Early and Sustained Activation of Autophagy in Degenerating Axons after Spinal Cord Injury

Axonal degeneration is one of the initial steps in many neurological disorders and has been associated with increased autophagic activity. Although there are increasing data on the regulation of autophagy proteins in the neuronal soma after spinal cord injury (SCI), their characterization in the axon is scarce. Here, we examined the regulation of autophagy during axonal degeneration in a rat model of SCI following a lesion at Th 8. We analyzed the morphological and ultrastructural changes in injured axons by immunohistochemical evaluation of autophagy‐related proteins and electron microscopy at different time points following SCI. The expression of ULK1, Atg7 and Atg5 in damaged axons was rapidly upregulated within hours after SCI. The number of axonal LC3‐positive autophagosomes was also rapidly increased after SCI and remained at an increased level for up to 6 weeks. Ultrastructural analysis showed early signs of axonal degeneration and increased autophagy. In conclusion, we show that autophagy is increased early and for a sustained period in degenerating axons after SCI and that it might be an important executive step involved in axonal degeneration. Therefore, autophagy may represent a promising target for future therapeutic interventions in the treatment of axonal degeneration in traumatic central nervous system disorders.     

心脏手术后并发急性肾功能损伤的研究进展

近年来伴随着科学水平的提高,心脏外科手术进入了新的纪元,由于手术理念的革新,心脏外科手术适应症也逐步增宽,随着手术患者数量的增加,不仅对外科医生手术难度要求增加了,更加对手术术后管理提出了不小的考验。而体外循环（CPB）是直视下心脏手术的必备条件,CPB所涉及的心脏降温、血流动力学改变、持续血液抗凝、组织缺血后再灌注等,都对术后机体的恢复产生了影响,因此心脏手术术后多伴随诸多并发症,如心律失常、低心排综合征、急性肾功能损伤等。而急性肾功能损伤（AKI）又是体外循环术后较为常见的并发症,而且它风险高,病情重,一旦出现往往合并多系统器官功能衰竭,所以本文旨在收集和汇总近年来关于心脏手术后并发急性肾损伤的研究报道。     

The Effect of Specialized Continuous Renal Replacement Therapy Team in Acute Kidney Injury Patients Treatment

Purpose

Continuous renal replacement therapy (CRRT) has been established for critically ill acute kidney injury (AKI) patients. In addition, some centers consist of a specialized CRRT team (SCT) with physicians and nurses. To our best knowledge, however, ona a few studies have yet been carried out on the superiority of SCT management.

Materials and Methods

A total of 551 patients, who received CRRT between January 2008 and March 2009, were divided into two groups based on the controller of CRRT. The impact of the CRRT management on 28-day mortality was compared between two groups by Kaplan-Meier curve and Cox analysis.

Results

During the study period, the number of filters used, down-time per day, and intensive care unit length of day were significantly higher in non-SCT group than in SCT group (6.2 hrs vs. 5.0 hrs, p=0.042; 5.0 hrs vs. 3.8 hrs, p<0.001; 27.5 days vs. 21.1 days, p=0.027, respectively), while net ultrafiltration rate was significantly lower in non-SCT group than SCT group (28.0 mL/kg/hr vs. 29.5 mL/kg/hr, p=0.043, respectively). In addition, 28-day mortality rate was significantly lower in SCT group than with non-SCT group (p=0.031). Moreover, Cox regression analysis showed that 28-day mortality rate was significantly lower in SCT control group, even after adjusting for age, gender, severity scores, biomarkers, risk, injury, failure, loss, and end-stage renal disease, and contributing factors (hazard ratio 0.91, p=0.046).

Conclusion

A well-trained CRRT team could be beneficial for mortality improvement of AKI patients requiring CRRT.     

Tissue Kidney Injury Molecule-1 Expression in the Prediction of Renal Function for Several Years after Kidney Biopsy

Objectives. Retrospective study was designed to examine the importance of tissue kidney injury molecule-1 (KIM-1) expression in predicting kidney function in sixty patients (27 males) aged 34.15 ± 12.23 years with different kidney diseases over three years after kidney biopsy. Materials and Methods. Tissue KIM-1 expression was determined immunohistochemically and KIM-1 staining was scored semiquantitatively, as well as tubulointerstitialis (TIN), inflammation, atrophy, and fibrosis. Kidney function (MDRD formula) and proteinuria/day were evaluated at the time of biopsy (GFR0) and 6, 12, 24, and 36 months later. Results. Significantly positive correlations between tissue KIM-1 expression and age (r = 0.313), TIN inflammation (r = 0.456), fibrosis (r = 0.317), and proteinuria at 6 months (r = 0.394) as well as negative correlations with GFR0 (r = −0.572), GFR6 (r = −0.442), GFR24 (r = −0.398), and GFR36 (r = −0.412) were found. Meanwhile, TIN inflammation was the best predictor of all measured kidney functions during three years, while tissue KIM-1 expression (P = 0.016) was a predictor only at 6 months after biopsy. Conclusion. Tissue KIM-1 expression significantly predicts kidney function solely at 6 months after biopsy, when the effects of immune and nonimmune treatments are the strongest.     

Impact of Acute Kidney Injury on Long-Term Mortality after Nonmyeloablative Hematopoietic Cell Transplantation

Acute kidney injury (AKI) occurs frequently after nonmyeloablative hematopoietic cell transplantation (HCT). The severity of AKI after nonmyeloablative HCT has association with short-term mortality. However, the long-term effect of AKI on survival after nonmyeloablative HCT is not known. We performed a retrospective analysis of patients who underwent an HLA matched nonmyeloablative HCT between 1997 and 2006. Patients were followed for a median of 36 (range: 3-99) months. AKI occurring up to day 100 was defined as a >2-fold increase in serum creatinine or requirement of dialysis. Of the 358 patients who were included in the analysis, 200 (56%) had AKI, 158 (44%) had no AKI. Overall, 158 patients (43%) died during follow-up. After controlling for potential confounders, the adjusted hazard ratio for overall mortality associated with AKI was 1.57 (95 % confidence interval [CI] 1.2-2.3; P = .0006). The adjusted hazards ratio of nonrelapse mortality (NRM) associated with AKI was 1.72 (95% CI 0.9-3.1; P = .07). AKI is an independent predictor of overall mortality after nonmyeloablative HCT. This finding reiterates the importance of identifying preventative strategies in nonmyeloablative HCT for attenuating incidence and severity of AKI.     

Circulating Monoclonal Light Chains and Acute Kidney Injury: The Role of the Renal Biopsy with Emphasis on Ultrastructural Evaluation in Assessing and Understanding Renal Injury

Tubular interstitial injury as a consequence of circulating monotypical light chains in patients with an underlying plasma cell dyscrasia may be difficult to identify. Renal involvement is a common early manifestation in these patients, and accurate/careful pathologic evaluation can uncover an underlying plasma cell dyscrasia. While immunofluorescence evaluation can detect monotypical deposition of light chains in the tubular interstitial compartment and may suggest a possible underlying plasma cell dyscrasia, electron microscopic examination is crucial in documenting such involvement. Ultrastructural immunolabeling can help in solidifying the pathological assessment.     

连续肾脏替代疗法对感染性休克致急性肾损伤患者的临床意义

目的 探讨连续肾脏替代疗法(CRRT)治疗对感染性休克(SS)致急性肾损伤(AKI)患者治疗效果及生存率的影响.方法 将我院收治的252例SS致AKI患者随机分为接受CRRT治疗的CRRT组和接受间歇性血液透析(IHD)治疗的IHD组,各126例,比较两组治疗前后血二氧化碳结合力(CO2-CP)、肾功能指标、血乳酸、急性生理和慢性健康状况评分系统Ⅱ(APACHEⅡ)评分及生存率等情况.结果 治疗24、48h后,两组血CO2-CP水平均明显升高(P＜0.05),血乳酸、肌酐和尿素氮水平均明显降低(P＜0.05);APACHEⅡ、SOFA评分均明显降低(P＜0.05);CRRT组与IHD组血CO2-CP、乳酸、肌酐、尿素氮水平比较,差异有统计学意义(P＜0.05);CRRT组与IHD组APACHEⅡ、序贯器官衰竭(SOFA)评分比较,差异有统计学意义(P＜0.05);CRRT组与IHD组多器官功能障碍综合征(MODS)发生率和死亡率比较,差异有统计学意义(P＜0.05).结论 CRRT治疗SS致AKI疗效确切,可改善患者酸碱平衡和肾功能,提高生存率.     

Shock Duration after Resuscitation Is Associated with Occurrence of Post-Cardiac Arrest Acute Kidney Injury

This retrospective observational study investigated the clinical course and predisposing factors of acute kidney injury (AKI) developed after cardiac arrest and resuscitation. Eighty-two patients aged over 18 yr who survived more than 24 hr after cardiac arrest were divided into AKI and non-AKI groups according to the diagnostic criteria of the Kidney Disease/Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for AKI. Among 82 patients resuscitated from cardiac arrest, AKI was developed in 66 (80.5%) patients (AKI group) leaving 16 (19.5%) patients in the non-AKI group. Nineteen (28.8%) patients of the AKI group had stage 3 AKI and 7 (10.6%) patients received renal replacement therapy during admission. The duration of shock developed within 24 hr after resuscitation was shorter in the non-AKI group than in the AKI group (OR 1.02, 95% CI 1.01-1.04, P < 0.05). On Multiple logistic regression analysis, the only predisposing factor of post-cardiac arrest AKI was the duration of shock. In conclusion, occurrence and severity of post-cardiac arrest AKI is associated with the duration of shock after resuscitation. Renal replacement therapy is required for patients with severe degree (stage 3) post-cardiac arrest AKI.     

Rare Acute Kidney Injury Secondary to Hypothyroidism-Induced Rhabdomyolysis

Purpose

Acute kidney injury (AKI) caused by hypothyroidism-induced rhabdomyolysis is a rare and potentially life-threatening syndrome. The aim of this study was to investigate the clinical characteristics of such patients.

Materials and Methods

We retrospectively analyzed five patients treated at the Second Affiliated Hospital of Chongqing Medical University with AKI secondary to hypothyroidism-induced rhabdomyolysis from January 2006 to December 2010.

Results

Of the five cases reviewed (4 males, age range of 37 to 62 years), adult primary hypothyroidism was caused by amiodarone (1 case), chronic autoimmune thyroiditis (1 case), and by uncertain etiologies (3 cases). All patients presented with facial and lower extremity edema. Three patients presented with weakness, while two presented with blunted facies and oliguria. Only one patient reported experiencing myalgia and proximal muscle weakness, in addition to fatigue and chills. Creatine kinase, lactate dehydrogenase, and renal function normalized after thyroid hormone replacement, except in two patients who improved through blood purification.

Conclusion

Hypothyroidism should be considered in patients presenting with renal impairment associated with rhabdomyolysis. Moreover, further investigation into the etiology of the hypothyroidism is warranted.     

Cathelicidin protects mice from Rhabdomyolysis-induced Acute Kidney Injury

Background: Cathelicidins are ancient and well-conserved antimicrobial peptides (AMPs) with intriguing immunomodulatory properties in both infectious and non-infectious inflammatory diseases. In addition to direct antimicrobial activity, cathelicidins also participate in several signaling pathways inducing both pro-inflammatory and anti-inflammatory effects. Acute kidney injury (AKI) is common in critically ill patients and is associated with high mortality and morbidity. Rhabdomyolysis is a major trigger of AKI.Objectives: Here, we investigated the role of cathelicidins in non-infectious Acute kidney Injury (AKI).Method: Using an experimental model of rhabdomyolysis, we induced AKI in wild-type and cathelicidin-related AMP knockout (CRAMP^-/-) mice. Results: We previously demonstrated that CRAMP^-/- mice, as opposed wild-type mice, are protected from AKI during sepsis induced by cecal ligation and puncture. Conversely, in the current study, we show that CRAMP^-/- mice are more susceptible to the rhabdomyolysis model of AKI. A more in-depth investigation of wild-type and CRAMP^-/- mice revealed important differences in the levels of several inflammatory mediators.Conclusion: Cathelicidins can induce a varied and even opposing repertoire of immune-inflammatory responses depending on the subjacent disease and the cellular context.     

Predicting Acute Kidney Injury Following Mitral Valve Repair

Background: Acute kidney injury (AKI) after cardiac surgery is associated with short-term and long-term adverse outcomes. Novel biomarkers have been identified for the early detection of AKI; however, examining these in every patient who undergoes cardiac surgery is prohibitively expensive. Society of Thoracic Surgeons (STS) and Age, Creatinine, and Ejection Fraction (ACEF) scores have been proven to predict mortality in bypass surgery. The aim of this study was to determine whether these scores can be used to predict AKI after mitral valve repair.Materials and Methods: Between January 2010 and December 2013, 196 patients who underwent mitral valve repair were enrolled. The clinical characteristics, outcomes, and scores of prognostic models were collected. The primary outcome was postoperative AKI, defined using the Kidney Disease Improving Global Outcome 2012 clinical practice guidelines for AKI.Results: A total of 76 patients (38.7%) developed postoperative AKI. The STS renal failure (AUROC: 0.797, P < .001) and ACEF scores (AUROC: 0.758, P < .001) are both satisfactory tools for predicting all AKI. The STS renal failure score exhibited superior accuracy compared with the ACEF score in predicting AKI stage 2 and 3. The overall accuracy of both scores was similar for all AKI and AKI stage 2 and 3 when the cut-off points of the STS renal failure and ACEF scores were 2.2 and 1.1, respectively.Conclusion: In conclusion, the STS renal failure score can be used to accurately predict stage 2 and 3 AKI after mitral valve repair. The ACEF score is a simple tool with satisfactory power in screening patients at risk of all AKI stages. Additional studies can aim to determine the clinical implications of combining preoperative risk stratification and novel biomarkers.     

Candida Administration Worsens Neutrophil Extracellular Traps in Renal Ischemia Reperfusion Injury Mice: An Impact of Gut Fungi on Acute Kidney Injury

Because of gut-barrier defect (gut-leakage) after acute kidney injury (AKI) and higher abundance of Candida albicans in human intestines compared with mouse guts, Candida administration in renal ischemia reperfusion injury (I/R) mice possibly more closely resemble patients with AKI than non-Candida model. Fungi in feces were detectable only in mice with Candida administration. Candida renal-I/R mice, when compared with non-Candida I/R, demonstrated more profound injuries, including (i) gut-leakage; FITC-dextran assay and serum (1→3)-β-D-glucan (BG), (ii) systemic inflammation (serum cytokines), and (iii) neutrophil extracellular traps (NETs); gene expression of peptidyl arginase 4 (PAD4) and IL-1β, nuclear morphology staining by 4′,6-diamidino-2-phenylindole (DAPI) and co-staining of myeloperoxidase (MPO) with neutrophil elastase (NE) in peripheral blood neutrophils. Although renal excretory function (serum creatinine) and renal histology score were nondifferent between renal-I/R mice with and without Candida, prominent renal NETs (PAD4 and IL-1β expression with MPO and NE co-staining) was demonstrated in Candida renal-I/R mice. Additionally, neutrophil activation by lipopolysaccharide (LPS) plus BG (LPS + BG), when compared with LPS alone, caused (i) NETs formation; dsDNA, DAPI-stained nuclear morphology and MPO with NE co-staining, (ii) inflammatory responses; Spleen tyrosine kinase (Syk) and NFκB expression, and (iii) reduced cell energy status (maximal respiratory capacity using extracellular flux analysis). Also, LPS + BG-activated NETs formation was inhibited by a dectin-1 inhibitor, supporting an impact of BG signaling. In conclusion, Candida-renal I/R demonstrated more prominent serum BG and LPS from gut translocation that increased systemic inflammation and NETs through TLR-4 and dectin-1 activation. The influence of gut fungi in AKI should be concerned.     

Acute Kidney Injury after Using Contrast during Cardiac Catheterization in Children with Heart Disease

Acute kidney injury (AKI) is closely associated with the mortality of hospitalized patients and long-term development of chronic kidney disease, especially in children. The purpose of our study was to assess the evidence of contrast-induced AKI after cardiac catheterization in children with heart disease and evaluate the clinical usefulness of candidate biomarkers in AKI. A total of 26 children undergoing cardiac catheterization due to various heart diseases were selected and urine and blood samples were taken at 0 hr, 6 hr, 24 hr, and 48 hr after cardiac catheterization. Until 48 hr after cardiac catheterization, there was no significant increase in serum creatinine level in all patients. Unlike urine kidney injury molecule-1, IL-18 and neutrophil gelatinase-associated lipocalin, urine liver-type fatty acid-binding protein (L-FABP) level showed biphasic pattern and the significant difference in the levels of urine L-FABP between 24 and 48 hr. We suggest that urine L-FABP can be one of the useful biomarkers to detect subclinical AKI developed by the contrast before cardiac surgery.

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Delayed Diagnosis of Falciparum Malaria with Acute Kidney Injury

Prompt malaria diagnosis is crucial so antimalarial drugs and supportive care can then be rapidly initiated. A 15-year-old boy who had traveled to Africa (South Africa, Kenya, and Nigeria between January 3 and 25, 2011) presented with fever persisting over 5 days, headache, diarrhea, and dysuria, approximately 17 days after his return from the journey. Urinalysis showed pyuria and hematuria. Blood examination showed hemolytic anemia, thrombocytopenia, disseminated intravascular coagulation, and hyperbilirubinemia. Plasmapheresis and hemodialysis were performed for 19 hospital days. Falciparum malaria was then confirmed by peripheral blood smear, and antimalarial medications were initiated. The patient’s condition and laboratory results were quickly normalized. We report a case of severe acute renal failure associated with delayed diagnosis of falciparum malaria, and primary use of supportive treatment rather than antimalarial medicine. The present case suggests that early diagnosis and treatment is important because untreated tropical malaria can be associated with severe acute renal failure and fatality. Physicians must be alert for correct diagnosis and proper management of imported tropical malaria when patients have travel history of endemic areas.     

Relationship between Serum Uric Acid Concentration and Acute Kidney Injury after Coronary Artery Bypass Surgery

An elevated serum concentration of uric acid may be associated with an increased risk of acute kidney injury (AKI). The aim of this study was to investigate the impact of preoperative uric acid concentration on the risk of AKI after coronary artery bypass surgery (CABG). Perioperative data were evaluated from patients who underwent CABG. AKI was defined by the AKI Network criteria based on serum creatinine changes within the first 48 hr after CABG. Multivariate logistic regression was utilized to evaluate the association between preoperative uric acid and postoperative AKI. We evaluated changes in C statistic, the net reclassification improvement, and the integrated discrimination improvement to determine whether the addition of preoperative uric acid improved prediction of AKI. Of the 2,185 patients, 787 (36.0%) developed AKI. Preoperative uric acid was significantly associated with postoperative AKI (odds ratio, 1.18; 95% confidence interval, 1.10-1.26; P<0.001). Adding uric acid levels improved the C statistic and had significant impact on risk reclassification and integrated discrimination for AKI. Preoperative uric acid is related to postoperative AKI and improves the predictive ability of AKI. This finding suggests that preoperative measurement of uric acid may help stratify risks for AKI in in patients undergoing CABG.

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肾移植术后药源性肾损伤生物标志物的研究

肾脏移植是治疗肾脏疾病终末期的有效手段之一。随着对肾移植术后研究的不断深入,研究者发现了许多用于肾移植术后药源性肾损伤诊断、治疗效果评估和判断早期预警的生物标志物。本文旨在对肾移植术后药源性肾损伤相关生物标志物的研究作一综述。     

COMT-Val158Met-Polymorphism Is Not a Risk Factor for Acute Kidney Injury after Cardiac Surgery

Background. Cardiac surgery-associated acute kidney injury (CSA-AKI) depicts a major complication after cardiac surgery using cardiopulmonary bypass (CPB). Objective. CSA-AKI has clearly been linked to increased perioperative morbidity and mortality. Dysregulations of vasomotor tone are assumed to be causal for CSA-AKI. While catechol-O-methyltransferase (COMT) is involved in metabolizing catecholamines, a single-nucleotide polymorphism (SNP) in the COMT gene leads to different enzyme activities according to genotype. Pilot studies found associations between those COMT genotypes and CSA-AKI. Methods. We prospectively included 1741 patients undergoing elective cardiac surgery using cardiopulmonary bypass (CPB). Patients were genotyped for COMT-Val158Met-(G/A) polymorphism (rs4680). Results. Demographic characteristics and procedural data revealed no significant differences between genotypes. No association between COMT genotypes and the RIFLE criteria could be detected. A multiple linear regression analysis for postoperative creatinine increase revealed highly significant associations for aortic cross-clamp time (P < 0.001), CPB time (P < 0.001), norepinephrine (P < 0.001), and age (P < 0.001). No associations were found for COMT genotypes or baseline creatinine. With an R² = 0.39 and a sample size of 1741, the observed power of the regression analysis was >99%. Conclusions. Based on our results, we can rule out an association between the COMT-Val158Met-(G/A) polymorphism and the appearance of CSA-AKI.     

Hepatocyte Necroptosis Induced by Ischemic Acute Kidney Injury in Rats

Abstract

While ischemic acute kidney injury (IAKI) is known often to cause hepatic injury, little is known about necroptosis involved in the hepatic injury. The purposes of this study were to identify necroptosis involvement and observe morphological changes of hepatocytes in hepatic injury induced by IAKI in rats. Based on successfully established IAKI rat models, enzyme-linked immunosorbent assay illustrated a significant higher level of tumor necrosis factor a in serums of IAKI animals. Tumor necrosis factor receptor a (TNFRa) and receptor interacting protein kinase 3 (RIPk3) showed significant higher expressions in immunoblot analyses and positive hepatocytes of RIPk3 immunohistochemical staining were also evident in livers of IAKI rats. In addition, light microscopy revealed necrotic lesions that contain hepatocytes ongoing necroptosis besides necrotic cells in IAKI livers. Electron microscopy revealed at least three types of necrotic hepatocytes, they were edema necrosis, vacuolization necrosis, and necroptosis. Hepatocytes undergoing necroptosis had both necrosis and apoptosis morphological characteristics, they were necrosis cytoplasm and apoptosis-like nucleus. Among cellular organelles of hepatocyte with necrosis, membranous structures, such as cell membrane, endoplasmic reticular system, and mitochondria were more vulnerable to the stress of IAKI and deformed nucleuses varied in shape and lytic or pyknotic chromatin appearances were noted under insults of IAKI. In conclusion, hepatocyte undergoing necroptosis, RIPk3-mediated necroptosis partly contributes to hepatic necrosis induced by IAKI. Both membranous structures and nucleuses of hepatocyte were vulnerable to ischemic acute kidney injury.