Mechanistically, we found that the overexpression of CTRP3 can increase expression of Nrf2 and inhibit the activation of MAPK phosphorylation (ERK, JNK, and p38). Furthermore, inhibition of ERK, JNK and p38 activity eliminated aggravation of cisplatin-induced inflammation and apoptosis caused by CTRP3 knockdown. Additionally, the cisplatin-induced oxidative stress and activation of MAPK phosphorylation (ERK, JNK, and p38) in HK-2 cells were reversed by Nrf2 suppression by siRNA. Collectively, these results indicated that CTRP3 may identify as a novel target for AKI treatment and protect against cisplatin-induced AKI through the Nrf2/MAPK pathway.

Mackinawite nanozymes as reactive oxygen species scavengers for acute kidney injury alleviation

BackgroundIron sulfide nanomaterials have been successfully employed as therapeutic agents for bacterial infection therapy and catalytic-ferroptosis synergistic tumor therapy due to their unique structures, physiochemical properties, and biocompatibility. However, biomedical research and understanding of the biological functions of iron sulfides are insufficient, and how iron sulfide nanomaterials affect reactive oxygen species (ROS) in diseases remains unknown. Acute kidney injury (AKI) is associated with high levels of ROS, and therefore nanomedicine-mediated antioxidant therapy has emerged as a novel strategy for its alleviation.ResultsHere, mackinawite nanozymes were synthesized from glutathione (GSH) and iron ions (Fe3+) (denoted as GFeSNs) using a hydrothermal method, and then evaluated as ROS scavengers for ROS-related AKI treatment. GFeSNs showed broad-spectrum ROS scavenging ability through synergistic interactions of multiple enzymes-like and hydrogen polysulfide-releasing properties. Furthermore, both in vitro and in vivo experiments demonstrated that GFeSNs exhibited outstanding cytoprotective effects against ROS-induced damage at extremely low doses and significantly improved treatment outcomes in AKI.ConclusionsGiven the synergetic antioxidant properties and high biocompatibility, GFeSNs exhibit great potential for the treatment of AKI and other ROS-associated diseases.Graphical

Single-cell dissection of cellular and molecular features underlying mesenchymal stem cell therapy in ischemic acute kidney injury

Mesenchymal stem cells (MSCs) exert beneficial therapeutic effects in acute kidney injury (AKI), while the detailed repair mechanism remains unclear. Herein, we probed the underlying mechanisms of MSC therapy in AKI by performing unbiased single-cell RNA sequencing in IRI model with/without MSC treatment. Our analyses uncovered the tubular epithelial cells (TECs) and immune cells transcriptomic diversity and highlighted a repair trajectory involving renal stem/progenitor cell differentiation. Our findings also suggested that profibrotic TECs expressing pro-fibrotic factors such as Zeb2 and Pdgfb promoted the recruitment of inflammatory monocytes and Th17 cells to injured kidney tissue, inducing TGF-β1 secretion and renal fibrosis. Finally, in addition to activating the repair properties of renal progenitor/stem cells, we uncovered a role for MSC-derived miR-26a-5p in mediating the therapeutic effects of MSCs by inhibiting Zeb2 expression and suppressing pro-fibrotic TECs and its subsequent recruitment of immune cell subpopulations. These findings may help to optimize future AKI treatment strategies.

Effects of photobiomodulation and caffeine treatment on acute kidney injury in a hypoxic ischemic neonatal rat model.

Hypoxic ischemic encephalopathy (HIE) occurs in 2-5/1000 births, with acute kidney injury (AKI) occurring in 40%. AKI increases morbidity and mortality. Caffeine, an adenosine receptor antagonist, and photobiomodulation (PBM), working on cytochrome c oxidase, are potential treatments for AKI. To examine effects of caffeine and PBM on AKI in rats, Day 7 pups underwent a HIE intervention (Modified Rice-Vannucci model) replicating pathology observed in humans. Caffeine was administered for 3 days and/or PBM for 5 days following HIE. Weights and urine for biomarkers (NGAL, albumin, KIM-1, osteopontin) were collected prior to HIE, daily post intervention and at sacrifice. Both treatments reduced kidney injury seen on electron microscopy, but not when combined. HIE elevated urinary NGAL and albumin on Days 1-3 post-HIE, before returning to control levels. This elevation was significantly reduced by PBM or caffeine. KIM-1 was significantly elevated for 7 days post-HIE and was reduced by both treatments. Osteopontin was not altered by HIE or the treatments. Treatments, individually but not in combination, improved HIE-induced reductions in the enzymatic activity of mitochondrial complexes II-III. PBM and caffeine also improved weight gain. PBM and caffeine reduces AKI diagnosed by urinary biomarkers and confirmed by EM findings.

TREATMENT WITH HUMAN UMBILICAL CORD-DERIVED MESENCHYMAL STEM CELLS IN A PIG MODEL OF SEPSIS-INDUCED ACUTE KIDNEY INJURY: EFFECTS ON MICROVASCULAR ENDOTHELIAL CELLS AND TUBULAR CELLS IN THE KIDNEY.

Background: Approximately 50% of patients with sepsis develop acute kidney injury (AKI), which is predictive of poor outcomes, with mortality rates of up to 70%. The endothelium is a major target for treatments aimed at preventing the complications of sepsis. We hypothesized that human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) could attenuate tubular and endothelial injury in a porcine model of sepsis-induced AKI. Methods: Anesthetized pigs were induced to fecal peritonitis, resulting in septic shock, and were randomized to treatment with fluids, vasopressors, and antibiotics (sepsis group; n = 11) or to that same treatment plus infusion of 1 × 10 6 cells/kg of hUC-MSCs (sepsis+MSC group; n = 11). Results: At 24 h after sepsis induction, changes in serum creatinine and mean arterial pressure were comparable between the two groups, as was mortality. However, the sepsis+MSC group showed some significant differences in comparison with the sepsis group: lower fractional excretions of sodium and potassium; greater epithelial sodium channel protein expression; and lower protein expression of the Na-K-2Cl cotransporter and aquaporin 2 in the renal medulla. Expression of P-selectin, thrombomodulin, and vascular endothelial growth factor was significantly lower in the sepsis+MSC group than in the sepsis group, whereas that of Toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) was lower in the former. Conclusion: Treatment with hUC-MSCs seems to protect endothelial and tubular cells in sepsis-induced AKI, possibly via the TLR4/NF-κB signaling pathway. Therefore, it might be an effective treatment for sepsis-induced AKI.

Inhibition of MiR-106b-5p mediated by exosomes mitigates acute kidney injury by modulating transmissible endoplasmic reticulum stress and M1 macrophage polarization.

Acute kidney injury (AKI), mainly caused by Ischemia/reperfusion injury (IRI), is a common and severe life-threatening disease with high mortality. Accumulating evidence suggested a direct relationship between endoplasmic reticulum (ER) stress response and AKI progression. However, the role of the transmissible ER stress response, a new modulator of cell-to-cell communication, in influencing intercellular communication between renal tubular epithelial cells (TECs) and macrophages in the AKI microenvironment remains to be determined. To address this issue, we first demonstrate that TECs undergoing ER stress are able to transmit ER stress to macrophages via exosomes, promoting macrophage polarization towards the pro-inflammatory M1 phenotype in vitro and in vivo. Besides, the miR-106b-5p/ATL3 signalling axis plays a pivotal role in the transmission of ER stress in the intercellular crosstalk between TECs and macrophages. We observed an apparent increase in the expression of miR-106b-5p in ER-stressed TECs. Furthermore, we confirmed that ALT3 is a potential target protein of miR-106b-5p. Notably, the inhibition of miR-106b-5p expression in macrophages not only restores ATL3 protein level but also decreases transmissible ER stress and hinders M1 polarization, thus alleviating AKI progression. Additionally, our results suggest that the level of exosomal miR-106b-5p in urine is closely correlated with the severity of AKI patients. Taken together, our study sheds new light on the crucial role of transmissible ER stress in the treatment of AKI through the regulation of the miR-106b-5p/ATL3 axis, offering new ideas for treating AKI.

Determination of Risk Factors for Postoperative Acute Kidney Injury in Patients With Gynecologic Malignancies.

Background Postoperative acute kidney injury (AKI) is an important cause of mortality and morbidity among surgical patients. There is little information on the occurrence of AKI after operations for gynecologic malignancies. This study aimed to determine the incidence of AKI in patients who underwent surgery for gynecological malignancies and determine the risk factors in those who developed postoperative AKI. Methodology A total of 1,000 patients were enrolled retrospectively from January 2007 to March 2013. AKI was defined according to the Kidney Disease Improving Global Outcomes 2012 Clinical Practice Guideline for Acute Kidney Injury. Perioperative variables of patients were collected from medical charts. Results The incidence of postoperative AKI was 8.8%, with stage 1 occurring in 5.9%, stage 2 in 2.4%, and stage 3 in 0.5% of the patients. Patients who had AKI were significantly older, had higher body mass index (BMI) higher preoperative C-reactive protein (CRP) levels, and more frequently had a history of distant organ metastasis when compared with those who did not have AKI. When compared with patients who did not develop AKI postoperatively, longer operation times and intraoperative usage of higher amounts of erythrocyte suspension and fresh frozen plasma were seen in those who developed AKI. Conclusions Patients who had AKI were older, had higher BMI with higher preoperative CRP levels, more frequent distant organ metastasis, longer operation times, and higher amounts of blood transfused intraoperatively. Defining preoperative, intraoperative, and postoperative risk factors for postoperative AKI and taking necessary precautions are important for the early detection and intervention of AKI.

Serum myoglobin modulates kidney injury via inducing ferroptosis after exertional heatstroke.

Myoglobin released by rhabdomyolysis (RM) is considered to be involved in pathogenesis of kidney disease caused by crush injury, but whether high level of serum myoglobin predisposes patients to acute kidney injury (AKI) and its molecular mechanisms are still unclear in exertional heatstroke (EHS). We aimed to determine the association and potential mechanism of myoglobin and AKI, and further investigate the targeted therapeutic agents for myoglobinemia. Serum myoglobin concentrations in patients with EHS were measured at admission, 24 h and 48 h after admission and discharge. The risk of AKI at 48 h was the primary outcome; the secondary outcome was composite outcome events with myoglobin levels and AKI at discharge and death at 90 days. In experimental studies, we further investigated the mechanisms of human kidney proximal tubular (HK-2) cells that were exposed to human myoglobin under heat stress conditions and the effect of baicalein. Our measurements showed that the highest myoglobin quartile (vs. the lowest) had an adjusted odds ratio (OR) of 18.95 (95% confidence interval [CI], 6.00-59.83) for AKI and that the OR (vs. quartile 2) was 7.92 (95% CI, 1.62-38.89) for the secondary outcome. The survival rate of HK-2 cells treated with myoglobin under heat stress was significantly decreased, and the production of Fe2+ and reactive oxygen species (ROS) was markedly increased, accompanied by changes in ferroptosis proteins, including increased p53, decreased SLC7A11 and GPX4, and alterations in endoplasmic reticulum stress (ERS) marker proteins. Treatment with baicalein attenuated HK-2 cell ferroptosis induced by myoglobin under heat stress through inhibition of ERS. High myoglobin was associated with AKI in the EHS, and its mechanisms involved ERS-associated ferroptosis. Baicalein may be a potential therapeutic drug for the treatment of AKI in patients with high myoglobin induced by rhabdomyolysis following EHS.

Biomarkers in acute kidney injury: On the cusp of a new era?

The field of nephrology has been slow in moving beyond the utilization of creatinine as an indicator for chronic kidney disease and acute kidney injury (AKI). Early diagnosis and establishment of etiology, in particular, are important for treatment of AKI. In the setting of hospital-acquired AKI, tubular injury is more common, but acute interstitial nephritis (AIN) has a more treatable etiology. However, it is likely that AIN is under- or misdiagnosed due to current strategies that largely rely on clinical gestalt. In this issue of the JCI, Moledina and colleagues made an elegant case for the chemokine called C-X-C motif ligand 9 (CXCL9) as a biomarker of AIN. The authors used urine proteomics and tissue transcriptomics in patients with and without AIN to identify CXCL9 as a promising, noninvasive, diagnostic biomarker of AIN. These results have clinical implications that should catalyze future research and clinical trials in this space.

Peroxynitrite activated near-infrared fluorescent probe for evaluating ferroptosis-mediated acute kidney injury

Ferroptosis is a form of programmed cell death mostly characterized by a serious misadjustment in the production and degradation of lipid reactive oxygen species (ROS). Meanwhile, numerous studies have indicated that ferroptosis is crucial to the progression and pathophysiology of acute kidney injury (AKI). ROS have been implicated as a pivotal causative factor in cell damage, peroxynitrite (ONOO−) is one of the most prominent ROS which is intimately correlated to ferroptosis-mediated AKI. Therefore, monitoring ONOO− levels in ferroptosis-mediated AKI is important for exploring its physiological and pathological roles. Nevertheless, no probes for detecting ONOO− in ferroptosis-mediated AKI have been reported. Meanwhile, resveratrol (Res) is a bioactive component and has been used to the treatment of AKI. However, the effect of Res on ferroptosis during AKI progression remains elusive. Herein, we evaluated the fluctuation of ONOO− during ferroptosis-mediated AKI using the near-infrared (NIR) fluorescence probe (NFP-ONOO) for the first time. The probe NFP-ONOO showed excellent specificity and sensitivity for the detection of ONOO−. Furthermore, utilizing this probe, we demonstrated Res effectively mitigates AKI induced by folic acid (FA) and cisplatin (CP) by inhibitingferroptosis. Collectively, this work will provide a powerful guidance for the prophylaxis, diagnosis, and therapy of ferroptosis-mediated AKI.

Onconephrology: Acute kidney injury in cancer patients

Acute kidney injury (AKI) is a common complication of cancer, occurring in up to 50% of neoplastic patients during the natural course of their disease. Furthermore, it has a significant impact on key outcomes, such as overall prognosis, length of hospitalization, and costs. AKI in cancer patients has various causes, including patient-related, tumor-related, or treatment-related factors.&#x0D; Patient-related risk factors for AKI are similar to those in the general population. Tumor-related risk factors can involve compression, obstruction, direct kidney infiltration by the tumor, as well as precipitation, aggregation, crystallization, or misfolding of paraproteins in conditions like multiple myeloma. Treatment-related risk factors are the most commonly observed in clinical practice and can present as features of tumor lysis syndrome or, for example, immune checkpoint inhibitor-related AKI.&#x0D; In the absence of validated biomarkers for AKI, a multidisciplinary clinical approach involving oncologists, intensivists, nephrologists, or onconephrologists is essential. This approach incorporates thorough assessment, the use of appropriate preventive measures, and early intervention to reduce the incidence of AKI in cancer patients. Understanding the essence of preventive measures, timely initiation of treatment, and knowing when to terminate treatment will reduce the frequency of this life-threatening condition and improve the effectiveness of cancer treatment and the quality of life and life expectancy of cancer patients.&#x0D; This work aims to improve physicians' awareness of the latest data on the prevention, diagnosis, and treatment of AKI specifically related to oncopathology, tumor lysis syndrome, and acute kidney injury induced by cancer immunotherapy drugs.

#6635 ARNT AND ALK3 MEDIATE RENO PROTECTION AFTER ISCHEMIC PRECONDITIONING

Abstract Background and Aims Ischemia and following hypoxia are a common cause of acute kidney injury (AKI). Strategies for prevention and treatment of AKI are limited. In several animal models, ischemic preconditioning (IPC) has been established as an effective intervention to prevent ischemic organ injury. An IPC protocol of ischemia and reperfusion mediates organ protection for a few hours. This first phase of organ protection is followed by a second, protective phase occurring after 24–48 h. The second phase, named second window of protection (SWOP), persists for 3–4 d. Mechanisms and transcriptional mediators during SWOP are mostly unknown. The aim of the underlying study was to investigate effectors and target genes during SWOP and to identify a potential pharmacological therapeutic target. Method 6–8-week-old C57BL/6 mice were undergoing an IPC intervention; five minutes of renal sinistra artery ischemia was followed by five minutes of reperfusion. This cycle was performed five times. Mice were sacrificed 2, 4, 8, 12, 25, 48, 72 h after IPC. Two additional groups of mice were pharmacologically preconditioned for 48 h with low dose FK506 and small molecule GPI1046. Analysis of murine kidneys were performed by SDS-Page and Western blot. Results The first phase after IPC (2–4 h) was characterized by an increasing expression of hypoxia inducible factor-1α (HIF1α); 48 h after intervention a significant increase of expression of aryl hydrocarbon receptor nuclear translocator (ARNT) and consecutive activin receptor-like kinase 3 (ALK3) was observed. Comparable induction of ARNT and ALK3 expression was obtained by pharmacological preconditioning with FK506 or GPI1046. Conclusion Affected by hypoxia, HIF1α activates transcriptional upregulation of ARNT 48 h after IPC. The increasing expression of ARNT, follows an increased ARNT homodimerization. ARNT homodimer binds to the palindromic E-box 5′-CACGTG-3′ of the proximal ALK3 promoter. By this it induces the expression of the renoprotective ALK3 during SWOP. The organ-protective effects of constitutively expressed ARNT during SWOP can be mimicked pharmacologically by administration of FK506 or GPI1046 and may be used as a future therapeutic target.