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Damage-associated molecular patterns secreted from activated kidney cells initiate the inflammatory response, a critical step in the development of sepsis-induced acute kidney injury (AKI). However, the underlying mechanism remains to be clarified. Here, we established a mouse model of sepsis-induced AKI through intraperitoneal injection of lipopolysaccharide (LPS) and demonstrated that LPS induced dramatical upregulation of C-C motif chemokine ligand 2 (CCL2) at both the mRNA and protein levels in the kidney, which was mainly expressed by tubular epithelial cells (TECs), especially by proximal TECs. Proximal tubule-specific ablation of CCL2 reduced LPS-induced macrophage infiltration, proinflammatory cytokine expression, and attenuated AKI. In vitro, using a Transwell migration assay, we found that deficiency of CCL2 in TECs decreased macrophage migration ability. However, myeloid-specific depletion of CCL2 could not protect the kidneys from the aforementioned effects. Mechanistically, LPS activated Toll-like receptor (TLR)2 signaling in TECs, which induced activation of its downstream effector NF-κB. Blockade of TLR2 signaling or inhibition of NF-κB activation in TECs significantly suppressed LPS-induced CCL2 expression. Furthermore, chromatin immunoprecipitation analyses confirmed a direct binding of NF-κB p65 in the CCL2 promoter region, and LPS increased the binding of NF-κB p65 to the CCL2 promoter, suggesting that TLR2/NF-κB p65 regulates CCL2 expression in TECs. Together, these results demonstrate that endogenous CCL2 released from proximal TECs, not from myeloid cells, was responsible for sepsis-induced kidney inflammation and AKI. Specifically targeting tubular TLR2/NF-κB/CCL2 signaling may be a potential therapeutic strategy for the prevention or attenuation of septic AKI.

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.

Diabetic nephropathy (DN) is the primary cause of end-stage renal disease, and renal tubular cell dysfunction contributes to the pathogenesis of many kidney diseases. Our previous study demonstrated that dual-specificity protein phosphatase 1 (DUSP1) reduced hyperglycemia-mediated mitochondrial damage; however, its role in hyperglycemia-driven dysfunction of tubular cells is still not fully understood. In this study, we found that DUSP1 is reduced in human proximal tubular epithelial (HK-2) cells under high-glucose conditions. DUSP1 overexpression in HK-2 cells partially restored autophagic flux, improved mitochondrial function, and reduced reactive oxygen species generation and cell apoptosis under high-glucose conditions. Surprisingly, overexpressing DUSP1 abolished the decrease in mitochondrial parkin expression caused by high-glucose stimulation. In addition, knockdown of parkin in HK-2 cells reversed the effects of DUSP1 overexpression on mitophagy and apoptosis under high-glucose conditions. Overall, these data indicate that DUSP1 plays a defensive role in the pathogenesis of DN by restoring parkin-mediated mitophagy, suggesting that it may be considered a prospective therapeutic strategy for the amelioration of DN.

BACKGROUND: Acute kidney injury (AKI) is one of the more serious complications after cardiac surgery. Elevated red cell distribution width (RDW) was reported as a predictor for cardiac surgery associated acute kidney injury (CSAKI). However, the increment of RDW by erythrocyte transfusion makes its prognostic role doubtful. The aim of this study is to elucidate the impact of erythrocyte transfusion on the prognostic role of elevated RDW for predicting CSAKI. METHODS: A total of 3207 eligible patients who underwent cardiac surgery during 2016–2017 were enrolled. Changes of RDW was defined as the difference between preoperative RDW and RDW measured 24 h after cardiac surgery. The primary outcome was CSAKI which was defined by the Kidney Disease: Improving Global Outcomes Definition and Staging (KDIGO) criteria. Univariate and multivariate analysis were performed to identify predictors for CSAKI. RESULTS: The incidence of CSAKI was 38.07% and the mortality was 1.18%. CSAKI patients had higher elevated RDW than those without CSAKI (0.65% vs. 0.39%, p < 0.001). Multivariate regression showed that male, age, New York Heat Association classification 3–4, elevated RDW, estimated glomerular filtration rate < 60 mL/min/1.73 m(2), cardiopulmonary bypass time > 120 min and erythrocyte transfusion were associated with CSAKI. Subgroup analysis showed elevated RDW was an independent predictor for CSAKI in the non-transfused subset (adjusted odds ratio: 1.616, p < 0.001) whereas no significant association between elevated RDW and CSAKI was found in the transfused patients (odds ratio: 1.040, p = 0.497). CONCLUSIONS: Elevated RDW is one of the independent predictors of CSAKI in the absence of erythrocyte transfusion, which limits the prognostic role of the former on predicting CSAKI.

In this study, we applied a composite index of neutrophil-lymphocyte * platelet ratio (NLPR), and explore the significance of the dynamics of perioperative NLPR in predicting cardiac surgery-associated acute kidney injury (CSA-AKI). During July 1st and December 31th 2019, participants were prospectively derived from the ‘Zhongshan Cardiovascular Surgery Cohort’. NLPR was determined using neutrophil counts, lymphocyte and platelet count at the two-time points. Dose-response relationship analyses were applied to delineate the non-linear odds ratio (OR) of CSA-AKI in different NLPR levels. Then NLPRs were integrated into the generalized estimating equation (GEE) to predict the risk of AKI. Of 2449 patients receiving cardiovascular surgery, 838 (34.2%) cases developed CSA-AKI with stage 1 (n = 658, 26.9%), stage 2–3 (n = 180, 7.3%). Compared with non-AKI patients, both preoperative and postoperative NLPR were higher in AKI patients (1.1[0.8, 1.8] vs. 0.9[0.7,1.4], p < 0.001; 12.4[7.5, 20.0] vs. 10.1[6.4,16.7], p < 0.001). Such an effect was a ‘J’-shaped relationship: CSA-AKI’s risk was relatively flat until 1.0 of preoperative NLPR and increased rapidly afterward, with an odds ratio of 1.13 (1.06–1.19) per 1 unit. Similarly, patients whose postoperative NLPR value >11.0 were more likely to develop AKI with an OR of 1.02. Integrating the dynamic NLPRs into the GEE model, we found that the AUC was 0.806(95% CI 0.793–0.819), which was significantly higher than the AUC without NLPR (0.799, p < 0.001). Dynamics of perioperative NPLR is a promising marker for predicting acute kidney injury. It will facilitate AKI risk management and allow clinicians to intervene early so as to reverse renal damage.

Diabetic nephropathy (DN) is the direct cause of end-stage renal disease, and nephritic inflammation plays a role in its growth and advancement. Aberrant expression of long non-coding RNAs (lncRNAs) correlates with many diseases, including DN. In this study, we investigated whether lncRNA small nucleolar RNA host gene 1 (Snhg1) was mechanistically involved in inflammation and mesangial cell (MC) proliferation in DN. We found that Snhg1 was significantly upregulated in DN renal tissues and high glucose (HG)-treated MCs. Overexpression of Snhg1 promoted inflammatory cytokine expression in MCs and MC proliferation under low-glucose conditions; meanwhile, Snhg1 knockdown suppressed inflammatory cytokine production and MC proliferation under HG conditions. Mechanistically, Snhg1 was found to directly bind miR-27b, thereby preventing the miRNA from binding its target KDM6B mRNA. Furthermore, miR-27b overexpression recapitulated the inhibitory effects of Snhg1 knockdown, whereas restoration of Snhg1 expression attenuated the function of miR-27b in MCs under HG conditions. Taken together, these results indicate that suppression of Snhg1 inhibited HG-induced inflammation and proliferation of MCs by regulating the miR-27b/KDM6B axis.

Xin Chen,1,* Jiarui Xu,1,* Yang Li,1 Xialian Xu,1 Bo Shen,1 Zhouping Zou,1 Xiaoqiang Ding,1,2 Jie Teng,1,2 Wuhua Jiang1 1Department of Nephrology, Zhongshan Hospital, Fudan University; Shanghai Institute of Kidney Disease and Dialysis (SIKD), Shanghai Laboratory of Kidney Disease and Dialysis, Shanghai Medical Center of Kidney Disease, Shanghai, People’s Republic of China; 2Department of Nephrology, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoqiang Ding; Wuhua JiangDepartment of Nephrology, Zhongshan Hospital, Fudan University ; No.108, Fenglin Road, Xuhui District, Shanghai, People’s Republic of ChinaTel +86-21-64041990Email ding.xiaoqiang@zs-hospital.sh.cn xIntroduction: Electrolyte disorders are common among hospitalized patients with acute kidney injury (AKI) and adversely affect the outcome. This study aimed to explore the potential role of abnormal electrolyte levels on predicting AKI and severe AKI.Methods: In this retrospective, observational study, we included all hospitalized patients in our hospital in China from October 01, 2014, to September 30, 2015. Since only a few patients had arterial blood gas analysis (ABG), all subjects involved were divided into two groups: patients with ABG and patients without ABG. Severe AKI was defined as AKI stage 2 or 3 according to KDIGO guideline.Results: A total of 80,091 patients were enrolled retrospectively and distributed randomly into the test cohort and the validation cohort (2:1). Logistic regression was performed in the test cohort to analyze risk factors including electrolyte disorders and elucidate the association. The test data (derivation cohort) led to AUC values of 0.758 (95% CI: 0.743– 0.773; AKI with ABG), 0.751 (95% CI: 0.740– 0.763; AKI without ABG), 0.733 (95% CI: 0.700– 0.767; severe AKI with ABG), 0.853 (95% CI: 0.824– 0.882; severe AKI without ABG). Application of the scoring system in the validation cohort led to AUC values of 0.724 (95% CI: 0.703– 0.744; AKI with ABG), 0.738 (95% CI: 0.721– 0.755; AKI without ABG), 0.774 (95% CI: 0.732– 0.815; severe AKI with ABG), 0.794 (95% CI: 0.760– 0.827; severe AKI without ABG). Hosmer–Lemeshow tests revealed a good calibration.Conclusion: The risk scoring systems involving electrolyte disorders were established and validated adequately efficient to predict AKI and severe AKI in hospitalized patients. Electrolyte imbalance needs to be carefully monitored and corrections should be made on time to avoid further adverse outcome.Keywords: acute kidney injury, electrolyte disorders, risk score

Background The aim of the study was to explore associations between elevated red cell distribution width (RDW) and acute kidney injury (AKI) in patients undergoing cardiac surgery (CS-AKI). Methods Preoperative, intraoperative and postoperative data of 10,274 patients undergoing cardiac surgery, including demographic data, were prospectively collected from January 2009 to December 2014. Propensity score matching was used on the basis of clinical characteristics and preoperative variables. An elevated RDW was defined as the difference between RDW 24 h after cardiac surgery and the latest RDW before cardiac surgery. Results A total of 10,274 patients were included in the unmatched cohort, and 3146 patients in the propensity-matched cohort. In the unmatched cohort, the overall CS-AKI incidence was 32.8% (n = 3365) with a hospital mortality of 5.5% (n = 185). In the propensity-matched cohort, the elevated RDW in AKI patients was higher than in patients without AKI (0.3% (0.0%, 0.7%) vs 0.5% (0.1, 1.1%), P

Background/Aims: To explore the association of body mass index (BMI) with the risk of developing acute kidney injury after cardiac surgery (CS-AKI) and for AKI requiring renal replacement therapy (AKI-RRT) after cardiac surgery. Methods: Clinical data of 8,455 patients undergoing cardiac surgery, including demographic preoperative, intraoperative, and postoperative data were collected. Patients were divided into underweight (BMI Results: The mean age of the patients was 53.2 ± 13.9 years. The overall CS-AKI incidence was 33.8% (n = 2,855) with a hospital mortality of 5.4% (n = 154). The incidence of AKI-RRT was 5.2% (n = 148) with a mortality of 54.1% (n = 80). For underweight, normal weight, overweight, and obese cardiac surgery patients, the AKI incidences were 29.9, 31.0, 36.5, and 46.0%, respectively (p < 0.001). The hospital mortality of AKI patients in the 4 groups was 9.5, 6.0, 3.8, and 4.3%, whereas the hospital mortality of AKI-RRT patients in the 4 groups was 69.2, 60.8, 36.4, and 58.8%, both significantly different (p < 0.05). Hospital and ICU stay durations were not significantly different in the 4 BMI groups. Conclusion: The hospital prognosis of AKI and AKI-RRT patients after cardiac surgery was best when their BMI was in the 24-28 range.

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.