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Acute kidney injury (AKI) is a life-threatening condition that is one of most common side effects of cisplatin therapy. Fatty acid oxidation (FAO) is the main source of energy production in kidney proximal tubular epithelial cells (PTECs) but it is inhibited in AKI. Recent work demonstrated that activation of the farnesoid X receptor (FXR) protects against AKI, but the underlying mechanism remains elusive. Using a model of cisplatin-induced AKI, we found that FXR and FAO-related genes were remarkably downregulated while kidney lipid accumulated. Proximal tubule-specific or whole body FXR knockout worsened, while pharmacological activation attenuated these effects. Conversely, FXR knockout in non-proximal tubules did not. RNA-sequencing of PTECs demonstrated increased transcripts involved in metabolic pathways in cells overexpressing FXR versus control after cisplatin treatment, specifically transcripts associated with FAO and peroxisome proliferator-activated receptor-γ (PPARγ) signaling. Furthermore, FXR overexpression or activation improved FAO and inhibited intracellular lipid accumulation in cisplatin-treated cells. In vivo studies have shown that pharmacological activation of PPARγ can prevent cisplatin-induced lipid accumulation, kidney tubule injury and kidney function decline. However, inhibition of PPARγ eliminated the protective effects of FXR compared to control mice during the cisplatin treatment phase and after ischemia-reperfusion injury. Consistent with findings in vivo, FXR/PPARγ reduced lipid accumulation by improving FAO in cisplatin-treated cells. Furthermore, the inhibition of carnitine palmitoyltransferase 1α abolished the protective effect of FXR in cisplatin-treated mice. Thus, FXR improves FAO and reduced lipid accumulation via PPARγ in PTECs of the kidney. Hence, reconstruction of the FXR/PPARγ/FAO axis may be a novel therapeutic strategy for preventing or treating AKI.

Objectives Cumulative fluid overload may influence acute kidney injury (AKI) diagnosis due to the dilution effect. The authors hypothesized a small increase of early postoperative serum creatinine (SCr) adjusted for fluid balance might have superior discrimination ability in subsequent AKI prediction. Design Retrospective analyses. Setting A single-center study in a university hospital. Participants The study comprised 1,016 adult patients who underwent elective isolated or combined valve surgery in 2015. Interventions None. Measurements and Main Results Baseline characteristics, intraoperative parameters, and intraoperative and postoperative fluid balance were collected through a retrospective chart review. Early postoperative SCr level was drawn within 12 hours of surgical completion and then measured daily. Early relative changes of SCr were categorized as a cutoff value of 10% with or without adjustment for cumulative fluid balance. Kidney Disease: Improving Global Outcomes criteria were used to detect AKI. Logistic analyses were performed to determine risk factors for subsequent AKI with the inclusion of measured or fluid-adjusted early relative changes of SCr, respectively. In this study, 355 patients (34.9%) developed AKI. Multivariate logistic analyses showed age, weight, European System for Cardiac Operative Risk Evaluation II, and cardiopulmonary bypass duration were associated independently with the development of AKI. Model discrimination for AKI prediction was improved significantly when the addition of measured (area under the receiver operating characteristic curve [AUROC] 0.830) and fluid-adjusted early changes of SCr to the basic model (AUROC 0.850). Conclusions Early fluid-adjusted relative changes of SCr could improve the predictive ability for subsequent development of AKI in valve surgery patients.

Renal ischemia-reperfusion (I/R) can induce oxidative stress and injury via the generation of reactive oxygen species (ROS). Renal proximal tubular cells are susceptible to oxidative stress, and the dysregulation of renal proximal tubular cellular homeostasis can damage cells via apoptotic pathways. A recent study showed that the generation of ROS can increase perilipin 2 (Plin2) expression in HepG2 cells. Some evidence has also demonstrated the association between Plin2 expression and renal tumors. However, the underlying mechanism of Plin2 in I/R-induced acute kidney injury (AKI) remains elusive. Here, using a mouse model of I/R-induced AKI, we found that ROS generation was increased and the expression of Plin2 was significantly upregulated. An in vitro study further revealed that the expression of Plin2, and the generation of ROS were significantly upregulated in primary tubular cells treated with hydrogen peroxide. Accordingly, Plin2 knockdown decreased apoptosis in renal proximal tubular epithelial cells treated with hydrogen peroxide, which depended on the activation of peroxisome proliferator-activated receptor α (PPARα). Overall, the present study demonstrated that Plin2 is involved in AKI; knockdown of this marker might limit apoptosis via the activation of PPARα. Consequently, the downregulation of Plin2 could be a novel therapeutic strategy for AKI.

BackgroundFluid overload is related to the development and prognosis of cardiac surgery-associated acute kidney injury (CSA-AKI). The study is to investigate the influence of serum creatinine (SCr) corrected by fluid balance on the prognosis of patients with cardiac surgery.MethodsA retrospective study was conducted in 1334 patients who underwent elective cardiac surgery from January 1 to December 31, 2015. Kidney Disease: Improving Global Outcomes (KDIGO) criteria for AKI were applied to identify CSA-AKI. SCr was measured every 24 h during ICU period and was accordingly adjusted for cumulative fluid balance. Changes in SCr, defined as ∆Crea, were determined by difference between before and after adjustment for cumulative fluid balance. All patients were then divided into three groups: underestimation group (∆Crea ≥ P75), normal group (P25 75) and overestimation group (∆Crea ≤ P25).ResultsThe incidence of AKI increased from 29.5% to 31.8% after adjustment for fluid balance. Patients in underestimation group showed prolonged length of ICU stay compared with normal group and overestimation group (3.2 [1.0–4.0] vs 2.1 [1.0–3.0] d,P P P ConclusionsCumulative fluid balance after cardiac surgery disturbs accurate measurement of serum creatinine. Patients with underestimation of SCr were associated with poor prognosis.

Background We aimed to investigate the relationship between the perioperative hemodynamic parameters and the occurrence of cardiac surgery-associated acute kidney injury. Methods A retrospective study was performed in patients who underwent cardiac surgery at a tertiary referral teaching hospital. Acute kidney injury was determined according to the KDIGO criteria. We investigated the association between the perioperative hemodynamic parameters and cardiac surgery-associated acute kidney injury to identify the independent hemodynamic predictors for acute kidney injury. Subgroup analysis was further performed in patients with chronic hypertension. Results Among 300 patients, 29.3% developed acute kidney injury during postoperative intensive care unit period. Multivariate logistic analysis showed the postoperative nadir diastolic perfusion pressure, but not mean arterial pressure, central venous pressure and mean perfusion pressure, was independently linked to the development of acute kidney injury after cardiac surgery (odds ratio 0.945, P = 0.045). Subgroup analyses in hypertensive subjects (n = 91) showed the postoperative nadir diastolic perfusion pressure and peak central venous pressure were both independently related to the development of acute kidney injury (nadir diastolic perfusion pressure, odds ratio 0.886, P = 0.033; peak central venous pressure, odds ratio 1.328, P = 0.010, respectively). Conclusions Postoperative nadir diastolic perfusion pressure was independently associated with the development of cardiac surgery-associated acute kidney injury. Furthermore, central venous pressure should be considered as a potential hemodynamic target for hypertensive patients undergoing cardiac surgery.

High estimated pulmonary artery systolic pressure (ePASP) has been established as a detrimental predictor for adverse outcomes in patients with chronic kidney disease. However, the relation between preoperative high ePASP and the development of cardiac surgery associated acute kidney injury (CSA-AKI) has not been validated. We performed a retrospective cohort study of adult patients who underwent valve surgery in 2015 at Zhongshan Hospital, Fudan University. Right ventricular systolic pressure, a surrogate for pulmonary systolic pressure, was estimated in the study group of 1056 patients by preoperative echocardiography. CSA-AKI was defined based on the Kidney Disease Improving Global Outcomes criteria. The relation between preoperative ePASP and CSA-AKI was demonstrated with the use of multivariate analysis after adjusting for potential risk factors for CSA-AKI. Of these patients, preoperative ePASP was 44.5 ± 14.9 mm Hg. 401 (38%) patients developed CSA-AKI in which 73 patients (6.9%) suffered from severe AKI (stage II and III). Multivariate analysis showed that preoperative ePASP was independently associated with CSA-AKI (odds ratio per 10 mm Hg increment, 1.099; 95% confidence interval, 1.003 to 1.204; p = 0.042). Preoperative ePASP more than 60 mm Hg was found to be linked with the increasing incidence of AKI by 62% and in-hospital mortality by over 300%, but not linked with severe AKI or renal replacement therapy. In conclusion, an increase in preoperative ePASP was independently and significantly associated with the development of CSA-AKI in patients who underwent valve surgery. Such relation between preoperative ePASP and CSA-AKI could provide a novel therapeutic target against prevention of AKI.

Chronic intermittent hypoxia (CIH), as the foremost pathophysiological change of obstructive sleep apnea (OSA), contributes to continued deterioration in renal function. Nucleotide-binding domain like receptor protein 3 (NLRP3) inflammasome is a multiprotein complex that triggers innate immune responses to infection and cell stress through activation of caspase-1 and maturation of inflammatory pro-interleukin-1β cytokine. Emerging evidence indicates that inhibition of the NLRP3 inflammasome ameliorates renal injury. Nevertheless, it is uncertain whether NLRP3 inflammasome participates in CIH-induced renal injury. The molecular mechanisms modulating NLRP3 inflammasome activation remain to be elucidated. Compared with wild-type mice, NLRP3 knockout mice dramatically protected them from kidney injury, as indicated by the restoration of creatinine levels, lessened histopathological alterations, and the suppression of macrophages infiltration stained with F4/80. NLRP3 deficiency notably reversed CIH-induced oxidative stress (malondialdehyde and superoxide dismutase), concomitantly with the abrogated apoptosis-related proteins and proinflammatory signaling pathway. Consistently, NLRP3-deficient tubular cells remarkably inhibited reactive oxygen species generation and NLRP3 inflammasome activation. Furthermore, our study revealed that microRNA-155 (miR-155) was augmented in the renal tissue and HK-2 cells exposed to CIH. In addition, we investigated the role of miR-155 in the regulation of NLRP3 inflammasome. Inhibition of miR-155 suppressed the CIH-induced NLRP3 inflammasome activation in renal tubular cells, whereas overexpression of miR-155 promoted oxidation and enhanced NLRP3 pathway. Collectively, we demonstrated that miR-155 might be a positive-regulator of NLRP3 pathway by inhibiting the targeted FOXO3a gene. These results established a link between the miR-155/FOXO3a pathway and the NLRP3 inflammasome, suggesting pharmacological blockage of NLRP3 as a potential therapeutic strategy for OSA-associated chronic kidney disease.

Background Acute kidney injury (AKI) following cardiac surgery is common and associated with poor patient outcomes. Early risk assessment for development of AKI remains a challenge. The combination of urinary tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) has been shown to be an excellent predictor of AKI following cardiac surgery, but reported studies are for predominately non-Asian populations. Methods Adult patients were prospectively enrolled at Zhongshan hospital in Shanghai, China. The primary analysis was prediction of AKI and stage 2–3 AKI by [TIMP-2]*[IGFBP7] measured 4 h after postoperative ICU admission assessed using receiver operating characteristic curve (ROC) analysis. Kinetics of [TIMP-2]*[IGFBP7] following ICU admission were also examined. Results We prospectively enrolled 57 cardiac surgery patients, of which 20 (35%) developed AKI and 6 (11%) developed stage 2–3 AKI. The area under the ROC curve (AUC) of [TIMP-2]*[IGFBP7] at 4 h after ICU admission was 0.80 (95% confidence interval (CI): 0.68–0.91) for development of AKI and 0.83 (95% CI: 0.69–0.96) for development of stage 2–3 AKI. Urinary [TIMP-2]*[IGFBP7] values at 4 h after ICU admission were significantly (P

BackgroundCardiac surgery–associated acute kidney injury (CSA‐AKI) is a common complication with a poor prognosis. In order to identify modifiable perioperative risk factors forAKI, which existing risk scores are insufficient to predict, a dynamic clinical risk score to allow clinicians to estimate the risk ofCSA‐AKIfrom preoperative to early postoperative periods is needed.Methods and ResultsA total of 7233 cardiac surgery patients in our institution from January 2010 to April 2013 were enrolled prospectively and distributed into 2 cohorts. Among the derivation cohort, logistic regression was used to analyzeCSA‐AKIrisk factors preoperatively, on the day ofICUadmittance and 24 hours afterICUadmittance. Sex, age, valve surgery combined with coronary artery bypass grafting, preoperativeNYHAscore >2, previous cardiac surgery, preoperative kidney (without renal replacement therapy) disease, intraoperative cardiopulmonary bypass application, intraoperative erythrocyte transfusions, and postoperative low cardiac output syndrome were identified to be associated withCSA‐AKI. Among the other 1152 patients who served as a validation cohort, the point scoring of risk factor combinations led to area under receiver operator characteristics curves (AUROC) values forCSA‐AKIprediction of 0.74 (preoperative), 0.75 (on the day ofICUadmission), and 0.82 (postoperative), and Hosmer–Lemeshow goodness‐of‐fit tests revealed a good agreement of expected and observedCSA‐AKIrates.ConclusionsThe first dynamic predictive score system, with Kidney Disease: Improving Global Outcomes (KDIGO) AKI definition, was developed and predictive efficiency forCSA‐AKIwas validated in cardiac surgery patients.