Strategy For Acute Kidney Injury Research Articles

The effect of mannitol on postoperative renal function in patients undergoing coronary artery bypass surgery: A double-blinded randomized controlled trial.

Mannitol, an osmotic diuretic solution, is commonly utilized in priming cardiopulmonary bypass (CPB) and can impact kidney function. This study was conducted to investigate the impact of mannitol use during CPB on kidney function in patients undergoing coronary artery bypass surgery. This randomized, double-blind clinical trial studied 90 patients undergoing coronary artery bypass surgery. In the control group (n=45), the prime solution included Ringer's lactate, and in the intervention group (n=45), the prime solution had 200 ml of mannitol 20% and Ringer's lactate. A P-value<0.05 was considered significant. The primary endpoint of this study is renal function. Demographic characteristics and risk factors were not significantly different between the two groups (P>0.05). Additionally, there was no statistically significant difference between two groups in terms of CPB time, aortic cross-clamp time, length of time connected to mechanical ventilation, 30-day mortality, ICU, and hospital stay time (P>0.05). Furthermore, no statistically significant difference was observed between the two groups in serum creatinine levels (P=0.53) or BUN levels (P=0.13). The study also found no statistically significant difference in the diuresis rate between the two groups (P=0.10). The present study has shown that adding mannitol to the prime has no effect on kidney function, length of time connected to mechanical ventilation, length of stay in the ICU, or 30-day mortality. Therefore, it suggests that mannitol cannot be used as a preventative strategy for acute kidney injury after cardiac surgery.

#2339 All-trans retinoic acid enhances the efficacy of mesenchymal stem cells in acute kidney injury

Abstract Background and Aims Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic strategy for acute kidney injury (AKI), but still suffer from the drawbacks of low survival rate, low homing rate, and uncertain differentiation. In search of better therapeutic strategies, we explored all-trans retinoic acid (ATRA) pretreatment of MSCs to observe whether it could improve the therapeutic efficacy on AKI. Method We established a renal ischemia/reperfusion (I/R) injury model induced by clamping of left renal artery for 30 minutes and contralateral nephrectomy. C57BL/6 mice were randomly divided into 4 groups: sham group, IRI group, MSCs group, and ATRA-MSCs group. MSCs or ATRA-pretreated MSCs were injected via tail vein. GFR was measured by transcutaneous monitoring the clearance of FITC-sinistrin. These mice were sacrificed 3 days after surgery, and the serum creatinine (SCr) and blood urea nitrogen (BUN) levels were measured. The renal pathological changes were examined by Periodic Acid-Schiff staining (PAS). The in vitro hypoxia/reoxygenation (H/R) model was established using human proximal tubular epithelial cells (HK-2 cells). Co-culturing HK-2 cells with MSCs or ATRA-pretreated MSCs. Western blot, quantitative real time-PCR (qRT-PCR), and immunohistochemistry were used to detect mRNA or protein expression. We performed RNA sequencing (RNA-seq) analysis in ATRA-pretreated MSCs. The content of hyaluronic acid (HA) in the supernatant of ATRA-pretreated MSCs culture was detected by ELISA. Hyaluronan synthase mRNA expression level in ATRA-pretreated MSCs assessed by qRT-PCR analysis. The HAS2 promoter-binding transcription factors were forecasted by the JASPAR Transcription Factor Binding Site database. Western blot was used to detect whether P13K/AKT pathway was activated by ATRA-pretreated MSCs. Whether this nephroprotective effect could be reversed were explored by silencing HAS2 or CD44 antibodies. Results The AKI mice showed a significant decrease in GFR and even complete loss of renal function. Administration of MSCs significantly increased GFR, and MSCs pretreated with ATRA further increased GFR. Mice injected with ATRA-pretreated MSCs had significantly lower levels of SCr, BUN and ATN scores compared with untreated MSCs. Western blot, quantitative real-time PCR (qRT-PCR), and immunohistochemistry showed that ATRA pretreated MSCs were more effective in reducing AKI inflammation and apoptosis and promoting proliferative repair than untreated MSCs. GO enrichment analysis demonstrated that the hyaluronan biosynthetic process may be a significantly expressed. HAS2 expression and HA content of MSCS were significantly increased after the addition of ATRA. Analysis for potential transcription factor binding sites revealed that the HAS2 promoter region has multiple potential binding sites for the retinoic acid receptor. Based on the predictions from the JASPAR database, the RXR-RAR heterodimer had the highest prediction score. We then performed ChIP analysis to experimentally verify the binding of RXR-RAR heterodimer transcription factor to HAS2 promoters. We further found that ATRA-pretreated MSCs activated the PI3K/AKT signaling pathway in AKI. As expected, we found that ATRA-pretreated MSCs anti-inflammatory, anti-apoptosis, and pro-proliferation effects were substantially reversed by silencing HAS2 or blocking CD44. Conclusion ATRA promotes HA secretion from MSCs and activates the PI3K/AKT pathway, which in turn enhances the therapeutic efficacy of MSCs on AKI.

Mitochondria-mediated ferroptosis induced by CARD9 ablation prevents MDSCs-dependent antifungal immunity

BackgroundCaspase Recruitment Domain-containing protein 9 (CARD9) expressed in myeloid cells has been demonstrated to play an antifungal immunity role in protecting against disseminated candidiasis. Hereditary CARD9 ablation leads to fatal disseminated candidiasis. However, the myeloid cell types and molecular mechanisms implicated in CARD9 protecting against disseminated candidiasis remain wholly elusive.MethodsThe role of CARD9 ablation in exacerbating disseminated candidiasis was determined in vivo and in vitro. The molecular mechanism by which CARD9 ablation promotes acute kidney injury in disseminated candidiasis was identified by RNA-sequencing analysis. The expression of mitochondrial proteins and ferroptosis-associated proteins were measured by Quantitative real-time PCR and western blot.ResultsCARD9 ablation resulted in a reduced proportion of myeloid-derived suppressor cells (MDSCs) and a substantially lower expression of solute carrier family 7 member 11 (SLC7A11) in the kidneys, which increased susceptibility to acute kidney injury and renal ferroptosis during disseminated Candida tropicalis (C. tropicalis) infection. Moreover, CARD9-deficient MDSCs were susceptible to ferroptosis upon stimulation with C. tropicalis, which was attributed to augmented mitochondrial oxidative phosphorylation (OXPHOS) caused by reduced SLC7A11 expression. Mechanistically, C-type lectin receptors (CLRs)-mediated recognition of C. tropicalis promoted the expression of SLC7A11 which was transcriptionally manipulated by the Syk-PKCδ-CARD9-FosB signaling axis in MDSCs. FosB enhanced SLC7A11 transcription by binding to the promoter of SLC7A11 in MDSCs stimulated with C. tropicalis. Mitochondrial OXPHOS, which was negatively regulated by SLC7A11, was responsible for inducing ferroptosis of MDSCs upon C. tropicalis stimulation. Finally, pharmacological inhibition of mitochondrial OXPHOS or ferroptosis significantly increased the number of MDSCs in the kidneys to augment host antifungal immunity, thereby attenuating ferroptosis and acute kidney injury exacerbated by CARD9 ablation during disseminated candidiasis.ConclusionsCollectively, our findings show that CARD9 ablation enhances mitochondria-mediated ferroptosis in MDSCs, which negatively regulates antifungal immunity. We also identify mitochondria-mediated ferroptosis in MDSCs as a new molecular mechanism of CARD9 ablation-exacerbated acute kidney injury during disseminated candidiasis, thus targeting mitochondria-mediated ferroptosis is a novel therapeutic strategy for acute kidney injury in disseminated candidiasis.

A novel marine-derived anti-acute kidney injury agent targeting peroxiredoxin 1 and its nanodelivery strategy based on ADME optimization

Insufficient therapeutic strategies for acute kidney injury (AKI) necessitate precision therapy targeting its pathogenesis. This study reveals the new mechanism of the marine-derived anti-AKI agent, piericidin glycoside S14, targeting peroxiredoxin 1 (PRDX1). By binding to Cys83 of PRDX1 and augmenting its peroxidase activity, S14 alleviates kidney injury efficiently in Prdx1-overexpression (Prdx1-OE) mice. Besides, S14 also increases PRDX1 nuclear translocation and directly activates the Nrf2/HO-1/NQO1 pathway to inhibit ROS production. Due to the limited druggability of S14 with low bioavailability (2.6%) and poor renal distribution, a pH-sensitive kidney-targeting dodecanamine-chitosan nanoparticle system is constructed to load S14 for precise treatment of AKI. l-Serine conjugation to chitosan imparts specificity to kidney injury molecule-1 (Kim-1)-overexpressed cells. The developed S14-nanodrug exhibits higher therapeutic efficiency by improving the in vivo behavior of S14 significantly. By encapsulation with micelles, the AUC0‒t, half-life time, and renal distribution of S14 increase 2.5-, 1.8-, and 3.1-fold, respectively. The main factors contributing to the improved druggability of S14 nanodrugs include the lower metabolic elimination rate and UDP-glycosyltransferase (UGT)-mediated biotransformation. In summary, this study identifies a new therapeutic target for the marine-derived anti-AKI agent while enhancing its ADME properties and druggability through nanotechnology, thereby driving advancements in marine drug development for AKI.

Analysis of Risk Factors and Intervention Strategies for Acute Kidney Injury After Cardiac Valve Replacement [Letter

Analysis of Risk Factors and Intervention Strategies for Acute Kidney Injury After Cardiac Valve Replacement [Letter

Rosuvastatin and diosmetin inhibited the HSP70/TLR4 /NF-κB p65/NLRP3 signaling pathways and switched macrophage to M2 phenotype in a rat model of acute kidney injury induced by cisplatin

Numerous efforts to manage acute kidney injury (AKI) were unsuccessful because its pathophysiology is still poorly understood. Thus, our research hotspot was to explore the possible renoprotective effects of rosuvastatin (Ros) and diosmetin (D) on macrophage polarization and the role of HSP70/TLR4/MyD88/NF-κB p65/NLRP3/STAT3 signaling in cis-induced AKI and study the activity of D against uropathogenic bacteria. Fifty-four albino male rats were randomized into 9 groups equally: Control, Ros, D20, D40, untreated Cis, and Cis groups cotreated with Ros, D20, D40 and Ros+D40 for 10 days. Our results indicated that Ros and D, in a dose-dependent manner, markedly restored body weight, systolic blood pressure, and renal histological architecture besides significantly upregulated SOD levels, expression of anti-inflammatory CD163 macrophages, arginase1levels, IL-10 levels,STAT3 and PCNA immunoreactivity. Also, they significantly downregulated renal index, serum urea, serum creatinine, serum cystatin c, inflammatory biomarkers (C reactive protein, IL1β & TNF-α), MDA levels, HSP70/TLR4/MyD88/NF-κB p65/NLRP3 expressions, proinflammatory CD68 macrophages and caspase-3 immunoreactivity, resulting in a reversal of cis-induced renal damage. These findings were further confirmed by molecular docking that showed the binding affinity of Ros and D towards TLR4 and NLRP3. Furthermore, D had antibacterial action with a minimum inhibitory concentration ranging from 128 to 256 µg/mL and caused a delay in the growth of the tested isolates, and negatively affected the membrane integrity. In conclusion, Ros and D had antioxidant, anti-inflammatory and antiapoptotic properties and switched macrophage from proinflammatory CD68 to anti-inflammatory CD163. Additionally, the targeting of HSP70/TLR4/MyD88/NF-κB p65/NLRP3/STAT3 signals are effective therapeutic strategy in AKI.

Utilising routine clinical laboratory data to support quality improvement in health care: Application of a national acute kidney injury alert system as a proof of concept.

Acute kidney injury (AKI) is a global health issue known to cause avoidable harm and death. Improvement in its prevention and management is therefore considered an important goal for the health-care sector. The work here aimed to develop a tool which could be used to robustly and reliably measure, monitor, and compare the effectiveness of health-care interventions related to AKI across the Welsh NHS, a mechanism which did not exist previously. Using serum creatinine (SCr) as a biomarker for AKI and a validated national data-set collected from the all Wales Laboratory Information Management System, work involved applying Donabedian's framework to develop indicators with which to measure outcomes related to AKI, and exploring the potential of statistical process control (SPC) techniques for analysing data on these indicators. Rate of AKI incidence and 30-day AKI-associated mortality are proposed as valid, feasible indicators with which to measure the effectiveness of health-care interventions related to AKI. The control chart, funnel plot, and Pareto chart are proposed as appropriate, robust SPC techniques to analyse and visualise variation in AKI-related outcomes. This work demonstrates that routinely collected large SCr data offer a significant opportunity to monitor and therefore inform improvement in patient outcomes related to AKI. Moreover, while this work concerns utilisation of SCr data for improvement in AKI strategies, it is a proof of concept which could be replicated for other routinely collected clinical laboratory data, to improve the prevention and/or management of the conditions to which they relate.

Early recognition and prevention of acute kidney injury in hospitalised children.

Acute kidney injury is common in hospitalised children and is associated with poor patient outcomes. Once acute kidney injury occurs, effective therapies to improve patient outcomes or kidney recovery are scarce. Early identification of children at risk of acute kidney injury or at an early injury stage is essential to prevent progression and mitigate complications. Paediatric acute kidney injury is under-recognised by clinicians, which is a barrier to optimisation of inpatient care and follow-up. Acute kidney injury definitions rely on functional biomarkers (ie, serum creatinine and urine output) that are inadequate, since they do not account for biological variability, analytical issues, or physiological responses to volume depletion. Improved predictive tools and diagnostic biomarkers of kidney injury are needed for earlier detection. Novel strategies, including biomarker-guided care algorithms, machine-learning methods, and electronic alerts tied to clinical decision support tools, could improve paediatric acute kidney injury care. Clinical prediction models should be studied in different paediatric populations and acute kidney injury phenotypes. Research is needed to develop and test prevention strategies for acute kidney injury in hospitalised children, including care bundles and therapeutics.

Unveiling the potential of mitochondrial dynamics as a therapeutic strategy for acute kidney injury.

Acute Kidney Injury (AKI), a critical clinical syndrome, has been strongly linked to mitochondrial malfunction. Mitochondria, vital cellular organelles, play a key role in regulating cellular energy metabolism and ensuring cell survival. Impaired mitochondrial function in AKI leads to decreased energy generation, elevated oxidative stress, and the initiation of inflammatory cascades, resulting in renal tissue damage and functional impairment. Therefore, mitochondria have gained significant research attention as a potential therapeutic target for AKI. Mitochondrial dynamics, which encompass the adaptive shifts of mitochondria within cellular environments, exert significant influence on mitochondrial function. Modulating these dynamics, such as promoting mitochondrial fusion and inhibiting mitochondrial division, offers opportunities to mitigate renal injury in AKI. Consequently, elucidating the mechanisms underlying mitochondrial dynamics has gained considerable importance, providing valuable insights into mitochondrial regulation and facilitating the development of innovative therapeutic approaches for AKI. This comprehensive review aims to highlight the latest advancements in mitochondrial dynamics research, provide an exhaustive analysis of existing studies investigating the relationship between mitochondrial dynamics and acute injury, and shed light on their implications for AKI. The ultimate goal is to advance the development of more effective therapeutic interventions for managing AKI.

Analysis of Risk Factors and Intervention Strategies for Acute Kidney Injury After Cardiac Valve Replacement.

To investigate the risk factors and intervention strategies for the development of acute kidney injury (AKI) after cardiac valve replacement with extracorporeal circulation. Retrospective analysis of the clinical data of a total of 106 patients diagnosed with heart valve disease and undergoing extracorporeal circulation heart valve replacement surgery from January 2021 to December 2021 in the Department of Cardiac and Major Vascular Surgery of our hospital. The two groups were divided into AKI and non-AKI groups according to whether acute kidney injury occurred after surgery, and the preoperative, intraoperative and postoperative clinical data were compared. Single-factor analysis and multi-factor logistic regression analysis were used to explore the risk factors for acute kidney injury after extracorporeal heart valve replacement, and to improve the prognosis by giving kidney function protection strategies as early as possible. Univariate analysis showed that age, preoperative blood creatinine >130umol/L, LVEF <45%, presence of subacute infective endocarditis (SIE), concurrent coronary artery bypass grafting (CABG), time to extracorporeal circulation, time to surgery, MAP <70mmHg, urine output <0.5mL/(kg-h), pulmonary infection, low cardiac output, and bacteraemia were risk factors for postoperative AKI. Multi-factor regression analysis showed that preoperative blood creatinine >130umol/l, LVEF <45%, combined infective endocarditis, extracorporeal circulation time >2h, intraoperative and postoperative hypotension, low cardiac output, and postoperative bacteremia were independent risk factors for postoperative AKI. Active intervention strategies in the perioperative period can reduce the occurrence of postoperative AKI and improve patient prognosis.

Targeting RNA oxidation by ISG20-mediated degradation is a potential therapeutic strategy for acute kidney injury

Oxidative stress plays a central role in the pathophysiology of acute kidney injury (AKI). Although RNA is one of the most vulnerable cell components to oxidative damage, it is unclear whether RNA oxidation is involved in the pathogenesis of AKI. In this study, we found that the level of RNA oxidation was significantly enhanced in kidneys of patients with acute tubular necrosis (ATN) and in the renal tubular epithelial cells (TECs) of mice with AKI, and oxidized RNA overload resulted in TEC injury. We further identified interferon-stimulated gene 20 (ISG20) as a novel regulator of RNA oxidation in AKI. Tubule-specific deficiency of ISG20 significantly aggravated renal injury and RNA oxidation in the ischemia/reperfusion-induced AKI mouse model and ISG20 restricted RNA oxidation in an exoribonuclease activity-dependent manner. Importantly, overexpression of ISG20 protected against oxidized RNA overproduction and renal ischemia/reperfusion injury in mice and ameliorated subsequent protein aggresome accumulation, endoplasmic reticulum stress, and unfolded protein response. Thus, our findings provide direct evidence that RNA oxidation contributes to the pathogenesis of AKI and that ISG20 importantly participates in the degradation of oxidized RNA, suggesting that targeting ISG20-handled RNA oxidation may be an innovative therapeutic strategy for AKI.

No difference in mortality after three different kidney replacement therapy initiation strategies in acute kidney injury.

No difference in mortality after three different kidney replacement therapy initiation strategies in acute kidney injury.

WITHDRAWN: SGLT2i reduces renal injury by improving mitochondrial metabolism and biogenesis

Despite advances in treatment, an effective therapeutic strategy for acute kidney injury (AKI) is still lacking. Considering the widely reported clinical benefits of canagliflozin in the kidneys, we assessed the effects of canagliflozin on AKI. Lipopolysaccharide was used to induce AKI in the presence of canagliflozin. Canagliflozin treatment reduced blood urea nitrogen and serum creatinine levels and improved the renal tubular structure in mice with lipopolysaccharide-induced septic AKI. Canagliflozin also suppressed the inflammatory response, oxidative stress and tubular cell death in the kidneys during septic AKI. Invitro, canagliflozin supplementation maintained mitochondrial function in lipopolysaccharide-treated HK-2 cells by restoring the mitochondrial membrane potential, inhibiting mitochondrial reactive oxygen species production and normalizing mitochondrial respiratory complex activity. In HK-2 cells, canagliflozin stimulated the adenosine monophosphate-activated protein kinase catalytic subunit alpha 1 (AMPKα1)/peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α)/nuclear respiratory factor 1 (NRF1) pathway, thus elevating the number of live and healthy mitochondria following lipopolysaccharide treatment. Inhibition of the AMPKα1/PGC1α/NRF1/mitochondrial biogenesis pathway abolished the protective effects of canagliflozin on renal cell mitochondria and tubular viability. Similarly, the protective effects of canagliflozin on kidney function and tubular structure were abrogated in AMPKα1-knockout mice. Canagliflozin could be used to treat septic AKI by activating the AMPKα1/PGC1α/NRF1/mitochondrial biogenesis pathway.

Mitochondrial Targeted Antioxidant SKQ1 Ameliorates Acute Kidney Injury by Inhibiting Ferroptosis.

Emerging evidence suggests that ferroptosis is highly correlated with the pathogenesis of acute kidney injury (AKI). Ferroptosis, an iron-dependent form of cell death, is manifested by a toxic accumulation of lipid peroxides and ultrastructural changes in mitochondria. We herein investigated the effect of Visomitin (SKQ1), a novel mitochondria-targeting antioxidant, on several AKI models in vivo and in vitro. Our results revealed that SKQ1 treatment greatly reversed renal outcomes in cisplatin, ischemia-reperfusion injury (IRI), or folic acid-induced AKI models. These effects were reflected in attenuated levels of renal injury biomarkers, histologic indices of tubular injury, and inflammatory infiltration in the SKQ1-treated groups. Transcriptomics analysis depicted ferroptosis signaling as the most pronounced pathway downregulated after SKQ1 treatment. Consequently, administration of SKQ1 significantly ameliorated lipid peroxide accumulation and inhibited ferroptosis in the kidneys of mice with AKI. In cultured human proximal tubule epithelial cells (HK2), SKQ1 treatment markedly mitigated cisplatin-induced mitochondrial reactive oxygen species (ROS) production, resulting in lower levels of lipid peroxidation and ferroptosis. In conclusion, SKQ1 treatment protected against ischemic- or nephrotoxic-induced AKI by inhibiting ferroptosis in vivo and in vitro. These results could facilitate a broader understanding of the interaction between mitochondrial antioxidants and ferroptotic defense mechanisms, providing a possible therapeutic strategy in AKI.

FC 133: Knockout Of ZEB2 Ameliorates Progression of Renal Tubulointerstitial Fibrosis in a Mouse Model of Renal Ischemia-Reperfusion Injury

Abstract BACKGROUND AND AIMS Zeb2, a zinc finger E-box-binding homeobox transcription factor, reportedly regulates transforming growth factor (TGF)-β signaling pathway. However, its role in the pathogenesis of acute kidney injury (AKI) and AKI to chronic kidney disease (CKD) transition is unclear. METHOD We evaluated Zeb2 function in a bilateral renal ischemia-reperfusion injury (IRI)-induced AKI model using proximal tubule-specific Zeb2 conditional knockout (Zeb2-cKO) and wild-type (WT) mice. In Zeb2-cKO mice, plasma creatinine and blood urea nitrogen levels post-IRI were significantly lower than those in WT mice. Immunohistological analysis revealed mild tubular injury, less fibrotic changes, and reduced expression of fibrotic proteins, such as collagen type IV, α-smooth muscle actin (α-SMA), fibronectin and connective tissue growth factor (CTGF), at 3–14 days post-IRI in Zeb2-cKO mice. We also evaluated Zeb2 expression in human renal biopsy samples, including AKI to CKD patients, by immunohistological methods. RESULTS Zeb2 expression was mainly upregulated in proximal tubular cells post-IRI in WT mice. Zeb2 siRNA transfection reduced TGF-β-stimulated mRNA and protein expression of collagen type IV, α-SMA, fibronectin and CTGF in cultured renal tubular cells. Notably, patients with AKI to CKD transition showed high Zeb2 expression in renal tubules, as determined by evaluation of their renal biopsy samples. Furthermore, hypoxia and CoCl2-treatment upregulated Zeb2 promoter activity and mRNA and protein expression in cultured renal tubular epithelial cells, suggesting regulatory role of hypoxia. CONCLUSION Thus, we demonstrated Zeb2 upregulation in renal tissues in both mice and humans with AKI and showed that Zeb2 regulates fibrotic pathways in pathogenesis of AKI and AKI to CKD transition. Our findings suggest that Zeb2 blockage could serve as a potential therapeutic strategy in AKI.

Ferroptosis and Acute Kidney Injury (AKI): Molecular Mechanisms and Therapeutic Potentials.

Acute kidney injury (AKI), a common and serious clinical kidney syndrome with high incidence and mortality, is caused by multiple pathogenic factors, such as ischemia, nephrotoxic drugs, oxidative stress, inflammation, and urinary tract obstruction. Cell death, which is divided into several types, is critical for normal growth and development and maintaining dynamic balance. Ferroptosis, an iron-dependent nonapoptotic type of cell death, is characterized by iron overload, reactive oxygen species accumulation, and lipid peroxidation. Recently, growing evidence demonstrated the important role of ferroptosis in the development of various kidney diseases, including renal clear cell carcinoma, diabetic nephropathy, and AKI. However, the exact mechanism of ferroptosis participating in the initiation and progression of AKI has not been fully revealed. Herein, we aim to systematically discuss the definition of ferroptosis, the associated mechanisms and key regulators, and pharmacological progress and summarize the most recent discoveries about the role and mechanism of ferroptosis in AKI development. We further conclude its potential therapeutic strategies in AKI.

The Hippo pathway and its correlation with acute kidney injury.

Acute kidney injury (AKI) is a significant clinical complication with a substantial impact on morbidity and mortality, for which therapeutic options remain limited. The Hippo signaling pathway is an evolutionarily conserved pathway implicated in cell proliferation, dedifferentiation, and apoptosis via phosphorylation and inactivation of its downstream effectors Yes-associated protein (YAP)/ transcriptional co-activator with PDZ-binding motif (TAZ). Recent studies have revealed that the Hippo pathway plays a pivotal role in the pathogenesis and repair of AKI. The Hippo pathway can mediate renal dysfunction through modulation of mitochondrial apoptosis under AKI conditions. Transient activation of YAP/TAZ in the acute phase of AKI may benefit renal recovery and regeneration, whereas persistent activation of YAP/TAZ in severe AKI may lead to maladaptive repair and transition to chronic kidney disease. This review aims to summarize recent findings on the associations between the Hippo pathway and AKI and to identify new therapeutic targets and strategies for AKI.

Acute kidney injury after cardiac surgery in children

Acute kidney injury (AKI) after cardiac surgery in children remains a common clinical concern. The approaches developed recently and applied in clinical practice have sufficiently helped in clarifying the epidemiology, risk factors and pathophysiology of AKI in paediatric cardiac surgery. Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease criteria (pRIFLE), Acute Kidney Injury Network (AKIN) and Kidney Disease: Improving Global Outcomes (KDIGO), which are based on changes in serum creatinine levels and urine output rate, enable the identification and ranking of AKI according to severity. However, the diagnostic strategies for AKI have developed beyond creatinine levels and recommend the use of markers of renal tissue damage. Currently, two markers, neutrophil gelatinase-associated lipocalin and TIMP-2/IGFBP-7 (tissue inhibitor of metalloproteinase 2 and protein that binds insulin-like growth factor-7), can be used for the early diagnosis of AKI in paediatric cardiac surgery. Various risk factors, both renal and extrarenal, can predict AKI after cardiac surgery, among which age, the duration of cardiopulmonary bypass and the need for mechanical ventilation and inotropic support before surgery, are the most significant. Strategies for addressing modifiable risk factors (maintaining appropriate perfusion pressure during cardiopulmonary bypass and avoiding nephrotoxic drugs and fluid overload) will reduce the risk of developing AKI. There has been a significant increase in survival rates due to the introduction of ultrafiltration techniques and the early initiation of renal replacement therapy in the postoperative period. The purpose of this review is to analyse the current literature data on AKI in paediatric cardiac surgery. The review results demonstrate the differences in the incidence of AKI associated with cardiac surgery and the effectiveness of certain methods for prevention and treatment of this complication. Further comprehensive research on the issue of AKI in children, creation of medical electronic databases on patients, minimisation of the influence of possible risk factors and timely prevention and treatment of complications would prevent the development of AKI and reduce the possibility of complication progression to a more severe stage. Received 12 April 2021. Revised 24 June 2021. Accepted 25 June 2021. Funding: The study did not have sponsorship. Conflict of interest: Authors declare no conflict of interest. Contribution of the authors: The authors contributed equally to this article.

Renal Cell-Targeted Drug Delivery Strategy for Acute Kidney Injury and Chronic Kidney Disease: A Mini-Review.

Kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD), have become a global public health concern associated with high morbidity, mortality, and healthcare costs. However, at present, very few effective and specific drug therapies are available, owing to the poor therapeutic efficacy and systemic side effects. Kidney-targeted drug delivery, as a potential strategy for solving these problems, has received great attention in the fields of AKI and CKD in recent years. Here, we review the literature on renal targeted, more specifically, renal cell-targeted formulations of AKI and CKD that offered biodistribution data. First, we provide a broad overview of the unique structural characteristics and injured cells of acute and chronic injured kidneys. We then separately summarize literature examples of renal targeted formulations according to the difference of target cells and elaborate on the appropriate formulation design criteria for AKI and CKD. Finally, we propose a hypothetic strategy to improve the renal accumulation of glomerular cell-targeted formulation by escaping the uptake of the reticuloendothelial system and provide some perspectives for future studies.

Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Potential Therapeutic Strategy for Acute Kidney Injury.

Acute kidney injury (AKI) is a common and potential life-threatening disease in patients admitted to hospital, affecting 10%–15% of all hospitalizations and around 50% of patients in the intensive care unit. Severe, recurrent, and uncontrolled AKI may progress to chronic kidney disease or end-stage renal disease. AKI thus requires more efficient, specific therapies, rather than just supportive therapy. Mesenchymal stem cells (MSCs) are considered to be promising cells for cellular therapy because of their ease of harvesting, low immunogenicity, and ability to expand in vitro. Recent research indicated that the main therapeutic effects of MSCs were mediated by MSC-derived extracellular vesicles (MSC-EVs). Furthermore, compared with MSCs, MSC-EVs have lower immunogenicity, easier storage, no tumorigenesis, and the potential to be artificially modified. We reviewed the therapeutic mechanism of MSCs and MSC-EVs in AKI, and considered recent research on how to improve the efficacy of MSC-EVs in AKI. We also summarized and analyzed the potential and limitations of EVs for the treatment of AKI to provide ideas for future clinical trials and the clinical application of MSC-EVs in AKI.