Post-Bypass Dexmedetomidine Use and Postoperative Acute Kidney Injury in Patients Undergoing Cardiac Surgery with Cardiopulmonary Bypass

Background

And Objectives: The aim of this retrospective investigation was to study the relationships among chronic kidney disease, acute kidney injury (AKI), and potential benefits by post-bypass dexmedetomidine use in patients undergoing cardiac surgery.

Methods

The patient data were reviewed from the institutional Society of Thoracic Surgeons National Adult Cardiac Surgery Database after IRB approval. 1,133 patients were identified and divided into two groups: those who received dexmedetomidine or those who did not during the post-bypass period. The postoperative outcomes include the incidence of AKI, any complication and all cause of mortality.

Results

Post-bypass dexmedetomidine use was associated with significantly reduced the incidence of total AKI (26.1% vs. 33.75%; adjusted OR, 0.7033; 95%CI, 0.540 to 0.916; p=0.0089). In addition, post-bypass dexmedetomidine use was more likely to reduce the incidence of AKI in these patients with preoperative normal kidney function (Stage1; 32.8% to 22.8%; p=0.0233) and mild CKD (Stage 2; 32.8% to 24.7; p=0.0003) after cardiac surgery. Post-bypass infusion of dexmedetomidine was associated with significantly reduced incidence of any complication and 30-day mortalities.

Conclusions

Post-bypass dexmedetomidine use is associated with a significant reduction in the incidence of AKI, especially mild AKI in patients with preoperative normal renal function and mild CKD undergoing cardiac surgery.     

Ulinastatin Protects against Acute Kidney Injury in Infant Piglets Model Undergoing Surgery on Hypothermic Low-Flow Cardiopulmonary Bypass

Objective

Infants are more vulnerable to kidney injuries induced by inflammatory response syndrome and ischemia-reperfusion injury following cardiopulmonary bypass especially with prolonged hypothermic low-flow (HLF). This study aims to evaluate the protective role of ulinastatin, an anti-inflammatory agent, against acute kidney injuries in infant piglets model undergoing surgery on HLF cardiopulmonary bypass.

Methods

Eighteen general-type infant piglets were randomly separated into the ulinastatin group (Group U, n = 6), the control group (Group C, n = 6), and the sham operation group (Group S, n = 6), and anaesthetized. The groups U and C received following experimental procedure: median thoracotomy, routine CPB and HLF, and finally weaned from CPB. The group S only underwent sham median thoracotomy. Ulinastatin at a dose of 5,000 units/kg body weight and a certain volume of saline were administrated to animals of the groups U and C at the beginning of CPB and at aortic declamping, respectively. Venous blood samples were collected at 3 different time points: after anesthesia induction in all experimental groups, 5 minutes, and 120 minutes after CPB in the Groups U and C. Markers for inflammation and acute kidney injury were tested in the collected plasma. N-acetyl-β-D-glucosaminidase (NAG) from urine, markers of oxidative stress injury and TUNEL-positive cells in kidney tissues were also detected.

Results

The expressions of plasma inflammatory markers and acute kidney injury markers increased both in Group U and Group C at 5 min and 120 min after CPB. Also, numbers of TUNEL-positive cells and oxidative stress markers in kidney rose in both groups. At the time point of 120-min after CPB, compared with the Group C, some plasma inflammatory and acute kidney injury markers as well as TUNEL-positive cells and oxidative stress markers in kidney were significantly reduced in the Group U. Histologic analyses showed that HLF promoted acute tubular necrosis and dilatation.

Conclusions

HLF cardiopulmonary bypass surgery could intensify systemic inflammatory responses and oxidative stress on infant piglets, thus causing acute kidney injury. Ulinastatin might reduce such inflammatory response and oxidative stress and the extent of kidney injury.     

Angiopoietin/Tie2 Dysbalance Is Associated with Acute Kidney Injury after Cardiac Surgery Assisted by Cardiopulmonary Bypass

Introduction

The pathophysiology of acute kidney injury (AKI) after cardiac surgery is not completely understood. Recent evidence suggests a pivotal role for the endothelium in AKI. In experimental models of AKI, the endothelial specific receptor Tie2 with its ligands Angiopoietin (Ang) 1 and Ang2 are deranged. This study investigates their status after cardiac surgery, and a possible relation between angiopoietins and AKI.

Methods

From a cohort of 541 patients that underwent cardiac surgery, blood and urine was collected at 5 predefined time points. From this cohort we identified 21 patients who had at least 50% post-operative serum creatinine increase (AKI). We constructed a control group (n = 21) using propensity matching. Systemic levels of Ang1, Ang2, and sTie2 were measured in plasma and the AKI markers albumin, kidney injury molecule-1 (KIM-1) and N-acetyl-beta-D-glucosaminidase (NAG) were measured in the urine.

Results

Ang2 plasma levels increased over time in AKI (from 4.2 to 11.6 ng/ml) and control patients (from 3.0 to 6.7 ng/ml). Ang2 levels increased 1.7-fold more in patients who developed AKI after cardiac surgery compared to matched control patients. Plasma levels of sTie2 decreased 1.6-fold and Ang1 decreased 3-fold over time in both groups, but were not different between AKI and controls (Ang1 P = 0.583 and sTie2 P = 0.679). Moreover, we found a positive correlation between plasma levels of Ang2 and urinary levels of NAG.

Conclusions

The endothelial Ang/Tie2 system is in dysbalance in patients that develop AKI after cardiac surgery compared to matched control patients.     

Association of STAT4 Polymorphisms with Susceptibility to Type-1 Autoimmune Hepatitis in the Japanese Population

Background/Aims

Recent studies demonstrated an association of STAT4 polymorphisms with autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis, indicating multiple autoimmune diseases share common susceptibility genes. We therefore investigated the influence of STAT4 polymorphisms on the susceptibility and phenotype of type-1 autoimmune hepatitis in a Japanese National Hospital Organization (NHO) AIH multicenter cohort study.

Methodology/Principal Findings

Genomic DNA from 460 individuals of Japanese origin including 230 patients with type-1 autoimmune hepatitis and 230 healthy controls was analyzed for two single nucleotide polymorphisms in the STAT4 gene (rs7574865, rs7582694). The STAT4 rs7574865T allele conferred risk for type-1 autoimmune hepatitis (OR = 1.61, 95% CI = 1.23–2.11; P = 0.001), and patients without accompanying autoimmune diseases exhibited an association with the rs7574865T allele (OR = 1.50, 95%CI = 1.13–1.99; P = 0.005). Detailed genotype-phenotype analysis of type-1 autoimmune hepatitis patients with (n = 44) or without liver cirrhosis (n = 186) demonstrated that rs7574865 was not associated with the development of liver cirrhosis and phenotype (biochemical data and the presence of auto-antibodies).

Conclusions/Significance

This is the first study to show a positive association between a STAT4 polymorphism and type-1 autoimmune hepatitis, suggesting that autoimmune hepatitis shares a gene commonly associated with risk for other autoimmune diseases.     

围术期应用他汀类药物对冠状动脉旁路移植术并发急性肾损伤疗效的研究进展

急性肾损伤是冠状动脉旁路移植术后常见并且严重的并发症,目前临床治疗主要以对症治疗和肾脏替代治疗为主。作为调节冠心病患者血脂的他汀类药物,其对于行冠状动脉旁路移植术患者肾脏的作用也成为了学者研究的热点问题。目前虽已有充分证据表明他汀类药物可以降低行冠状动脉旁路移植术患者院内死亡率,但是尚不清楚其能否降低患者术后急性肾损伤的发生率。对于在冠状动脉旁路移植术围手术期应用他汀类药物,其应用的时间窗以及应用的剂量学者们仍未达成统一意见。本文通过分析他汀类药物在冠心病整体防治中的作用机理机制,以及总结近几年关于他汀用药时间窗,用药剂量对于行CABG患者术后肾脏影响的相关文献,对围手术期应用他汀类药物对于行CABG患者术后急性肾损伤的影响展开综述。     

Association between Single Nucleotide Polymorphisms in the ADD3 Gene and Susceptibility to Biliary Atresia

Background and Objectives

Based on the results of previous studies, the ADD3 gene, located in the 10q24.2 region, may be a susceptibility gene of biliary atresia (BA). In this study, two single nucleotide polymorphisms (SNPs) in the ADD3 gene, rs17095355 C/T and rs10509906 G/C, were selected to investigate whether there is an association between these SNPs and susceptibility to BA in a Chinese population.

Methods

A total of 752 Han Chinese (134 BA cases and 618 ethnically matched healthy controls) were included in the present study. The ADD3 gene polymorphisms were genotyped using a TaqMan genotyping assay.

Results

Positive associations were found for the SNP rs17095355 in the codominant model; specifically, the frequencies of the CT and TT genotypes and the T allele were higher in the cases than the controls, demonstrating a significant risk for BA (odds ratio [OR] = 1.62, 95% confidence interval [CI] = 1.02–2.58; OR = 2.89, 95% CI = 1.72–4.86; and OR = 1.75, 95% CI = 1.34–2.29, respectively). Regarding rs10509906, the per-C-allele conferred an OR of 0.70 (95% CI = 0.49–1.00) under the additive model. A greater risk of BA was associated with the T_a-G_b (a for rs17095355 and b for rs10509906) haplotype (OR = 1.82, 95% CI = 1.27–2.61) compared with the C_a-C_b haplotype.

Conclusion

This study suggests that the ADD3 gene plays an important role in BA pathogenesis and reveals a significant association between two SNPs, rs17095355 and rs10509906, and BA.     

急性肾损伤患者血清胱抑素-C及尿NGAL 水平的变化及其临床意义

目的:观察急性肾损伤(Acute kidney injury,AKI)患者血清胱抑素-C(Cystatin-C,CysC)及尿中性粒细胞明胶酶相关脂质运载蛋白(Neutrophil gelatinase-associated lipocalin,NGAL)水平的变化及其临床意义。方法:选择60例AKI患者为实验组,50例正常健康人作为对照组,应用酶联免疫吸附法测定两组人群血清胱抑素-C和尿NGAL水平。结果:实验组与对照组相比血清胱抑素-C和尿NGAL水平显著升高,差异有统计学意义(P<0.05)。实验组尿NGAL检出率高于血清胱抑素-C、血肌酐,差异有统计学意义(P<0.05)。结论:急性肾损伤患者血清胱抑素-C和尿NGAL均升高,其中尿NGAL是反映AKI较敏感的生物学标志物,值得临床进一步研究。     

Heart Block and Acute Kidney Injury Due to Hyperparathyroidism-Induced Hypercalcemic Crisis

We describe a patient who presented with multi-system organ failure due to extreme hypercalcemia (serum calcium 19.8 mg/dL), resulting from primary hyperparathyroidism. He was found to have a 4.8 cm solitary atypical parathyroid adenoma. His course was complicated by complete heart block, acute kidney injury, and significant neurocognitive disturbances. Relevant literature was reviewed and discussed. Hyperparathyroidism-induced hypercalcemic crisis (HIHC) is a rare presentation of primary hyperparathyroidism and only a small minority of these patients develop significant cardiac and renal complications. In cases of HIHC, a multidisciplinary effort can facilitate rapid treatment of life-threatening hypercalcemia and definitive treatment by surgical resection. As such, temporary transvenous cardiac pacing and renal replacement therapy can provide a life-saving bridge to definitive parathyroidectomy in cases of HIHC.     

Association of the FCN2 Gene Single Nucleotide Polymorphisms with Susceptibility to Pulmonary Tuberculosis

Ficolin-2 (FCN2) is an innate immune pattern recognition molecule that can activate the complement pathway, opsonophagocytosis, and elimination of the pathogens. The present study aimed to investigate the association of the FCN2 gene single nucleotide polymorphisms (SNPs) with susceptibility to pulmonary tuberculosis (TB). A total of seven SNPs in exon 8 (+6359 C>T and +6424 G>T) and in the promoter region (-986 G>A, -602 G>A, -557 A>G, -64 A>C and -4 A>G) of the FCN2 gene were genotyped using the PCR amplification and DNA sequencing methods in the healthy controls group (n = 254) and the pulmonary TB group (n = 282). The correlation between SNPs and pulmonary TB was analyzed using the logistic regression method. The results showed that there were no significant differences in the distribution of allelic frequencies of seven SNPs between the pulmonary TB group and the healthy controls group. However, the frequency of the variant homozygous genotype (P = 0.037, -557 A>G; P = 0.038, -64 A>C; P = 0.024, +6424 G>T) in the TB group was significantly lower than the control group. After adjustment for age and gender, these variant homozygous genotypes were found to be recessive models in association with pulmonary TB. In addition, -64 A>C (P = 0.047) and +6424 G>T (P = 0.03) were found to be codominant models in association with pulmonary TB. There was strong linkage disequilibrium (r² > 0.80, P < 0.0001) between 7 SNPs except the -602 G>A site. Therefore, -557 A>G, -64 A>C and +6424 G>T SNPs of the FCN2 gene were correlated with pulmonary TB, and may be protective factors for TB. This study provides a novel idea for the prevention and control of TB transmission from a genetics perspective.     

Meta-Analysis of the Association between Insulin-Like Growth Factor Binding Protein 3 Genetic Polymorphisms and Colorectal Cancer Susceptibility

Insulin-like growth factor binding protein 3 (IGFBP-3) plays an important role in the development and progress of cancers. The association between IGFBP-3 polymorphisms and colorectal cancer remains controversial and ambiguous. The aim of this study is to explore the association between IGFBP3 A-202C and Gly32Ala polymorphisms and colorectal cancer susceptibility using meta-analyisi. Case-control studies on the association between IGFBP3 A-202C and Gly32Ala polymorphisms and colorectal cancer, which had sufficient data for estimating an odds ratio (OR) with 95% confidence interval (CI), were included in the meta-analysis. Abstracts, case reports, editorials, and review articles were excluded. Heterozygous and homozygous mutants were compared with the wild types to estimate combined OR values and 95%CIs with Review Manager 5.0. Six eligible studies were included, with 3157 patients and 6027 controls for A-202C and 1711 patients and 2995 controls for Gly32Ala. No significant association was found in all genetic models (for A-202C, AC vs. AA, OR = 0.99(0.88–1.11), CC vs. AA, OR = 1.06(0.92–1.22), dominant model, OR = 0.98(0.88–1.09), recessive model, OR = 0.94(0.84–1.05); and for Gly32Ala polymorphism, GC vs. GG, OR = 1.10(0.92–1.31), CC vs. GG, OR = 0.93(0.76–1.14), dominant model, OR = 1.05(0.89–1.24), recessive model, OR = 0.90(0.77–1.05)). The results suggest that the IGFBP3 A-202C and Gly32Ala polymorphisms are not associated with colorectal cancer susceptibility.     

NRAMP1基因3′UTR多态性与新疆哈萨克族结核病易感性的研究

为了研究人类自然抵抗相关巨噬细胞蛋白NRAMP1基因3′UTR多态性与新疆哈萨克族结核病易感性的关系,研究选取新疆哈萨克族活动性结核病患者213例,新疆哈萨克族正常对照者211人,用聚合酶链反应-限制性片断长度多态性(PCR-RFLP)分析的方法对NRAMP1基因3′UTR多态性进行基因分型,比较不同基因型及等位基因的频率,经统计学分析,探讨NRAMP1基因3′UTR多态性与新疆哈萨克族结核病易感性的关系.结果显示,在新疆哈萨克族活动性结核病患者组中NRAMP1基因3′UTR TGTG+/TGTG+基因型138例(64.8%),TGTG+/del基因型63例(29.6%),del/del基因型12例(5.6%);新疆哈萨克族正常对照组TGTG+/TGTG+基因型则为167例(79.1%),TGTG+/del基因型41例(19.5%),del/del基因型3例(1.4%).新疆哈萨克族结核病患者组TGTG+/del基因型和del/del基因型频率明显高于新疆哈萨克族正常对照组,差异有统计学意义(χ2=10.8,P0.01);在新疆哈萨克族结核病患者组的TGTG+等位基因频率为79.6%,del等位基因频率为20.4%,新疆哈萨克族正常对照组中TGTG+和del等位基因频率分别为88.9%和11.1%,del等位基因在新疆哈萨克族结核病患者组中的分布频率高,差异有统计学意义(χ2=13.7,P0.01).研究结果提示TGTG缺失等位基因可能是新疆哈萨克族结核病的易感基因,携带TGTG+/del和del/del基因型的新疆哈萨克族人群可能更易患结核病.     

U-Curve Association between Timing of Renal Replacement Therapy Initiation and In-Hospital Mortality in Postoperative Acute Kidney Injury

Background

Postoperative acute kidney injury (AKI) is associated with poor outcomes in surgical patients. This study aims to evaluate whether the timing of renal replacement therapy (RRT) initiation affects the in-hospital mortality of patients with postoperative AKI.

Methodology

This multicenter retrospective observational study, which was conducted in the intensive care units (ICUs) in a tertiary hospital (National Taiwan University Hospital) and its branch hospitals in Taiwan between January, 2002, and April, 2009, included adult patients with postoperative AKI who underwent RRT for predefined indications. The demographic data, comorbid diseases, types of surgery and RRT, and the indications for RRT were documented. Patients were categorized according to the period of time between the ICU admission and RRT initiation as the early (EG, ≦1 day), intermediate (IG, 2–3 days), and late (LG, ≧4 days) groups. The in-hospital mortality rate censored at 180 day was defined as the endpoint.

Results

Six hundred forty-eight patients (418 men, mean age 63.0±15.9 years) were enrolled, and 379 patients (58.5%) died during the hospitalization. Both the estimated probability of death and the in-hospital mortality rates of the three groups represented U-curves. According to the Cox proportional hazard method, LG (hazard ratio, 1.527; 95% confidence interval, 1.152–2.024; P = 0.003, compared with IG group), age (1.014; 1.006–1.021), diabetes (1.279; 1.022–1.601; P = 0.031), cirrhosis (2.147; 1.421–3.242), extracorporeal membrane oxygenation support (1.811; 1.391–2.359), initial neurological dysfunction (1.448; 1.107–1.894; P = 0.007), pre-RRT mean arterial pressure (0.988; 0.981–0.995), inotropic equivalent (1.006; 1.001–1.012; P = 0.013), APACHE II scores (1.055; 1.037–1.073), and sepsis (1.939; 1.536–2.449) were independent predictors of the in-hospital mortality (All P<0.001 except otherwise stated).

Conclusions

The current study found a U-curve association between the timing of the RRT initiation after the ICU admission and patients’ in-hospital mortalities, and alerts physicians of certain factors affecting the outcome after the RRT initiation.     

IL-10基因启动子-627位点多态性与过敏性哮喘

目的：探讨白细胞介素-10（IL-10）启动子-627C／A基因多态性和等位基因频率与过敏性哮喘血清IgE、IL-10浓度以及病情严重程度的相互关系。方法：从哮喘病人DNA文库中选择青岛地区过敏性哮喘病人518例和健康志愿者501例,采用PCR—RFLP方法对IL．10基因启动子．627位点多态性进行观察,比较两组基因型和等位基因的分布频率,同时测定血清中总IgE、IL-10浓度和肺功能检查（FEV1、FVC、FEV1／FVC）。结果：轻度和中一重度哮喘组AA、CA和CC基因型所占比例分别为38．1％、46．0％、15．9％和45．6％、46．2％和8．2％（P=0．0168,X2=8．232,df=2）。A等位基因与哮喘病轻的严重程度有明显相关性（P〈0．05）。AA基因型哮喘病人血清的IgE浓度显著升高（P〈0．01）,但其血清IL-10浓度比CC基因型携带者明显降低（P〈0．01）。结论：IL-10基因启动子-627位点多态性与过敏性哮喘的发生有一定的相关性,等位基因A是哮喘患病的风险基因,而等位基因C则是哮喘病的保护基因。     

IL-10基因启动子-627位点多态性与过敏性哮喘

目的:探讨白细胞介素-10(IL-10)启动子-627C/A基因多态性和等位基因频率与过敏性哮喘血清IgE、IL-10浓度以及病情严重程度的相互关系。方法:从哮喘病人DNA文库中选择青岛地区过敏性哮喘病人518例和健康志愿者501例,采用PCR-RFLP方法对IL-10基因启动子-627位点多态性进行观察,比较两组基因型和等位基因的分布频率,同时测定血清中总IgE、IL-10浓度和肺功能检查(FEV1、FVC、FEVl/FVC)。结果:轻度和中-重度哮喘组AA、CA和CC基因型所占比例分别为38.1%、46.0%、15.9%和45.6%、46.2%和8.2%(P=0.0168,X~2=8.232,df=2)A等位基因与哮喘病轻的严重程度有明显相关性(P<0.05)。AA基因型哮喘病人血清的IgE浓度显著升高(P<0.01),但其血清IL-10浓度比CC基因型携带者明显降低(P<0.01)。结论:IL-10基因启动子-627位点多态性与过敏性哮喘的发生有一定的相关性,等位基因A是哮喘患病的风险基因,而等位基因C则是哮喘病的保护基因。     

SMAD4错义突变与先天性心脏病易感性的相关性研究

SMAD4在心脏发育过程中发挥重要作用,已有研究显示,Smad4 缺陷小鼠心脏功能异常.为了进一步探究SMAD4基因错义突变与先天性心脏病(congenital heart disease,CHD)发生的相关性,本研究选取了来自中国山东汉族的417例CHD患者样本和213例健康对照样本,并靶向SMAD4的编码区进行深度...     

A Novel Therapy to Attenuate Acute Kidney Injury and Ischemic Allograft Damage after Allogenic Kidney Transplantation in Mice

Ischemia followed by reperfusion contributes to the initial damage to allografts after kidney transplantation (ktx). In this study we tested the hypothesis that a tetrapeptide EA-230 (AQGV), might improve survival and attenuate loss of kidney function in a mouse model of renal ischemia/reperfusion injury (IRI) and ischemia-induced delayed graft function after allogenic kidney transplantation. IRI was induced in male C57Bl/6N mice by transient bilateral renal pedicle clamping for 35 min. Treatment with EA-230 (20–50mg/kg twice daily i.p. for four consecutive days) was initiated 24 hours after IRI when acute kidney injury (AKI) was already established. The treatment resulted in markedly improved survival in a dose dependent manner. Acute tubular injury two days after IRI was diminished and tubular epithelial cell proliferation was significantly enhanced by EA-230 treatment. Furthermore, CTGF up-regulation, a marker of post-ischemic fibrosis, at four weeks after IRI was significantly less in EA-230 treated renal tissue. To learn more about these effects, we measured renal blood flow (RBF) and glomerular filtration rate (GFR) at 28 hours after IRI. EA-230 improved both GFR and RBF significantly. Next, EA-230 treatment was tested in a model of ischemia-induced delayed graft function after allogenic kidney transplantation. The recipients were treated with EA-230 (50 mg/kg) twice daily i.p. which improved renal function and allograft survival by attenuating ischemic allograft damage. In conclusion, EA-230 is a novel and promising therapeutic agent for treating acute kidney injury and preventing IRI-induced post-transplant ischemic allograft injury. Its beneficial effect is associated with improved renal perfusion after IRI and enhanced regeneration of tubular epithelial cells.     

Netrin-1 and Semaphorin 3A Predict the Development of Acute Kidney Injury in Liver Transplant Patients

Acute kidney injury (AKI) is a serious complication after liver transplantation. Currently there are no validated biomarkers available for early diagnosis of AKI. The current study was carried out to determine the usefulness of the recently identified biomarkers netrin-1 and semaphorin 3A in predicting AKI in liver transplant patients. A total of 63 patients’ samples were collected and analyzed. AKI was detected at 48 hours after liver transplantation using serum creatinine as a marker. In contrast, urine netrin-1 (897.8±112.4 pg/mg creatinine), semaphorin 3A (847.9±93.3 pg/mg creatinine) and NGAL (2172.2±378.1 ng/mg creatinine) levels were increased significantly and peaked at 2 hours after liver transplantation but were no longer significantly elevated at 6 hours after transplantation. The predictive power of netrin-1, as demonstrated by the area under the receiver-operating characteristic curve for diagnosis of AKI at 2, 6, and 24 hours after liver transplantation was 0.66, 0.57 and 0.59, respectively. The area under the curve for diagnosis of AKI was 0.63 and 0.65 for semaphorin 3A and NGAL at 2 hr respectively. Combined analysis of two or more biomarkers for simultaneous occurrence in urine did not improve the AUC for the prediction of AKI whereas the AUC was improved significantly (0.732) only when at least 1 of the 3 biomarkers in urine was positive for predicting AKI. Adjusting for BMI, all three biomarkers at 2 hours remained independent predictors of AKI with an odds ratio of 1.003 (95% confidence interval: 1.000 to 1.006; P = 0.0364). These studies demonstrate that semaphorin 3A and netrin-1 can be useful early diagnostic biomarkers of AKI after liver transplantation.