Development and validation of a deep neural network-based model to predict acute kidney injury following intravenous administration of iodinated contrast media in hospitalized patients with chronic kidney disease: a multicohort analysis.

BACKGROUND: Stratification of chronic kidney disease (CKD) patients [estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2] at risk for post-contrast acute kidney injury (PC-AKI) following intravenous administration of iodinated contrast media (ICM) is important for clinical decision-making and clinical trial enrollment. METHODS: The derivation and internal validation cohorts originated from the Second Xiangya Hospital. The external validation cohort was generated from the Xiangya Hospital and the openly accessible database Medical Information Mart for Intensive CareIV. PC-AKI was defined based on the serum creatinine criteria of the Kidney Disease: Improving Global Outcomes (KDIGO). Six feature selection methods were used to identify the most influential predictors from 79 candidate variables. Deep neural networks (DNNs) were used to establish the model and compared with logistic regression analyses. Model discrimination was evaluated by area under the receiver operating characteristic curve (AUC). Low-risk and high-risk cutoff points were set to stratify patients. RESULTS: Among 4218 encounters studied, PC-AKI occurred in 10.3, 10.4 and 11.4% of encounters in the derivation, internal and external validation cohorts, respectively. The 14 variables-based DNN model had significantly better performance than the logistic regression model with AUC being 0.939 (95% confidence interval: 0.916-0.958) and 0.940 (95% confidence interval: 0.909-0.954) in the internal and external validation cohorts, respectively, and showed promising discrimination in subgroup analyses (AUC ≥ 0.800). The observed PC-AKI risks increased significantly from the low- to intermediate- to high-risk group (<1.0 to >50%) and the accuracy of patients not developing PC-AKI was 99% in the low-risk category in both the internal and external validation cohorts. CONCLUSIONS: A DNN model using routinely available variables can accurately discriminate the risk of PC-AKI of hospitalized CKD patients following intravenous administration of ICM.

Effects of intravenous hydration in preventing post-contrast acute kidney injury in patients with eGFR < 30 mL/min/1.73 m2.

OBJECTIVES: To investigate the effects of intravenous hydration in preventing post-contrast outcomes in patients with estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 undergoing intravenous administration of iodinated contrast media (ICM). METHODS: Hospitalized patients with eGFR < 30 mL/min/1.73 m2 and intravenous ICM exposure between 2015 and 2021 were included. Post-contrast outcomes include post-contrast acute kidney injury (PC-AKI) (defined by 2012 Kidney Disease: Improving Global Outcomes (KDIGO) or European Society of Urogenital Radiology (ESUR)), chronic dialysis at discharge, and in-hospital mortality. Confounding effects between the two groups were reduced to a minimum using propensity score-based matching and overlap weighting. Association between intravenous hydration and outcomes was analyzed using logistic regression. RESULTS: In total, 794 patients were included in the study, with 284 receiving intravenous hydration, and 510 not. After 1:1 propensity score matching, 210 pairs were generated. No significant differences were found in the outcomes between the intravenous hydration and no intravenous hydration groups: PC-AKI by KDIGO, 25.2% vs 24.8% (odds ratio (OR), 0.93; 95% confidence interval (CI), 0.57-1.50); PC-AKI by ESUR, 31.0% vs 25.2% (OR, 1.34; 95% CI, 0.86-2.08); chronic dialysis at discharge, 4.3% vs 3.3% (OR, 1.56; 95% CI, 0.56-4.50); in-hospital mortality, 1.9% vs 0.5% (OR, 4.08; 95% CI, 0.58-81.08). Overlap propensity score-weighted analysis also showed no significant effects of intravenous hydration on the incidences of the post-contrast outcomes. CONCLUSIONS: Intravenous hydration was not associated with lower risks of PC-AKI, chronic dialysis at discharge, and in-hospital mortality in patients with eGFR < 30 mL/min/1.73 m2 undergoing intravenous administration of ICM. CLINICAL RELEVANCE STATEMENT: This study provides new evidence in supporting that intravenous hydration is not beneficial to patients with eGFR < 30 mL/min/1.73 m2 before and after intravenous administration of iodinated contrast media. KEY POINTS: • Intravenous hydration before and after intravenous administration of ICM is not associated with lower risks in PC-AKI, chronic dialysis at discharge, and in-hospital mortality in patients with eGFR < 30 mL/min/1.73 m2. • Withholding intravenous hydration may be considered in patients with eGFR < 30 mL/min/1.73 m2 around intravenous administration of ICM.

Association of underweight and obesity with adverse postoperative renal outcomes in infants and young children undergoing congenital heart surgery.

Postoperative acute kidney injury (AKI) is a prevalent condition and associated with increased morbidity and mortality following cardiac surgery. This study aimed to investigate the association of underweight and obesity with adverse postoperative renal outcomes in infants and young children undergoing congenital heart surgery. This retrospective cohort study included patients aged from 1 month to 5 years who underwent congenital heart surgery with cardiopulmonary bypass at the Second Xiangya Hospital of Central South University from January 2016 to March 2022. On the basis of the percentile of body mass index (BMI) for age and sex, eligible participants were divided into three nutritional groups: normal bodyweight, underweight (BMI P5), and obesity (BMI P95). Primary outcomes included postoperative AKI and major adverse kidney events within 30 days (MAKE30). Multivariable logistic regression was performed to determine the association of underweight and obesity with postoperative outcomes. The same analyses were reproduced for classifying patients using weight-for-height instead of BMI. A total of 2,079 eligible patients were included in the analysis, including 1,341 (65%) patients in the normal bodyweight group, 683 (33%) patients in the underweight group, and 55 (2.6%) patients in the obesity group. Postoperative AKI (16% vs. 26% vs. 38%; P < 0.001) and MAKE30 (2.5% vs. 6.4% vs. 9.1%; P < 0.001) were more likely to occur in the underweight and obesity groups. After adjusting for potential confounders, underweight (OR1.39; 95% CI 1.08-1.79; P = 0.008) and obesity (OR 3.85; 95% CI 1.97-7.50; P < 0.001) were found to be associated with an increased risk of postoperative AKI. In addition, both underweight (OR 1.89; 95% CI 1.14-3.14; P = 0.014) and obesity (OR 3.14; 95% CI 1.08-9.09; P = 0.035) were independently associated with MAKE30. Similar results were also found when weight-for-height was used instead of BMI.    Conclusion: In infants and young children undergoing congenital heart surgery, underweight and obesity are independently associated with postoperative AKI and MAKE30. These results may help assess prognosis in underweight and obese patients, and will guide future quality improvement efforts. What is Known: • Postoperative acute kidney injury (AKI) is prevalent and associated with increased morbidity and mortality following pediatric cardiac surgery. • Major adverse kidney events within 30 days (MAKE30) have been recommended as a patient-centered endpoint for evaluating AKI clinical trajectories. A growing concern arises for underweight and obesity in children with congenital heart disease. What is New: • Prevalence of underweight and obesity among infants and young children undergoing congenital heart surgery was 33% and 2.6%, respectively. • Both underweight and obesity were independently associated with postoperative AKI and MAKE30 following congenital heart surgery.

Machine Learning-Based Prediction of Acute Kidney Injury Following Pediatric Cardiac Surgery: Model Development and Validation Study.

BACKGROUND: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a major complication following pediatric cardiac surgery, which is associated with increased morbidity and mortality. The early prediction of CSA-AKI before and immediately after surgery could significantly improve the implementation of preventive and therapeutic strategies during the perioperative periods. However, there is limited clinical information on how to identify pediatric patients at high risk of CSA-AKI. OBJECTIVE: The study aims to develop and validate machine learning models to predict the development of CSA-AKI in the pediatric population. METHODS: This retrospective cohort study enrolled patients aged 1 month to 18 years who underwent cardiac surgery with cardiopulmonary bypass at 3 medical centers of Central South University in China. CSA-AKI was defined according to the 2012 Kidney Disease: Improving Global Outcomes criteria. Feature selection was applied separately to 2 data sets: the preoperative data set and the combined preoperative and intraoperative data set. Multiple machine learning algorithms were tested, including K-nearest neighbor, naive Bayes, support vector machines, random forest, extreme gradient boosting (XGBoost), and neural networks. The best performing model was identified in cross-validation by using the area under the receiver operating characteristic curve (AUROC). Model interpretations were generated using the Shapley additive explanations (SHAP) method. RESULTS: A total of 3278 patients from one of the centers were used for model derivation, while 585 patients from another 2 centers served as the external validation cohort. CSA-AKI occurred in 564 (17.2%) patients in the derivation cohort and 51 (8.7%) patients in the external validation cohort. Among the considered machine learning models, the XGBoost models achieved the best predictive performance in cross-validation. The AUROC of the XGBoost model using only the preoperative variables was 0.890 (95% CI 0.876-0.906) in the derivation cohort and 0.857 (95% CI 0.800-0.903) in the external validation cohort. When the intraoperative variables were included, the AUROC increased to 0.912 (95% CI 0.899-0.924) and 0.889 (95% CI 0.844-0.920) in the 2 cohorts, respectively. The SHAP method revealed that baseline serum creatinine level, perfusion time, body length, operation time, and intraoperative blood loss were the top 5 predictors of CSA-AKI. CONCLUSIONS: The interpretable XGBoost models provide practical tools for the early prediction of CSA-AKI, which are valuable for risk stratification and perioperative management of pediatric patients undergoing cardiac surgery.

Utilization of interpretable machine learning model to forecast the risk of major adverse kidney events in elderly patients in critical care.

Major adverse kidney events within 30 d (MAKE30) implicates poor outcomes for elderly patients in the intensive care unit (ICU). This study aimed to predict the occurrence of MAKE30 in elderly ICU patients using machine learning. The study cohort comprised 2366 elderly ICU patients admitted to the Second Xiangya Hospital of Central South University between January 2020 and December 2021. Variables including demographic information, laboratory values, physiological parameters, and medical interventions were used to construct an extreme gradient boosting (XGBoost) -based prediction model. Out of the 2366 patients, 1656 were used for model derivation and 710 for testing. The incidence of MAKE30 was 13.8% in the derivation cohort and 13.2% in the test cohort. The average area under the receiver operating characteristic curve of the XGBoost model was 0.930 (95% CI: 0.912-0.946) in the training set and 0.851 (95% CI: 0.810-0.890) in the test set. The top 8 predictors of MAKE30 tentatively identified by the Shapley additive explanations method were Acute Physiology and Chronic Health Evaluation II score, serum creatinine, blood urea nitrogen, Simplified Acute Physiology Score II score, Sequential Organ Failure Assessment score, aspartate aminotransferase, arterial blood bicarbonate, and albumin. The XGBoost model accurately predicted the occurrence of MAKE30 in elderly ICU patients, and the findings of this study provide valuable information to clinicians for making informed clinical decisions.

Differential renal proteomics analysis in a novel rat model of iodinated contrast-induced acute kidney injury.

Contrast-induced acute kidney injury (CI-AKI), which occurs after the use of iodinated contrast media, has become the third leading cause of hospital-acquired acute kidney injury (AKI). It is associated with prolonged hospitalization and increased risks of end-stage renal disease and mortality. The pathogenesis of CI-AKI is unclear and effective treatments are lacking. By comparing different post-nephrectomy times and dehydration times, we constructed a new, short-course CI-AKI model using dehydration for 24 h two weeks after unilateral nephrectomy. We found that the low-osmolality contrast media iohexol caused more severe renal function decline, renal morphological damage, and mitochondrial ultrastructural alterations compared to the iso-osmolality contrast media iodixanol. The shotgun proteomics based on Tandem Mass Tag (TMT) was used to conduct proteomics research on renal tissue in the new CI-AKI model, and 604 distinct proteins were identified, mainly involving complement and coagulation cascade, COVID-19, PPAR signalling pathway, mineral absorption, cholesterol metabolism, ferroptosis, staphylococcus aureus infection, systemic lupus erythematosus, folate biosynthesis, and proximal tubule bicarbonate reclamation. Then, using parallel reaction monitoring (PRM), we validate 16 candidate proteins, of which five were novel candidates (Serpina1, Apoa1, F2, Plg, Hrg) previously unrelated to AKI and associated with an acute response as well as fibrinolysis. The pathway analysis and 16 candidate proteins may help to discover new mechanisms in the pathogenesis of CI-AKI, allowing for early diagnosis and outcome prediction.

Temporal trends of post-contrast acute kidney injury in patients with intravenous administration of iodinated contrast medium.

Little is known about whether preventative practices for post-contrast acute kidney injury (PC-AKI) recommended in guidelines have been adopted in clinical practice and translated into a lower incidence of PC-AKI. The aim of this study was to examine the yearly trends in the incidence of PC-AKI, and comorbidities and care practices associated with PC-AKI in hospitalized patients who received intravenous administration of iodinated contrast medium (ICM). Adult patients receiving intravenous ICM at the Second Xiangya Hospital of Central South University in China between 2015 and 2021 were included. Temporal trends in the incidence and risk factors for PC-AKI were evaluated using logistic regression analyses with adjustments for relevant variables. The incidence of PC-AKI has declined significantly from 5.3% in 2015 to 4.1% in 2021 (p < 0.001). This decreasing trend persisted after extensive multivariable adjustments. Of the comorbidities associated with PC-AKI, the proportion of patients with congestive heart failure or hypertension increased, while the proportion of patients older than 75 years, or with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2, diabetic nephropathy, or renal stone disease decreased. Among the care practices associated with PC-AKI, the proportion of patients using nephrotoxic drugs decreased, whereas the proportion of patients receiving intravenous fluids > 1000 mL on the day of ICM administration or using iso-osmolar ICM increased. In conclusion, a declining trend in PC-AKI incidence was observed in patients receiving intravenous ICM between 2015 and 2021, which may be related to increased awareness and efforts to prevent PC-AKI.

Apelin-13 alleviates contrast-induced acute kidney injury by inhibiting endoplasmic reticulum stress.

Contrast-induced acute kidney injury (CI-AKI) is a severe complication associated with significant morbidity and mortality, and effective therapeutic strategies are still lacking. Apelin is an endogenous physiological regulator with antioxidative, anti-inflammatory and antiapoptotic properties. However, the role of apelin-13 in CI-AKI remains unclear. In our study, we found that the protein expression levels of apelin were significantly downregulated in rat kidney tissues and HK-2 cells during contrast media treatment. Moreover, we explored the protective effect of apelin-13 on renal tubule damage using in vitro and in vivo models of CI-AKI. Exogenous apelin-13 ameliorated endoplasmic reticulum stress, reactive oxygen species and apoptosis protein expression in contrast media-treated cells and rat kidney tissues. Mechanistically, the downregulation of endoplasmic reticulum stress contributed critically to the antiapoptotic effect of apelin-13. Collectively, our findings reveal the inherent mechanisms by which apelin-13 regulates CI-AKI and provide a prospective target for the prevention of CI-AKI.

Is intravenous iodinated contrast medium administration really harmful in hospitalized acute kidney injury patients: a propensity score-matched study.

OBJECTIVES: To evaluate the effects of intravenous iodinated contrast medium (ICM) administration on the deterioration of renal function (DRF), new renal replacement therapy (RRT) induction and mortality of hospitalized acute kidney injury (AKI) patients. METHODS: Adult hospitalized patients undergoing a contrast-enhanced or unenhanced CT scan within 7 days after AKI diagnosis from January 2015 to December 2019 were identified in this retrospective study. Propensity score matching was performed. Outcomes in 7 and 30 days after CT scan were compared between the contrast and non-contrast groups. Additional analyses were also performed in patients stratified by SCr levels at AKI diagnosis, times and time of CT scan, and in patients without chronic kidney disease or RRT requirement prior to CT scan. RESULTS: In total, 1172 pairs were generated after 1:1 propensity score matching from 1336 cases exposed to ICM and 2724 unexposed. No significant differences were found in the outcomes between the two groups: DRF, 7.8% vs 9.0% (odds ratio (OR) 0.83, 95% confidence interval (CI) 0.62-1.11) in 7 days, 5.1% vs 5.4% (OR 0.93, 95%CI 0.64-1.34) in 30 days; new RRT induction, 2.3% vs 3.3% (OR 0.72,95%CI 0.43-1.18) in 7 days, 4.2% vs 4.5% (OR 0.95,95%CI 0.64-1.41) in 30 days; and mortality, 3.9% vs 4.8% (OR 0.83,95%CI 0.56-1.22) in 7 days, 9.0% vs 10.2% (OR 0.88,95%CI 0.68-1.15) in 30 days. Subset analyses showed similar results. CONCLUSION: Intravenous ICM administration during AKI duration did not increase the risks of DRF, new RRT induction, and mortality in 7 and 30 days after CT scan. KEY POINTS: • Intravenous ICM administration in hospitalized AKI patients does not increase the risks of deterioration of renal function, RRT induction, and mortality in 7 and 30 days after CT scan. • The effects of intravenous ICM on adverse outcomes are minimal even in AKI patients with high level of SCr values or multiple CT scans.

Early recovery status and outcomes after sepsis-associated acute kidney injury in critically ill patients. / å±é‡ç—‡æ‚£è€ è„“æ¯’ç—‡æ€¥æ€§è‚¾æŸä¼¤åŽçš„æ—©æœŸæ¢å¤æ¨¡å¼ä¸Žé¢„åŽ.

OBJECTIVES: Acute kidney injury (AKI) is one of the common complications in critically ill septic patients, which is associated with increased risks of death, cardiovascular events, and chronic renal dysfunction. The duration of AKI and the renal function recovery status after AKI onset can affect the patient prognosis. Nevertheless, it remains controversial whether early recovery status after AKI is closely related to the prognosis in patients with sepsis-associated AKI (SA-AKI). In addition, early prediction of renal function recovery after AKI is beneficial to individualized treatment decision-making and prevention of severe complications, thus improving the prognosis. At present, there is limited clinical information on how to identify SA-AKI patients at high risk of unrecovered renal function at an early stage. The study aims to investigate the association between early recovery status after SA-AKI, identify risk factors for unrecovered renal function, and to improve patients' quality of life. METHODS: We retrospectively analyzed clinical data of septic patients who were admitted to the intensive care unit (ICU) and developed AKI within the first 48 hours after ICU admission in the Second Xiangya Hospital and the Third Xiangya Hospital of Central South University from January 2015 to March 2017. Sepsis was defined based on the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). AKI was diagnosed and staged according to the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guideline. SA-AKI patients were assigned into 3 groups including a complete recovery group, a partial recovery group, and an unrecovered group based on recovery status at Day 7 after the diagnosis of AKI. Patients' baseline characteristics were collected, including demographics, comorbidities, clinical and laboratory examination information at ICU admission, and treatment within the first 24 hours. The primary outcome of the study was the composite of death and chronic dialysis at 90 days, and secondary outcomes included length of stay in the ICU, length of stay in the hospital, and persistent renal dysfunction. Multivariate regression analysis was performed to evaluate the prognostic value of early recovery status after AKI and to determine the risk factors for unrecovered renal function after AKI. Sensitivity analysis was conducted in patients who still stayed in hospital on Day 7 after AKI diagnosis, patients without premorbid chronic kidney disease, and patients with AKI Stage 2 to 3. RESULTS: A total of 553 SA-AKI patients were enrolled, of whom 251 (45.4%), 73 (13.2%), and 229 (41.4%) were categorized as the complete recovery group, the partial recovery group, and the unrecovered group, respectively. Compared with the complete or partial recovery group, the unrecovered group had a higher incidence of 90-day mortality (unrecovered vs partial recovery or complete recovery: 64.2% vs 26.0% or 22.7%; P<0.001) and 90-day composite outcome (unrecovered vs partial recovery or complete recovery: 65.1% vs 27.4% or 22.7%; P<0.001). The unrecovered group also had a shorter length of stay in the hospital and a larger proportion of progression into persistent renal dysfunction than the other 2 groups. After adjustment for potential confounders, patients in the unrecovered group were at an increased risk of 90-day mortality (HR=3.50, 95% CI 2.47 to 4.96, P<0.001) and 90-day composite outcome (OR=5.55, 95% CI 3.43 to 8.98, P<0.001) when compared with patients in the complete recovery group, but patients in the partial recovery group had no significant difference (P>0.05). Male sex, congestive heart failure, pneumonia, respiratory rate >20 beats per minute, anemia, hyperbilirubinemia, need for mechanical ventilation, and AKI Stage 3 were identified as independent risk factors for unrecovered renal function after AKI. The sensitivity analysis further supported that unrecovered renal function after AKI remained an independent predictor for 90-day mortality and composite outcome in the subgroups. CONCLUSIONS: The early recovery status after AKI is closely associated with poor prognosis in critically ill patients with SA-AKI. Unrecovered renal function within the first 7 days after AKI diagnosis is an independent predictor for 90-day mortality and composite outcome. Male sex, congestive heart failure, pneumonia, tachypnea, anemia, hyperbilirubinemia, respiratory failure, and severe AKI are risk factors for unrecovered renal function after AKI. Therefore, timely assessment for the renal function in the early phase after AKI diagnosis is essential for SA-AKI patients. Furthermore, patients with unrecovered renal function after AKI need additional management in the hospital, including rigorous monitoring, avoidance of nephrotoxin, and continuous assessment for the renal function, and after discharge, including more frequent follow-up, regular outpatient consultation, and prevention of long-term adverse events.

Post-contrast acute kidney injury in a hospitalized population: short-, mid-, and long-term outcome and risk factors for adverse events.

OBJECTIVES: To investigate the prognosis including major adverse kidney events within 30 days (MAKE30) and 90-day and 1-year adverse outcome in hospitalized patients with post-contrast acute kidney injury (PC-AKI) to identify high-risk factors. METHODS: This retrospective observational study included 288 PC-AKI patients selected from 277,898 patients admitted to hospitals from January 2015 to December 2015. PC-AKI was defined according to the 2018 guideline of European Society of Urogenital Radiology. Multivariable Cox regression and logistic regression analyses were used to analyze main outcome and risk factors. RESULTS: PC-AKI patients with AKI stage ≥ 2 had much higher incidence of MAKE30 than those with AKI stage 1 (RR = 7.027, 95% CI 4.918-10.039). Persistent renal dysfunction, heart failure, central nervous system failure, baseline eGFR < 60 mL/min/1.73 m2, oliguria or anuria, blood urea nitrogen ≥ 7.14 mmol/L, respiratory failure, and shock were independent risk factors of 90-day or 1-year adverse prognosis (p < 0.05). Compared with transient renal dysfunction, PC-AKI patients with persistent renal dysfunction had a higher all-cause mortality rate (RR = 3.768, 95% CI 1.612-8.810; RR = 4.106, 95% CI 1.765-9.551) as well as combined endpoints of death, chronic kidney disease, or end-stage renal disease (OR = 3.685, 95% CI 1.628-8.340; OR = 5.209, 95% CI 1.730-15.681) within 90 days or 1 year. CONCLUSIONS: PC-AKI is not always a transient, benign creatininopathy, but can result in adverse outcome. AKI stage is independently correlated to MAKE30 and persistent renal dysfunction may exaggerate the risk of long-term adverse events. KEY POINTS: • PC-AKI can result in adverse outcome such as persistent renal dysfunction, dialysis, chronic kidney disease (CKD), end-stage renal disease (ESRD), or death. • AKI stage is independently correlated to MAKE30. • Persistent renal dysfunction may exaggerate the risk of long-term adverse events.

Mitophagy Plays a Protective Role in Iodinated Contrast-Induced Acute Renal Tubular Epithelial Cells Injury.

BACKGROUND/AIMS: Contrast induced-acute kidney injury (CI-AKI) is one of the most common causes of acute kidney injury (AKI) in hospitalized patients. Mitophagy, the selective elimination of mitochondria via autophagy, is an important mechanism of mitochondrial quality control in physiological and pathological conditions. In this study, we aimed to determine effects of iohexol and iodixanol on mitochondrial reactive oxygen species (ROS), mitophagy and the potential role of mitophagy in CI-AKI cell models. METHODS: Cell viability was measured by cell counting kit-8. Cell apoptosis, mitochondrial ROS and mitochondrial membrane potential were detected by western blot, MitoSOX fluorescence and TMRE staining respectively. Mitophagy was detected by the colocalization of LC3-FITC with MitoTracker Red, western blot and electronic microscope. RESULTS: The results showed that mitophagy was induced in human renal tubular cells (HK-2 cells) under different concentrations of iodinated contrast media. Mitochondrial ROS displayed increased expression after the treatment. Rapamycin (Rap) enhanced mitophagy and alleviated contrast media induced HK-2 cells injury. In contrast, autophagy inhibitor 3-methyladenine (3-MA) down-regulated mitophagy and aggravated cells injury. CONCLUSIONS: Together, our finding indicates that iohexol and iodixanol contribute to the generation of mitochondrial ROS and mitophagy. The enhancement of mitophagy can effectively protect the kidney from iodinated contrast (iohexol)-induced renal tubular epithelial cells injury.

mTOR Signaling Regulates Protective Activity of Transferred CD4+Foxp3+ T Cells in Repair of Acute Kidney Injury.

CD4+Foxp3+ regulatory T cells (Tregs) are required for normal immune homeostasis. Recent studies suggested that Treg transfer facilitates recovery from acute kidney injury (AKI), but the molecular events that maintain Treg function after adoptive transfer remain unclear. This study aimed to investigate the regulation of mammalian target of rapamycin (mTOR) signaling in the Treg-mediated therapeutic effect on ischemic AKI. We noted significant Treg expansion in C57BL/6 mouse kidney, with enhanced immunosuppressive capacity after renal ischemia/reperfusion. mTOR inhibition significantly increased the frequency of Tregs in cultured CD4+ T cells, with enhanced production of anti-inflammatory cytokines, which, conversely, was reduced by mTOR activation. Rapamycin, an inhibitor of mTOR, was transiently administered to C57BL/6 mice before ischemia/reperfusion surgery. No beneficial effect of rapamycin treatment was seen in the early recovery of AKI as a result of its inhibitory effect on tubular regeneration. However, rapamycin markedly enhanced the expansion of kidney Tregs, with increased mRNA expression of anti-inflammatory cytokines. Adoptive transfer of rapamycin-treated Tregs markedly suppressed conventional T cells, responder myeloid cells, and reactive myofibroblasts; however, it promoted host Tregs and alternative macrophages, leading to better renal function and less kidney fibrosis. Taken together, Treg transfer with mTOR inhibition markedly improves outcomes of ischemic AKI. These findings reveal an important role for mTOR signaling in maintaining Treg activity after adoptive transfer and highlight the therapeutic potential of targeting Tregs in acute and chronic kidney disease.

Comparison of iohexol and iodixanol induced nephrotoxicity, mitochondrial damage and mitophagy in a new contrast-induced acute kidney injury rat model.

Recent progress in angiography and interventional therapy has revived interest in comparison of nephrotoxicity of low-or iso-osmolar contrast media, but detailed mechanisms and effective treatments of contrast-induced acute kidney injury (CI-AKI) remain elusive. We established a new model of CI-AKI and compared the nephrotoxicity of iohexol and iodixanol with a focus on renal oxidative stress, mitochondrial damage and mitophagy. Our results showed that 48-h dehydration plus furosemide injection before iohexol administration successfully induced CI-AKI in rats. Compared with iodixanol, iohexol induced a greater decrease in renal function, more severe morphological damage and mitochondrial ultrastructural changes, an increased number of apoptotic cells, decreased antioxidative enzymes with activation of NLRP3 inflammasome in renal tissue. Renal contrast media kinetics showed the immediate excretion of iohexol and the transient renal accumulation of iodixanol. Plasma mtDNA Tc numbers were positively correlated with markers of renal mitochondrial disruption but negatively correlated with the level of serum creatinine and the score of tubular injury. Of note, iodixanol appeared to induce a stronger activation of mitophagy than iohexol, evidenced by greater protein levels of LC3II and PINK1/Parkin in the renal tissue of iodixanol-treated rats. Taken together, our results indicate that iohexol induced more severe nephrotoxicity than iodixanol in vivo due to apoptosis, destruction of antioxidative defense machinery, activation of NLRP3 inflammasome, mitochondrial damage and mitophagy. Plasma mtDNA may serve as a biological marker for renal mitochondrial disruption and damage in CI-AKI. Antioxidative defense and mitophagy are involved in the process of CI-AKI and may be promising targets of therapies.

Serum cystatin c is not superior to serum creatinine for early diagnosis of contrast-induced nephropathy in patients who underwent angiography.

BACKGROUND: Iodiated contrast-induced nephropathy (CIN) is a serious complication of contrast-enhanced imaging. The aim of this study was to evaluate the diagnostic sensitivities and specificities of serum cystatin C (sCys C) and serum creatinine (sCr) for CIN and to further investigate difference of the incidence, risk factors, and in-hospital and 3-month prognosis of CIN according to sCys C criteria and sCr criteria. METHODS: We prospectively evaluated 213 patients who underwent angiography. The sCr and sCys C concentrations were detected before and at 48 hours, 72 hours after the procedure. The incidence, risk factors, and in-hospital and 3-month prognosis of CIN were analyzed. Receiver operating characteristic curve (ROC) analysis was performed for sCr and sCys C 48 hours after procedure. RESULTS: The incidence of CIN was 24.4% (sCys C criteria) and 8% (sCr criteria). Diabetes mellitus, dehydration, and hypoalbuminemia were independent risk factors for CIN. Area under the ROC of sCys C 48 hours after procedure was not superior to sCr (0.715 vs 0.790, P=.178). The mortality of patients with CIN in sCr criteria increased significantly (P<.05). CONCLUSION: In this study, the incidence and risk factors of CIN were related to diagnostic criteria. The sCys C was not superior to sCr for predicting CIN in the patients who underwent angiography.

High Glucose Enhances oxLDL-Induced Apoptosis in Human Renal Proximal Tubular Epithelial Cells Largely via Inducing Lectin-Like ox-LDL Receptor-1.

BACKGROUND: High blood glucose is characteristic of diabetic nephropathy (DN). Both lectin-like ox-LDL receptor-1 (LOX-1) and renal tubular epithelial cells apoptosis reportedly are important for the pathogenesis and progression of DN. In this study, we explored the regulatory effects of high glucose on the expression of LOX-1 and its impact on oxLDL-induced apoptosis in human renal proximal tubular epithelial cells (HRPTEpCs). METHODS: Primary HRPTEpCs were treated with high glucose with or without concurrent treatment with selective p38 mitogen-activated protein kinase (MAPK) inhibitor PD169316 or lentiviral knockdown of LOX-1. HRPTEpCs cultured in normal glucose concentration (5.5 mmol/l) was used as a control. RESULTS AND CONCLUSION: High glucose concentration dependency increased the expression of LOX-1, which led to increased ox-LDL binding in HRPTEpCs. In addition, high glucose upregulated the LOX-1 gene promoter activity but not its mRNA stability in HRPTEpCs; the effect was abolished by PD169316. Furthermore, high glucose markedly enhanced oxLDL-induced apoptosis in HRPTEpCs, which was largely abolished by knockdown of LOX-1. This study demonstrates that high glucose induces the expression of LOX-1 at the gene promoter/transcription level mainly by a p38 MAPK-dependent mechanism, which enhances oxLDL-induced apoptosis in renal tubular epithelial cells. It adds new insights into the molecular mechanisms underlying DN.

[Evaluation of risk factors and prognosis on diodone-induced acute kidney injury according to ESUR and KDIGO criteria].

OBJECTIVE: To investigate the incidence, risk factors and prognosis for contrast-induced acute kidney injury (CI-AKI) according to ESUR and KDIGO criteria in patients undergoing angiography.
 METHODS: We evaluated 260 patients undergoing angiography and/or intervention therapy from April 2011 to January 2012 in the Second Xiangya Hospital of Central South University. All patients received low-osmolality contrast agent (ioversol). Serum creatinine was measured before angiography or at 48 or 72 h after procedure. The multivariate logistic regression was used to analyze the risk factors of CI-AKI. The major adverse events were observed in a year of follow-up.
 RESULTS: Among the 260 patients, 23 experienced CI-AKI and the incidence was 8.8% according to ESUR criteria. Twelve patients experienced CI-AKI and the incidence was 4.6% according to KDIGO criteria. The multivariate logistic regression analysis showed that diabetes mellitus and dehydration were the independent risk factors for CI-AKI according to ESUR criteria; In another KDIGO criteria, chronic kidney disease (CKD), hypercholesterolemia and diabetes mellitus were the independent risk factors for CI-AKI. The prognosis study showed that the mortality of patients with CI-AKI were significantly higher than those without CI-AKI (P<0.05).
 CONCLUSION: The incidence of CI-AKI is associated with diagnostic criteria. Diabetes mellitus, CKD, dehydration and hypercholesterolemia were the independent risk factors for CI-AKI. CI-AKI is a relevant factor for mortality in a year after angiography and/or intervention therapy.

[Role of protein phosphatase 2A in renal interstitial fibrosis].

BACKGROUND: To explore the role of protein phosphatase 2A (PP2A) in renal interstitial fibrosis by using rat model of unilateral ureteral obstructive (UUO) or cell model of human kidney proximal tubular epithelial (HK)-2 cells treated with transforming growth factor-ß1 (TGF-ß1).
 METHODS: 1) A total of 15 Sprague-Dawley rats were randomly divided into a sham group, a UUO group and an okadaic acid (OA) treated group (OA group) (n=5 in each group). The OA [30 µg/(kg·d)], diluted with 1.8% alcohol, was given to the rats in the OA group through gastric tube after at 72 h after the surgery, while the equal volume of 1.8% alcohol was given to the rats in the sham group and the UUO group. After sacrificing rats, the blood and kidney were collected to detect the renal function and the expression of PP2Ac, fibronectin (FN), collagen-I (Col-I), E-cadherin (E-cad) and α-smooth muscle actin (α-SMA) by immunohistochemistry, Western blot and RT-PCR, respectively; 2) The likely concentration of OA was determined by Trypan blue dye exclusive assay and methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. The HK-2 cells were incubated with serum-free Dulbecco's modified eagle medium (DMEM) for 24 h; then they were divided into a control group, a TGF-ß1 group (treated with 5 ng/mL TGF-ß1 for 24 h) and a TGF-ß1+OA group (treated with 5 ng/mL TGF-ß1 and 40 nmol/L OA for 24 h). The HK-2 cells were collected and the expression of PP2Ac, FN, Col-I, E-cad and α-SMA were detected by Western blot.
 RESULTS: 1) Compared with the sham group, the BUN and Scr in the UUO group increased (both P<0.05); compared with the UUO group, the BUN and Scr in the OA group decreased (both P<0.05); the expression of PP2Ac, FN, Col-I and α-SMA was up-regulated while the expression of E-cad was down-regulated in the UUO group compared with those in the sham group (all P<0.05). The expression of PP2Ac, FN, Col-I and α-SMA was down-regulated while the expressions of E-cad was up-regulated in the OA group compared with those in the UUO group (all P<0.05); 2) The likely concentration of OA was 40 nmol/L. Western blot showed that the expression of PP2Ac, FN, Col-I and α-SMA was up-regulated while the expressions of E-cad was down-regulated in the TGF-ß1 group compared with those in the control group (all P<0.05); the expression of PP2Ac, FN, Col-I and α-SMA were down-regulated while the expression of E-cad was up-regulated in the TGF-ß1+OA group compared with those in the TGF-ß1 group (all P<0.05).
 CONCLUSIONS: PP2A might be able to promote the renal interstitial fibrosis.
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