Effect of Delayed Remote Ischemic Preconditioning on Acute Kidney Injury and Outcomes in Patients Undergoing Cardiac Surgery: A Randomized Clinical Trial.

BACKGROUND: Remote ischemic preconditioning (RIPC) has 2 time windows for organ protection: acute and delayed. Previous studies have mainly focused on the organoprotective effects of acute RIPC. We aimed to determine whether delayed RIPC can reduce the occurrence of acute kidney injury (AKI) and postoperative complications in patients undergoing cardiac surgery. METHODS: This prospective, single-center, double-blind, randomized controlled trial involved 509 patients at high risk for AKI who were scheduled for elective cardiac surgery requiring cardiopulmonary bypass. Patients were randomized to receive RIPC (4 cycles of 5-minute inflation and 5-minute deflation on 1 upper arm with a blood pressure cuff) 24 hours before surgery or a sham condition (control group) that was induced by 4 cycles of 5-minute inflation to a pressure of 20 mm Hg followed by 5-minute cuff deflation. The primary end point was the incidence of AKI within the prior 7 days after cardiac surgery. The secondary end points included renal replacement therapy during hospitalization, change in urinary biomarkers of AKI and markers of myocardial injury, duration of intensive care unit stay and mechanical ventilation, and occurrence of nonfatal myocardial infarction, stroke, and all-cause mortality by day 90. RESULTS: A total of 509 patients (mean age, 65.2±8.2 years; 348 men [68.4%]) were randomly assigned to the RIPC group (n=254) or control group (n=255). AKI was significantly reduced in the RIPC group compared with the control group (69/254 [27.2%] versus 90/255 [35.3%]; odds ratio, 0.68 [95% CI, 0.47-1.00]; P=0.048). There were no significant between-group differences in the secondary end points of perioperative myocardial injury (assessed by the concentrations of cardiac troponin T, creatine kinase myocardial isoenzyme, and NT-proBNP [N-terminal pro-brain natriuretic peptide]), duration of stay in the intensive care unit and hospital, and occurrence of nonfatal myocardial infarction, stroke, and all-cause mortality by day 90. CONCLUSIONS: Among high-risk patients undergoing cardiac surgery, delayed RIPC significantly reduced the occurrence of AKI. REGISTRATION: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR2000035568.

Urine metabolite changes after cardiac surgery predict acute kidney injury.

Background: Acute kidney injury (AKI) is a serious complication in patients undergoing cardiac surgery, with the underlying mechanism remaining elusive and a lack of specific biomarkers for cardiac surgery-associated AKI (CS-AKI). Methods: We performed an untargeted metabolomics analysis of urine samples procured from a cohort of patients with or without AKI at 6 and 24 h following cardiac surgery. Based on the differential urinary metabolites discovered, we further examined the expressions of the key metabolic enzymes that regulate these metabolites in kidney during AKI using a mouse model of ischemia-reperfusion injury (IRI) and in hypoxia-treated tubular epithelial cells (TECs). Results: The urine metabolomic profiles in AKI patients were significantly different from those in non-AKI patients, including upregulation of tryptophan metabolism- and aerobic glycolysis-related metabolites, such as l-tryptophan and d-glucose-1-phosphate, and downregulation of fatty acid oxidation (FAO) and tricarboxylic acid (TCA) cycle-related metabolites. Spearman correlation analysis showed that serum creatinine was positively correlated with urinary l-tryptophan and indole, which had high accuracy for predicting AKI. In animal experiments, we demonstrated that the expression of rate-limiting enzymes in glycolysis, such as hexokinase II (HK2), was significantly upregulated during renal IRI. However, the TCA cycle-related key enzyme citrate synthase was significantly downregulated after IRI. In vitro, hypoxia induced downregulation of citrate synthase in TECs. In addition, FAO-related gene peroxisome proliferator-activated receptor alpha (PPARα) was remarkably downregulated in kidney during renal IRI. Conclusion: This study presents urinary metabolites related to CS-AKI, indicating the rewiring of the metabolism in kidney during AKI, identifying potential AKI biomarkers.

The Association Between Serum Glutathione Peroxidase-3 Concentration and Risk of Acute Kidney Injury After Cardiac Surgery: A Nested Case-Control Study.

Oxidative stress has an integral role in the pathophysiology of cardiac surgery-associated acute kidney injury (CSA-AKI). Glutathione peroxidase 3 (GPx3) is an important antioxidant enzyme in circulation and is mainly secreted by the kidney. This study aimed to evaluate the relation between GPx3 protein and CSA-AKI. This study is a nested case-control study in Zhongshan Hospital affiliated with Fudan University. We examined serum samples from 80 CSA-AKI patients and 80 age- and gender-matched non-AKI patients who underwent cardiac surgery. AKI was defined according to Kidney Disease: Improving Global Outcomes (KDIGO) 2012 criteria. We measured serum GPx3 concentration using the enzyme-linked immunosorbent assay. GPx3 ratio is the ratio of preoperative and 6 hours postoperative of GPx3 protein concentration. We applied dose-response relation analyses to odds ratio in different GPx3 ratio levels and integrated it into the logistic model to predict the risk of AKI. The receiver operating characteristic curve and area under the curve (AUC) was used to assess the prediction models. Postoperative serum GPx3 concentrations were significantly lower in the AKI group compared with the non-AKI group (1.78 ± 0.33 vs 2.03 ± 0.27, p <0.001). Malondialdehyde was higher in the AKI than in the non-AKI group (17.74 ± 8.65 vs 7.48 ± 4.59, p <0.001). The AKI risk increased in a dose-dependent manner, which was flat in the first half of the GPx3 ratio and then tended to be faster. The peaking odds ratio of CSA-AKI was 2.615 at the GPx3 ratio of 1.21 to 1.40. The AUC value to predict CSA-AKI only included the GPx3 ratio was 72.3%. After gradually integrating other covariates (body mass index, aortic crossclamp time, and cardiopulmonary bypass), the model showed an AUC of 82.6%. The serum GPx3 concentration was significantly lower in the CSA-AKI group. GPx3 ratio has a good predictive value for CSA-AKI, which may be a potential early diagnostic marker for AKI.

Suppression of lncRNA Snhg1 inhibits high glucose-induced inflammation and proliferation in mouse mesangial cells.

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.

The ratio of monocytes to lymphocytes multiplying platelet predicts incidence of pulmonary infection-related acute kidney injury.

BACKGROUND: Inflammation is a crucial factor in the pathogenesis and development of acute kidney injury (AKI). Macrophages, as an important innate immune cell, regulate immune response and play a pathophysiological role in AKI. This study aimed to evaluate the predictive capacity of peripheral blood monocytes for the incidence of pulmonary infection-related AKI. METHODS: We recruited 1038 hospitalized patients with pulmonary infections from January 1 to December 31, 2019, in Zhongshan Hospital, Fudan University. Patients were divided into derivation and validation cohorts. Data on demographic characteristics, disease history, and biochemical indexes were retrieved from the electronic medical system. The composite inflammatory indexes were calculated as monocyte/(lymphocyte × platelet ratio) (MLPR). We applied dose-response relationship analyses to delineate the nonlinear odds ratio (OR) in different MLPR levels and integrated it into a logistic model to predict the risk of AKI. RESULTS: The incidence of hospital-acquired AKI was 18.8% in the derivation cohort. Compared to non-AKI, the MLPR levels were significantly higher in AKI patients. Dose-response curve revealed that the increase of AKI risk was faster in the first half of MLPR and then tended to flatten. After classifying the MLPR levels into six groups, the AKI incidence increased from 4.5% to 55.3% with a peaking OR of 24.38. The AUC values of the AKI model only including MLPR were 0.740, and after gradually integrating other covariates, the area under the receiver operating characteristic (AUC) value reached 0.866, which was significantly higher than the AUC of full models without MLPR (0.822). Moreover, the better prediction ability of AKI was observed in the external validation, with an AUC of 0.899. CONCLUSION: MLPR has good predictive efficiency in AKI, which can be used as a simple and easy clinical composite index to effectively predict early pulmonary infection-related AKI.

Chemokine CCL2 from proximal tubular epithelial cells contributes to sepsis-induced acute kidney injury.

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.NEW & NOTEWORTHY This study provides a mechanistic insight into how C-C motif chemokine ligand 2 (CCL2) is upregulated in renal tubular epithelial cells (TECs) and contributes to kidney dysfunction during sepsis. The data reveal that lipopolysaccharide induces CCL2 expression through the Toll-like receptor 2/NF-κB signaling pathway in TECs. Endogenous CCL2 released from TECs, not from myeloid cells, is responsible for sepsis-induced kidney inflammation and acute kidney injury.

LncRNA IRAR regulates chemokines production in tubular epithelial cells thus promoting kidney ischemia-reperfusion injury.

Increasing evidence demonstrates that long noncoding RNAs (lncRNAs) play an important role in several pathogenic processes of the kidney. However, functions of lncRNAs in ischemic acute kidney injury (AKI) remain undefined. In this study, global lncRNA profiling indicated that many lncRNA transcripts were deregulated in kidney after ischemia reperfusion (IR). Among them, we identified IRAR (ischemia-reperfusion injury associated RNA) as a potential lncRNA candidate, which was mostly expressed by the tubular epithelial cells (TECs) after IR, involved in the development of AKI. GapmeR-mediated silencing and viral-based overexpression of IRAR were carried out to assess its function and contribution to IR-induced AKI. The results revealed that in vivo silencing of IRAR significantly reduced IR-induced proinflammatory cells infiltration and AKI. IRAR overexpression induced chemokine CCL2, CXCL1 and CXCL2 expression both in mRNA and protein levels in TECs, while, silencing of IRAR resulted in downregulation of these chemokines. RNA immunoprecipitation and RNA pulldown assay validated the association between IRAR and CCL2, CXCL1/2. Further examination revealed that specific ablation of CCL2 in TECs reduced macrophages infiltration and proinflammatory cytokine production, attenuated renal dysfunction in IR mice. Inhibition of CXC chemokine receptor 2 (receptor of CXCL1/2) reduced neutrofils infiltration, but had no overt effect on kidney function. To explore the mechanism of IRAR upregulation in kidney during IR, we analyzed promoter region of IRAR and predicted a potential binding site for transcription factor C/EBP ß on IRAR promoter. Silencing of C/EBP ß reduced IRAR expression in TECs. A dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP) confirmed that IRAR was a transcriptional target of the C/EBP ß. Altogether, our findings identify IRAR as a new player in the development of ischemic AKI through regulating chemokine production and immune cells infiltration, suggesting that IRAR is a potential target for prevention and/or attenuation of AKI.

MicroRNA-382 Promotes M2-Like Macrophage via the SIRP-α/STAT3 Signaling Pathway in Aristolochic Acid-Induced Renal Fibrosis.

Aristolochic acid nephropathy (AAN) is a type of drug-induced nephropathy and is correlated with a potentially progression of kidney fibrosis. However, whether miR-382 is implicated in macrophage activation in AA-induced kidney fibrosis remains elusive. Here, cell-sorting experiments defined a significant miR-382 enrichment in renal macrophage after AAN 14 days. Then, we found that treatment of AA induced a significant switch in the phenotype of macrophage both in vivo and in vitro. Furthermore, miR-382 knockout (KO) mice and miR-382-/- bone marrow-derived macrophage (BMDM) were subjected to AA induction. We found that both systemic KO and macrophage-specific miR-382 depletion notably suppressed M2-like macrophage activation as well as kidney interstitial fibrosis. Additionally, adoptive transfer of miR-382 overexpression BMDMs into mice promoted AA-induced kidney injury. Moreover, in cultured macrophage, upregulation of miR-382 promoted M2-related gene expression, accompanied by downregulation of signal regulatory protein α (SIRP-α) and activation of signal transducer and activator of transcription 3 (STAT3). The interaction between miR-382 and SIRP-α was evaluated via dual-luciferase assay. Knockdown of SIRP-α upregulated phosphorylated STAT3 at S727 and Y705. Pharmacological inhibition of STAT3 was performed both in vivo and in vitro. Inhibition of STAT3 attenuated AA-induced kidney fibrosis, in parallel to lesser macrophage M2 polarization. Coculture experiments further confirmed that overexpressed miR-382 in macrophage promoted injuries of tubular cells. Luminex bio-chip detection suggested that IL-4 and CCL-5 were critical in the cross talk between macrophages and tubular cells. Taken together, our data suggest that miR-382 is a critical mediator in M2-like macrophage polarization and can be a promising therapeutic target for kidney fibrosis.

Nuclear farnesoid X receptor attenuates acute kidney injury through fatty acid oxidation.

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.

Perilipin 2 Impacts Acute Kidney Injury via Regulation of PPARα.

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.

Risk Scoring Systems Including Electrolyte Disorders for Predicting the Incidence of Acute Kidney Injury in Hospitalized Patients.

INTRODUCTION: 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.

Dynamics in perioperative neutrophil-to-lymphocyte*platelet ratio as a predictor of early acute kidney injury following cardiovascular surgery.

BACKGROUND: 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). METHODS: 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. RESULTS: 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). CONCLUSION: 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.

DUSP1 overexpression attenuates renal tubular mitochondrial dysfunction by restoring Parkin-mediated mitophagy in diabetic nephropathy.

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.

Erythrocyte transfusion limits the role of elevated red cell distribution width on predicting cardiac surgery associated acute kidney injury.

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 m2, 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.

Role of elevated red cell distribution width on acute kidney injury patients after cardiac surgery.

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 <  0.001) and the elevated RDW incidences were 0.4% (0.1%, 0.9%), 0.6% (0.2%, 1.1%) and 1.1% (0.3%, 2.1%) in stage 1, 2 and 3 AKI patients (P <  0.001). Among propensity-matched patients with CS-AKI, the level of elevated RDW in non-survivors was higher than in survivors [1.2% (0.5%, 2.3%) vs 0.5% (0.1%, 1.0%), P <  0.001] and a 0.1% increase in elevated RDW was associated with a 0.24% higher risk of within-hospital mortality in patients with CS-AKI. Estimating the receiver-operating characteristic (ROC) area under the curve (AUC) showed that an elevated RDW had moderate discriminative power for AKI development (AUC = 0.605, 95% CI, 0.586-0.625; P <  0.001) and hospital mortality (AUC = 0.716, 95% CI, 0.640-0.764; P <  0.001) in the propensity-matched cohort. CONCLUSIONS: An elevated RDW might be an independent prognostic factor for the severity and poor prognosis of CS-AKI.

Urinary TIMP-2 and IGFBP7 for the prediction of acute kidney injury following cardiac surgery.

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 < 0.001) higher in patients who developed AKI than in patients who did not develop AKI (mean (standard error) of 1.08 (0.34) (ng/mL)2/1000 and 0.29 (0.05) (ng/mL)2/1000, respectively). The time-profile of [TIMP-2]*[IGFBP7] suggests the markers started to elevate by the time of ICU admission in patients who developed AKI and either decreased or remained flat in patients without AKI. CONCLUSION: The combination of urinary TIMP-2 and IGFBP7 4 h after postoperative ICU admission identifies patients at risk for developing AKI, not just stage 2-3 AKI following cardiac surgery.

Role of Body Mass Index in Acute Kidney Injury Patients after Cardiac Surgery.

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 <18.5), normal weight (18.5≤ BMI <24), overweight (24≤ BMI <28), and obese (BMI ≥28) groups. The influence of BMI on CS-AKI incidence, duration of hospital, and intensive care unit (ICU) stays as well as AKI-related mortality was analyzed. 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.

Dynamic Predictive Scores for Cardiac Surgery-Associated Acute Kidney Injury.

BACKGROUND: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common complication with a poor prognosis. In order to identify modifiable perioperative risk factors for AKI, which existing risk scores are insufficient to predict, a dynamic clinical risk score to allow clinicians to estimate the risk of CSA-AKI from preoperative to early postoperative periods is needed. METHODS AND RESULTS: A 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 analyze CSA-AKI risk factors preoperatively, on the day of ICU admittance and 24 hours after ICU admittance. Sex, age, valve surgery combined with coronary artery bypass grafting, preoperative NYHA score >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 with CSA-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 for CSA-AKI prediction of 0.74 (preoperative), 0.75 (on the day of ICU admission), and 0.82 (postoperative), and Hosmer-Lemeshow goodness-of-fit tests revealed a good agreement of expected and observed CSA-AKI rates. CONCLUSIONS: The first dynamic predictive score system, with Kidney Disease: Improving Global Outcomes (KDIGO) AKI definition, was developed and predictive efficiency for CSA-AKI was validated in cardiac surgery patients.