LncTCONS_00058568 is involved in the pathophysiologic processes mediated by P2X7R in the lower thoracic spinal cord after acute kidney injury.

Acute kidney injury (AKI), a prevalent clinical syndrome, involves the participation of the nervous system in neuroimmune regulation. However, the intricate molecular mechanism that governs renal function regulation by the central nervous system (CNS) is complex and remains incompletely understood. In the present study, we found that the upregulated expression of lncTCONS_00058568 in lower thoracic spinal cord significantly ameliorated AKI-induced renal tissue injury, kidney morphology, inflammation and apoptosis, and suppressed renal sympathetic nerve activity. Mechanistically, the purinergic ionotropic P2X7 receptor (P2X7R) was overexpressed in AKI rats, whereas lncTCONS_00058568 was able to suppress the upregulation of P2X7R. In addition, RNA sequencing data revealed differentially expressed genes associated with nervous system inflammatory responses after lncTCONS_00058568 was overexpressed in AKI rats. Finally, the overexpression of lncTCONS_00058568 inhibited the activation of PI3K/Akt and NF-κB signaling pathways in spinal cord. Taken together, the results from the present study show that lncTCONS_00058568 overexpression prevented renal injury probably by inhibiting sympathetic nerve activity mediated by P2X7R in the lower spinal cord subsequent to I/R-AKI.

Reno-protective effect of fenofibrate and febuxostat against vancomycin-induced acute renal injury in rats: Targeting PPARγ/NF-κB/COX-II and AMPK/Nrf2/HO-1 signaling pathways.

BACKGROUND: Vancomycin (VCM) is used clinically to treat serious infections caused by multi-resistant Gram-positive bacteria, although its use is severely constrained by nephrotoxicity. This study investigated the possible nephroprotective effect of febuxostat (FX) and/or fenofibrate (FENO) and their possible underlying mechanisms against VCM-induced nephrotoxicity in a rat model. METHODS: Male Wistar rats were randomly allocated into five groups; Control, VCM, FX, FENO, and combination groups. Nephrotoxicity was evaluated histopathologically and biochemically. The oxidative stress biomarkers (SOD, MDA, GSH, total nitrite, GPx, MPO), the apoptotic marker, renal Bcl-2 associated X protein (Bax), and inflammatory and kidney injury markers (IL-1ß, IL-6, TNF-α, Nrf2, OH-1, kappa-light-chain-enhancer of activated B cells (NF-κB), NADPH oxidase, Kim-1, COX-II, NGAL, Cys-C were also evaluated. RESULTS: VCM resulted in significant elevation in markers of kidney damage, oxidative stress, apoptosis, and inflammatory markers. Co-administration of VCM with either/or FX and FENO significantly mitigated nephrotoxicity and associated oxidative stress, inflammatory and apoptotic markers. In comparison to either treatment alone, a more notable improvement was observed with the FX and FENO combination regimen. CONCLUSION: Our findings show that FX, FENO, and their combination regimen have a nephroprotective impact on VCM-induced kidney injury by suppressing oxidative stress, apoptosis, and the inflammatory response. Renal recovery from VCM-induced injury was accomplished by activation of Nrf2/HO-1 signaling and inhibition of NF-κB expression. This study highlights the importance of FX and FENO as effective therapies for reducing nephrotoxicity in VCM-treated patients.

Risk factors for mortality in patients receiving extracorporeal membrane oxygenation.

OBJECTIVE: Patients on extracorporeal membrane oxygenation (ECMO) are often complex and have a high mortality rate. Currently, risk assessment and treatment decisions for patients receiving ECMO are controversial. Therefore, we sought to identify risk factors for mortality in patients receiving ECMO and provide a reference for patient management. METHODS: We retrospectively analyzed the clinical data of 199 patients who received ECMO support from December 2013 to April 2023. Univariate and multivariable logistic regression analyses were used to identify risk factors. The cutoff value was determined by receiver operating characteristic (ROC) curve analysis. RESULTS: A total of 199 patients were selected for this study, and the mortality rate was 76.38%. More than half of the patients underwent surgery during hospitalization. Multivariable logistic regression analysis revealed that continuous renal replacement therapy (CRRT) implantation (OR = 2.994; 95% CI, 1.405-6.167; p = 0.004) and age (OR = 1.021; 95% CI, 1.002-1.040; p = 0.032) were the independent risk factors for mortality. In the ROC curve analysis, age had the best predictive effect (AUC 0.646, 95% CI 0.559-0.732, p = 0.003) for death when the cutoff value was 48.5 years. Furthermore, in patients receiving combined CRRT and ECMO, lack of congenital heart disease and previous surgical history were the independent risk factors for mortality. CONCLUSIONS: CRRT implantation and age were independent risk factors for patients with ECMO implantation in a predominantly surgical cohort. In patients receiving a combination of CRRT and ECMO, lack of congenital heart disease and previous surgical history were independent risk factors for mortality.

Risk factors associated with hospital mortality in non-surgical patients receiving extracorporeal membrane oxygenation and continuous renal replacement treatment: a retrospective analysis.

OBJECTIVES: The prognosis-predicting factors for non-surgical patients receiving continuous renal replacement therapy (CRRT) and extracorporeal membrane oxygenation (ECMO) remains limited. In this study, we aim to analyze prognosis-predicting factors in the non-surgical patients receiving these two therapies. METHODS: We retrospectively analyzed data from non-surgical patients with ECMO treatment from December 2013 until April 2023. Hospital mortality was primary endpoint of this study. The area under the curve and receiver operating characteristic curves were used to assess the sensitivity and specificity of mortality. The independent risk factors were identified by multivariate logistic regression. The prediction model was a nomogram, and decision curve analysis and the calibration plot were used to assess it. Using restricted cubic spline curves and Spearman correlation, the correlation analysis was performed. RESULTS: The model that incorporated CRRT duration and age surpassed the two variables alone in predicting hospital mortality in non-surgical patients with ECMO therapy (AUC value = 0.868, 95% CI = 0.779-0.956). Older age, CRRT implantation, and duration were independent risk factors for hospital mortality (all p < 0.05). The nomogram predicting outcomes model containing on CRRT implantation and duration was developed, and the consistency between the predicted probability and observed probability and clinical utility of the models were good. CRRT duration was negatively associated with hemoglobin concentration and positively associated with urea nitrogen and serum creatinine levels. CONCLUSION: Hospital mortality in non-surgical ECMO patients was found to be independently associated with older age, longer CRRT duration, and CRRT implantation.

Urolithiasis in Kidney Transplant Patients: A Multicenter KSER Research Series.

Background and Objectives: Urolithiasis occurrence is uncommon in kidney transplantation patients, though it has serious implications, including acute kidney injury in the transplanted kidney. This study investigates the leading causes of urolithiasis in kidney transplantation patients, the diagnostic process, and the outcomes of multimodal management. Materials and Methods: Data collection spanned from January 1997 to December 2021, involving kidney transplantation patients with urolithiasis from the database of the Korean Society of Endourology and Robotics (KSER) research committee. Analysis encompassed factors triggering urolithiasis, the diagnostic process, stone attributes, treatment methods, and outcomes. Results: Our analysis included 58 kidney transplantation patients with urolithiasis from eight medical centers. Of these patients, 37 were male and 4 had previous urolithiasis diagnoses. The mean age was 59.09 ± 10.70 years, with a mean duration from kidney transplantation to diagnosis of 76.26 ± 183.14 months. The most frequent method of stone detection was through asymptomatic routine check-ups (54.7%). Among the 58 patients, 51 underwent stone treatment. Notably, 95.3% of patients with ureter stones received treatment, a significantly higher rate than the 66.7% of patients with renal stones (p = 0.010). Success rates showed no significant differences between renal (70%) and ureter stone (78.0%) groups (p = 0.881). Conclusions: Urolithiasis in transplanted kidneys constitutes an acute condition requiring emergency intervention. Endo-urological interventions are effective for kidney transplantation patients with urolithiasis. To ensure prevention and early detection, diligent follow-up and routine imaging tests are necessary.

Anemonin inhibits sepsis-induced acute kidney injury via mitigating inflammation and oxidative stress.

Elevated inflammation and oxidative stress (OS) are the main pathologic features of acute kidney injury (AKI)-caused by sepsis. Here, we made an investigation into the protective effects of the natural compound Anemonin (ANE) on sepsis-induced AKI both in vitro and in vivo. Lipopolysaccharide (LPS) was applied to construct an in vitro AKI model in renal tubular epithelial cells, and the septic C57BL/6J mouse model was constructed via cecal ligation and puncture (CLP). Cell viability and apoptosis were detected. The levels of p53, Bax, Bcl2, Caspase3, Caspase8, Caspase9, AMP-activated protein kinase (AMPK), Sirt-1, and forkhead box O3 were determined by Western Blot or RT-PCR. The reactive oxygen species level and OS markers were measured. Furthermore, the pathological changes of kidneys were evaluated by hematoxylin-eosin staining and immunohistochemistry. As per the information presented, ANE improved LPS-elicited apoptosis, inflammatory response, and OS in a dose-dependent pattern in renal tubular epithelial cells. Besides, ANE activated the AMPK/Sirt-1 pathway, and the AMPK inhibitor (Compound C) and Sirt-1 inhibitor (EX-527) significantly attenuated ANE-mediated protection on renal tubular epithelial cells. In vivo, ANE mitigated the levels of serum creatinine and urea nitrogen in the CLP-induced mouse sepsis model, reduced the renal tissue injury score, and attenuated OS, inflammation, and apoptosis levels in the kidney. Taken together, this study suggested that ANE has protective effects in sepsis-triggered AKI through repressing inflammation, OS, and cell apoptosis by activating the AMPK/Sirt-1 pathway.

Risk factors for mortality in surgical patients on combined continuous renal replacement therapy and extracorporeal membrane oxygenation: single-center retrospective study.

OBJECTIVE: In patients receiving extracorporeal membrane oxygenation (ECMO), continuous renal replacement therapy (CRRT) is increasingly being used for renal replacement and fluid management. However, critically ill surgical patients receiving combined ECMO and CRRT tend to have a high mortality rate, and there are limited studies on this population. Therefore, we aimed to investigate the risk factors for mortality in surgical patients receiving combined ECMO and CRRT. METHODS: Data of surgical patients who underwent ECMO between December 2013 and April 2023 were retrospectively reviewed. Univariate and multivariate logistic regression analysis were used to identify the risk variables. Receiver operating characteristic (ROC) curve analysis was used to determine the cutoff value of albumin and age to predict death. RESULTS: A total of 199 patients on ECMO support were screened, of which 105 patients were included in the final analysis. Of 105 patients, 77 (73.33%) were treated with CRRT. Veno-arterial ECMO was performed in 97 cases (92.38%), and the rest were veno-venous ECMO (n = 8, 7.62%). Cardiovascular-related surgery was performed in the main patients (n = 86, 81.90%) and other types of surgery in 19 patients. In surgical patients on ECMO support, the logistic regression analysis showed that CRRT implantation, male sex, and age were the independent risks factors for mortality. Furthermore, the ROC curve analysis showed that age 48.5 years had the highest Youden index. In surgical patients on combined CRRT and ECMO, age, valvular heart disease, and albumin were the independent risk factors for prognosis. Albumin had the highest Youden index at a cutoff value of 39.95 g/L for predicting mortality, though the overall predictive value was modest (area under ROC 0.704). Age had the highest Youden index at a cutoff value of 48.5 years for predicting mortality. CONCLUSIONS: In our cohort of surgical patients requiring ECMO, which consisted mostly of patients undergoing cardiovascular surgery requiring VA-ECMO, the need for CRRT was an independent risk factor for mortality. In the subset of patients on combined CRRT and ECMO, independent risk factors for mortality included higher age, lack of valvular heart disease, and lower serum albumin.

Toll-like Receptor 4 in Acute Kidney Injury.

Acute kidney injury (AKI) is a common and devastating pathologic condition, associated with considerable high morbidity and mortality. Although significant breakthroughs have been made in recent years, to this day no effective pharmacological therapies for its treatment exist. AKI is known to be connected with intrarenal and systemic inflammation. The innate immune system plays an important role as the first defense response mechanism to tissue injury. Toll-like receptor 4 (TLR4) is a well-characterized pattern recognition receptor, and increasing evidence has shown that TLR4 mediated inflammatory response, plays a pivotal role in the pathogenesis of acute kidney injury. Pathogen-associated molecular patterns (PAMPS), which are the conserved microbial motifs, are sensed by these receptors. Endogenous molecules generated during tissue injury, and labeled as damage-associated molecular pattern molecules (DAMPs), also activate pattern recognition receptors, thereby offering an understanding of sterile types of inflammation. Excessive, uncontrolled and/or sustained activation of TLR4, may lead to a chronic inflammatory state. In this review we describe the role of TLR4, its endogenous ligands and activation in the inflammatory response to ischemic/reperfusion-induced AKI and sepsis-associated AKI. The potential regeneration signaling patterns of TLR4 in acute kidney injury, are also discussed.

Deficiency of mindin reduces renal injury after ischemia reperfusion.

BACKGROUND: Acute renal injury (AKI) secondary to ischemia reperfusion (IR) injury continues to be a significant perioperative problem and there is no effective treatment. Mindin belongs to the mindin/F-spondin family and involves in inflammation, proliferation, and cell apoptosis. Previous studies have explored the biological functions of mindin in liver and brain ischemic injury, but its role in AKI is unknown. METHOD: To investigate whether mindin has a pathogenic role, mindin knockout (KO) and wild-type (WT) mice were used to establish renal IR model. After 30 min of ischemia and 24 h of reperfusion, renal histology, serum creatinine, and inflammatory response were examined to assess kidney injury. In vitro, proinflammatory factors and inflammatory signaling pathways were measured in mindin overexpression or knockdown and vector cells after hypoxia/reoxygenation (HR). RESULTS: Following IR, the kidney mindin level was increased in WT mice and deletion of mindin provided significant protection for mice against IR-induced renal injury as manifested by attenuated the elevation of serum creatinine and blood urea nitrogen along with less severity for histological alterations. Mindin deficiency significantly suppressed inflammatory cell infiltration, TNF-α and MCP-1 production following renal IR injury. Mechanistic studies revealed that mindin deficiency inhibits TLR4/JNK/NF-κB signaling activation. In vitro, the expression levels of TNF-α and MCP-1 were increased in mindin overexpression cells compared with vector cells following HR. Moreover, TLR4/JNK/NF-κB signaling activation was elevated in the mindin overexpression cells in response to HR stimulation while mindin knockdown inhibited the activation of TLR4/JNK/ NF-κB signaling after HR in vitro. Further study showed that mindin protein interacted directly with TLR4 protein. And more, mindin protein was confirmed to be expressed massively in renal tubule tissues of human hydronephrosis patients. CONCLUSION: These data demonstrate that mindin is a critical modulator of renal IR injury through regulating inflammatory responses. TLR4/JNK/NF-κB signaling most likely mediates the biological function of mindin in this model of renal ischemia.

Co-delivery of celastrol and lutein with pH sensitive nano micelles for treating acute kidney injury.

To treat acute kidney injury with high efficiency and low toxicity, a novel nanoplatform was developed to remove excess reactive oxygen species (ROS). Lutein (LU) and celastrol (Cel) were loaded into low molecular weight chitosan (CS) to prepare Cel@LU-CA-CS nanomicelles. Renal tubular epithelial (HK-2) cell uptake experiments showed that the drugs could be internalized in renal tubular via the megalin receptor. In this study, the amide bond formed by the reaction of citraconic anhydride (CA) with an amino group of CS could be destroyed under acidic conditions. Therefore, the drugs were released in HK-2 cells due to the acidic environment of the lysosome. In vitro studies showed that the nanomicelles could reduce toxicity in non-target organs and enhance therapeutic efficacy in acute kidney injury (AKI). In addition, Cel@LU-CA-CS micelles had alleviated kidney oxidative stress disorder and stabilized the mitochondrial membrane potential quickly. Next, in vivo studies proved that Cel@LU-CA-CS micelles could inhibit the activation of the NF-κB p65 and p38 MAPK inflammatory signaling pathways. Therefore, the micelles further reduced the overexpression of related inflammatory factors. In conclusion, Cel@LU-CA-CS nanomicelles could treat AKI with high efficiency and low toxicity, and inhibit renal fibrosis.

Furosemide does not reduce the incidence of postoperative acute kidney injury in adult patients undergoing cardiac surgery: A PRISMA-compliant systematic review and meta-analysis.

OBJECTIVE: Acute kidney injury (AKI) is a common complication of cardiac surgical patients, the occurrence of which is multifactorial. Furosemide is the most common loop diuretic and widely used in cardiac surgery to reduce fluid overload, increase tubular flow and urine output. It remains unknown whether furosemide affects the incidence or prognosis of cardiac surgery-induced acute kidney injury (CS-AKI). Therefore, the current study was performed to address this question. METHODS: PubMed, Embase, Scopus, Cochrane Library, and Web of Science databases were searched for relevant studies. Primary outcomes of interest included postoperative CS-AKI incidence, need for renal replacement therapy (RRT) rate. Secondary outcomes of interest included postoperative serum creatinine (Scr) and blood urea nitrogen (BUN) levels, postoperative mechanical ventilation duration (MVD), length of stay (LOS) in intensive care unit (ICU) and in hospital, and mortality. The odds ratio (OR) and/or the weighted mean difference (WMD) with 95% confidence interval (CI) were used to pool the data. RESULTS: Database search yielded six studies including 566 adult patients, and 283 patients were allocated into Group Furosemide and 283 into Group Control (Placebo). Heterogeneity between studies was deemed acceptable, and the publication bias was low. Meta-analysis suggested that furosemide administration in adult cardiac surgical patients had no effect on CS-AKI incidence (n = 4 trials; OR = 0.92; 95% CI: 0.37-2.30; p = .86; I2 = 57%) and need for RRT rate (n = 2 trials; OR = 4.13; 95% CI: 0.44-38.51; p = .21; I2 = 0%). Diversely, furosemide administration in adult cardiac surgical patients significantly decreased postoperative BUN level (n = 3 trials; WMD = 0.71; 95% CI: 0.10-1.33; p = .02; I2 = 0%), postoperative MVD (n = 2 trials; WMD = -3.13; 95% CI: -3.78 to -2.49; p < .00001; I2 = 0%) and postoperative LOS in ICU (n = 3 trials; WMD = -0.47; 95% CI: -0.76 to -0.18; p = .001; I2 = 0%). However, it had no significant impact on postoperative Scr level, postoperative LOS in hospital, and postoperative mortality. CONCLUSION: This meta-analysis suggested that furosemide administration in adult cardiac surgical patients had no significant effect on CS-AKI incidence, need for RRT rate, postoperative Scr level, LOS in hospital and mortality, but could reduce postoperative BUN level, MVD, and LOS in ICU. As only a limited number of studies were included, these results should be interpreted carefully and cautiously. Future high-quality randomized controlled trials are needed to define the role of furosemide in CS-AKI prevention and management.

MicroRNA as an early diagnostic biomarker for contrast-induced acute kidney injury.

Contrast-induced acute kidney injury (CI-AKI) is a common clinical complication and an important cause of increased mortality, prolonged hospitalization, and increased medical costs. For taking effective interventions in CI-AKI, early diagnosis and active prevention are of key importance. Currently, early CI-AKI detection depends on serum creatinine (Scr) levels, which lags behind the actual time of renal injury and seriously affects early diagnosis and interventions. MicroRNA (miRNA) has been found to be a useful biomarker in early CI-AKI diagnosis. Several studies have reported on tissue and time-specific miRNAs in AKI as effective diagnostic biomarkers and potential therapeutic targets, but there are only a few studies on miRNA in CI-AKI. However, these studies are preliminary exploratory investigations on changes in miRNA expression in CI-AKI, and whether these specific miRNAs can be used as biomarkers for early CI-AKI diagnosis and as clinical therapeutic targets requires systematic and in-depth studies. Therefore, more sensitive and specific miRNAs of CI-AKI could be discovered, providing newer options and development directions for early diagnosis and intervention in clinical CI-AKI practice. This review evaluates the research progress on specific miRNAs in the early diagnosis of CI-AKI with an aim of providing basic data for the clinical application of these molecular markers in CI-AKI.

Continuous Renal Replacement Therapy with Regional Citrate Anticoagulation in Children with Liver Dysfunction/Failure.

Regional citrate anticoagulation (RCA) is an option but citrate accumulation is risk and it is a giving up cause for this situation. This retrospective study was conducted in the pediatric intensive care unit (PICU) between May 2019 and April 2021. We investigated 47 patients with liver failure (LF) in our PICU, and RCA during continuous renal replacement therapy (CRRT) was applied to 10 (21.3%) of them. Half of them were male (n: 5/10), their mean age was 104.7 ± 66.20 months. Nine of them needed vasoactive support during follow-up. The most common indication for CRRT was hepatorenal syndrome (40%). There was no significant difference between liver transaminases and liver function tests before and after CRRT (p > 0.05). In terms of citrate toxicity of the patients, there was no significant difference between total calcium/ionized calcium, lactate level, pH and bicarbonate values before and after CRRT (p > 0.05). The mean total CRRT time was 110.2 ± 118.2 h, and the mean circuit lifespan was 43.8 ± 48.7 h; the mean number of circuits was 2.7 ± 2.4. Total Ca/ionized Ca >2.5 was a clinically relevant endpoint, but no patient interrupted dialysis for this cause. There was no complication about RCA. This study did not observe any adverse effects on acid-base status, transaminases, an increase in bilirubin during RCA-CRRT treatment in pediatric patients with LF. Total calcium/ionized calcium ratio, serum lactate level and prothrombin time level should be closely monitored daily in terms of citrate accumulation in this patient group.

[About the safety profile of SGLT2 inhibitors]. / À propos de la sécurité d'emploi des inhibiteurs des SGLT2 (gliflozines).

Since their launch, sodium-glucose cotransporter type 2 inhibitors (SGLT2is) were suspected to be associated with various adverse events. They contributed to delay, as in France, or to restrict the use of this new pharmacological class in clinical practice, despite remarkable results reported in large cardiovascular or renal clinical trials. This article is devoted to three major adverse events that were imputed to SGLT2is : lower-limb extremity amputations, euglycaemic ketoacidosis and acute kidney injuries. In contrast to pharmacovigilance reports that raised suspicion, analysis of all data from the literature, either placebo-controlled trials or retrospective observational cohort studies, led to rather reassuring conclusions. The incidence of amputations does not appear to be increased while cases of acute kidney injury are reduced instead of increased as suspected earlier. Ketoacidosis events are almost doubled with SGLT2is versus comparators, yet their incidence remains extremely low among patients with type 2 diabetes. Of note, this potentially severe complication contributes to the denial of marketing authorization and reimbursement of SGLT2is in the population with type 1 diabetes.

Depuis leur mise sur le marché, les inhibiteurs des cotransporteurs sodium-glucose de type 2 (iSGLT2) ont été incriminés dans diverses manifestations indésirables. Celles-ci ont contribué à retarder, comme en France, ou à limiter la prescription de cette nouvelle classe pharmacologique en pratique clinique, malgré les résultats remarquables rapportés dans de grands essais à visée cardiovasculaire ou rénale. Cet article fait le point sur trois effets secondaires délétères importants imputés aux iSGLT2 : les amputations des extrémités des membres inférieurs, les acidocétoses dites euglycémiques et les insuffisances rénales aiguës. Malgré des données de pharmacovigilance qui avaient soulevé la suspicion, l'analyse de l'ensemble des données de la littérature, que ce soit les essais prospectifs contrôlés versus placebo ou les études observationnelles rétrospectives de cohorte versus des comparateurs actifs, aboutit à des conclusions assez rassurantes. Les amputations ne semblent pas être augmentées tandis que les cas d'insuffisance rénale aiguë sont plutôt en diminution au lieu de présenter une incidence accrue. Les cas d'acidocétose sont environ doublés sous iSGLT2 par rapport aux comparateurs, mais leur incidence reste extrêmement basse chez les patients diabétiques de type 2. Rappelons, néanmoins, que c'est cette complication potentiellement grave qui a entraîné le refus d'autorisation de mise sur le marché et du remboursement des iSGLT2 dans la population diabétique de type 1.

Knockout of farnesoid X receptor gene aggravates cisplatin-induced kidney injury. / æ³•å°¼é ¯Xå—ä½“åŸºå› æ•²é™¤åŠ é‡é¡ºé“‚æ‰€è‡´æ€¥æ€§è‚¾æŸä¼¤.

OBJECTIVES: Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand activated transcription factors and belongs to bile acid receptor. Studies have shown that the expression of FXR in renal tissue can reduce renal injury via regulation of glucose and lipid metabolism, inhibition of inflammatory response, reduction of oxidative stress and renal fibrosis. However, it is unclear whether FXR is involved in autophagy in renal diseases. This study aims to investigate the role of FXR in cisplatin-induced acute renal injury and whether its mechanism is related to autophagy regulation. METHODS: Twelve male WT or FXR-KO mice at 12 weeks were randomly divided into a WT group, a WT+cisplatin group, a FXR-KO group, and a FXR-KO+cisplatin group, with 6 mice in each group. The WT+cisplatin group and the FXR-KO+cisplatin group were intraperitoneally injected with cisplatin (20 mg/kg), and the WT group and the FXR-KO group were intraperitoneally injected with equal volume of cisplatin solvent. Seventy-two hours later, the mice were killed and blood and renal tissue samples were collected. The levels of SCr and BUN were detected by immunoturbidimetry. After the staining, the pathological changes of renal tissue were observed under optical microscope. The protein levels of LC3 and p62 were detected by Western blotting and immunohistochemistry. The clearance of damaged mitochondria and the accumulation of lysosomal substrate were observed under electron microscope. The apoptosis of renal tubular epithelial cells was detected by TUNEL. RESULTS: Compared with the WT group or the FXR-KO group, both SCr and BUN levels in the WT+cisplatin group or the FXR-KO+cisplatin group were significantly increased (P<0.01 or P<0.001), and SCr and BUN levels in the FXR-KO+cisplatin group were significantly higher than those in the WT+cisplatin group (both P<0.05). Under the light microscope, there were no obvious pathological changes in the renal tissue of mice in the WT group and the FXR-KO group. Both the WT+cisplatin group and the FXR-KO+cisplatin group had vacuolar or granular degeneration of renal tubular epithelial cells, flat cells, lumen expansion, brush edge falling off, and even exposed basement membrane and tubular formation. The scores of renal tubular injury in the WT+cisplatin group and the FXR-KO+cisplatin group were significantly higher than those in the WT group and the FXR-KO group, respectively (both P<0.001), and the score in the FXR-KO+cisplatin group was significantly higher than that in the WT+cisplatin group (P<0.05). Under the transmission electron microscope, the mitochondria of mouse tubular epithelial cell in the WT+cisplatin group and the FXR-KO+cisplatin group was swollen, round, vacuolated, cristae broken or disappeared; the lysosome was uneven and high-density clumps, and the change was more obvious in the FXR-KO+cisplatin group. Western blotting showed that the ratio of LC3-II to LC3-I was decreased and the expression of p62 was increased in the WT+cisplatin group compared with the WT group and the FXR-KO+cisplatin group compared with FXR-KO group (P<0.05 or P<0.01); compared with the FXR-KO group, the ratio of LC3-II to LC3-I was decreased and the expression of p62 was increased significantly in the FXR-KO+cisplatin group (both P<0.05). Immunohistochemistry results showed that the expression of total LC3 and p62 in renal cortex of the WT+cisplatin group and the FXR-KO+cisplatin group was increased significantly, especially in the FXR-KO+cisplatin group. TUNEL results showed that the mice in the WT group and the FXR-KO group had negative staining or only a few apoptotic tubular epithelial cells, and the number of apoptotic cells in the WT+cisplatin group and the FXR-KO+cisplatin group were increased. The apoptosis rates of renal tubular epithelial cells in the WT+cisplatin group and the FXR-KO+cisplatin group were significantly higher than those in the WT group and the FXR-KO group, respectively (both P<0.001), and the apoptosis rate in the FXR-KO+cisplatin group was significantly higher than that in the WT+cisplatin group (P<0.05). CONCLUSIONS: Knockout of FXR gene aggravates cisplatin induced acute renal injury, and its mechanism may be related to inhibiting autophagy and promoting apoptosis.

Association between mid-term worsening renal function and mortality after transcatheter aortic valve replacement in patients with chronic kidney disease.

INTRODUCTION: Chronic kidney disease (CKD), acute kidney injury (AKI) and worsening renal function at 30 days after transcatheter aortic valve replacement (TAVR) portend poor outcomes. We sought to evaluate the association between worsening renal function at 3-6 months and mortality among patients with baseline renal dysfunction undergoing TAVR. METHODS: This is a retrospective study of patients with glomerular filtration rate (GFR) < 60 ml/min undergoing TAVR between June 2011 and March 2019 at the Regional Cardiac Catheterization Lab at Kaiser Permanente Los Angeles. Worsening renal function at 3-6 months post-TAVR was defined as: increase in serum creatinine >1.5 times compared to baseline, absolute increase of ≥0.3 mg/dl, or initiation of dialysis. RESULTS: Of 683 patients reviewed, 176 were included in the analysis (median age 84 [IQR 79-88] years, 56% female). Of these, 27 (15.3%) had worsening renal function. AKI post-TAVR (OR 2.9, 95% CI 1.1-7.4, p = .03) and transfusion of ≥4 units red blood cells (OR 8.4, 95% CI 1.2-59, p = .03) were independent predictors of worsening renal function. Worsening renal function increased risk for mortality (HR 2.2, 95% CI 1.17-4.27, p = .015) at a median follow-up of 691 days. Those with improved/stable function with baseline GFR < 60 ml/min had comparable mortality risk to those with baseline GFR ≥ 60 ml/min (18% vs. 16.5%; HR 1.1, 95% CI 0.72-1.75, p = .62). CONCLUSION: Among patients with baseline renal dysfunction, only 15% developed worsening renal function at 3-6 months after TAVR, which was associated with increased mortality. Predictors for worsening renal function include AKI and blood transfusions. Preventative measures peri-procedurally and continued monitoring post-discharge are warranted to improve outcomes.

Curcumin alleviates acute kidney injury in a dry-heat environment by reducing oxidative stress and inflammation in a rat model.

Curcumin exhibits anti-inflammatory and antioxidant activities. We investigated the protective effects of curcumin in a renal injury rat model under dry-heat conditions. We divided Sprague-Dawley rats into four groups: dry-heat 0- (normal temperature control group), 50-, 100-, and 150-minute groups. Each group was divided into five subgroups (n = 10): normal saline (NS), sodium carboxymethylcellulose (CMCNa), and curcumin pretreated low, medium, and high-dose (50, 100, and 200 mg/kg, respectively) groups. Compared to the normal temperature group, serum creatinine, blood urea nitrogen, urinary kidney injury molecule-1, and neutrophil gelatinase-associated load changes in lipoprotein (NGAL) levels were significantly increased in the dry-heat environment group (P < .05); inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression and malondialdehyde (MDA) and related inflammatory factor levels were increased in the kidney tissue. Superoxide dismutase (SOD) and catalase (CAT) levels were decreased. However, following all curcumin pretreatment, the serum levels of kidney injury indicators and NGAL were decreased in the urine compared to those in the NS and CMCNa groups (P < .05), whereas renal SOD and CAT activities were increased and MDA was decreased (P < .05). Renal tissues of the 150-minute group showed obvious pathological changes. Compared to the NS group, pathological changes in the renal tissues of the 100- and 200-mg/kg curcumin groups were significantly reduced. Furthermore, iNOS and COX-2 expression and inflammatory factor levels were decreased after curcumin treatment. Curcumin exerted renoprotective effects that were likely mediated by its antioxidant and anti-inflammatory effects in a dry-heat environment rat model.

Ribociclib induced acute kidney injury: A case report.

INTRODUCTION: Among females, breast cancer is the most common type of cancer. Hormon receptor positive (HR+) subtype constitutes 75% of the diagnosed breast cancers. Combination of the cyclin D-cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and endocrine therapy significantly improves overall survival and progression-free survival. Ribociclib is an oral CDK 4/6 inhibitor and some adverse effects are identified. According to MONALEESA 2-3-7 studies, no adverse effect (AE) were reported due to grade 3 or 4 acute kidney injury (AKI) that caused treatment discontinuation. CASE REPORT: We report a ribociclib-induced grade 3 AKI in an elderly woman who was treated for metastatic breast cancer. During first cycle of therapy, she was admitted to the oncology clinic with diagnosis of AKI.Management and outcome: Ribociclib treatment was discontinued and secondary causes of AKI were excluded. During the follow-up, kidney function values returned to the normal range spontaneously. Ribociclib treatment was re-initiated by reducing the dose (400 mg daily). Despite dose reduction; grade 3 AKI recurred when ribociclib was re-initiated and the drug was permanently discontinued. DISCUSSION: According to MONALEESA 2-3-7 studies; no AE were reported due to grade 3 or 4 AKI. Despite these studies, the FDA reported that 20% of patients with ribociclib + letrozole combination therapy may have any stage elevation of creatinine. Ribociclib induced creatinine elevations are generally mild (grade 1-2) and can be managed by dose reduction or close monitoring of creatinine levels. We report the first case of grade 3 AKI that caused treatment discontinuation following administration of ribociclib.

Ischemic Preconditioning of the Kidney.

The phenomenon of ischemic preconditioning was discovered in 1986 in experiments with the heart, and then it was observed in almost all organs, the kidneys included. This phenomenon is underlain by conditioning of the tissues with short ischemia/reperfusion cycles intended for subsequent exposure to pathological ischemia. Despite the kidneys are not viewed as so vital organs as the brain or the heart, the acute ischemic injury to kidneys is a widespread pathology responsible for the yearly death of almost 2 million patients, while the number of patients with chronic kidney disease is estimated as hundreds of millions or nearly 10% adult population the world over. Currently, it is believed that adaptation of the kidneys to ischemia by preconditioning is the most effective way to prevent the development of acute kidney injury, so deep insight into its molecular mechanisms will be a launch pad for creating the nephroprotective therapy by elevating renal tolerance to oxygen deficiency. This review focuses on the key signaling pathways of kidney ischemic preconditioning, the potential pharmacological mimetics of its key elements, and the limitations of this therapeutic avenue associated with age-related decline of ischemic tolerance of the kidneys.

Protective effects of lutein against vancomycin-induced acute renal injury in mice via upregulation of peroxisome proliferator-activated receptor gamma/nuclear factor erythroid 2-related factor 2 and inhibition nuclear factor-kappaB/caspase 3.

Vancomycin, an antibiotic used occasionally as a last line of treatment for methicillin-resistant Staphylococcus aureus, is reportedly associated with nephrotoxicity. This study aimed at evaluating the protective effects of lutein against vancomycin-induced acute renal injury. Peroxisome proliferator-activated receptor gamma (PPARγ) and its associated role in renoprotection by lutein was also examined. Male BALB/c mice were divided into six treatment groups: control with normal saline, lutein (200 mg/kg), vancomycin (250 mg/kg), vancomycin (500 mg/kg), vancomycin (250 mg/kg) with lutein, and vancomycin (500 mg/kg) with lutein groups; they were euthanized after 7 days of treatment. Thereafter, samples of blood, urine, and kidney tissue of the mice were analyzed, followed by the determination of levels of N-acetyl-ß-D-glucosaminidase (NAG) in the urine, renal creatine kinase; protein carbonyl, malondialdehyde, and caspase-3 in the kidney; and the expression of PPARγ, nuclear factor erythroid 2-related factor 2 (Nrf2), and nuclear factor-kappaB (NF-κB) in renal tissue. Results showed that the levels of protein carbonyl and malondialdehyde, and the activity of NAG, creatine kinase and caspase-3, were significantly increased in the vancomycin-treatment groups. Moreover, the levels of Nrf2 significantly decreased, while NF-κB expression increased. Lutein ameliorated these effects, and significantly increased PPARγ expression. Furthermore, it attenuated vancomycin-induced histological alterations such as, tissue necrosis and hypertrophy. Therefore, we conclude that lutein protects against vancomycin-induced renal injury by potentially upregulating PPARγ/Nrf2 expression in the renal tissues, and consequently downregulating the pathways: inflammation by NF-κB and apoptosis by caspase-3.