Label-Free Quantitative Proteomics Reveals Differences in Molecular Mechanism of Atherosclerosis Related and Non-Related to Chronic Kidney Disease

The major cause of mortality in patients with chronic kidney disease (CKD) is atherosclerosis related to traditional and non-traditional risk factors. However, the understanding of the molecular specificity that distinguishes the risk factors for classical cardiovascular disease (CVD) and CKD-related atherosclerosis (CKD-A) is far from complete. In this study we investigated the disease-related differences in the proteomes of patients with atherosclerosis related and non-related to CKD. Plasma collected from patients in various stages of CKD, CVD patients without symptoms of kidney dysfunction, and healthy volunteers (HVs), were analyzed by a coupled label-free and mass spectrometry approach. Dysregulated proteins were confirmed by an enzyme-linked immunosorbent assay (ELISA). All proteomic data were correlated with kidney disease development and were subjected to bioinformatics analysis. One hundred sixty-two differentially expressed proteins were identified. By directly comparing the plasma proteomes from HVs, CKD, and CVD patients in one study, we demonstrated that proteins involved in inflammation, blood coagulation, oxidative stress, vascular damage, and calcification process exhibited greater alterations in patients with atherosclerosis related with CKD. These data indicate that the above nontraditional risk factors are strongly specific for CKD-A and appear to be less essential for the development of “classical” CVD.     

Chronic obstructive pulmonary disease in patients with end‐stage kidney disease on hemodialysis

The objectives of this study were to assess the prevalence of chronic obstructive pulmonary disease (COPD) in hemodialysis patients with spirometry and to examine the effects of fluid removal by hemodialysis on lung volumes. Patients ≥18 years at two Danish hemodialysis centers were included. Forced expiratory volume in one second (FEV₁), forced vital capacity (FVC), and FEV₁/FVC ratio were measured with spirometry before and after hemodialysis. The diagnosis of COPD was based on both the GOLD criteria and the lower limit of normal criteria. There were 372 patients in treatment at the two centers, 255 patients (69%) completed spirometry before dialysis and 242 of these (65%) repeated the test after. In the initial test, 117 subjects (46%) had airflow limitation indicative of COPD with GOLD criteria and 103 subjects (40.4%) with lower limit of normal criteria; COPD was previously diagnosed in 24 patients (9%). Mean FVC and FEV₁ decreased mildly after dialysis (FVC: 2.84 to 2.79 L, P < 0.01. FEV₁: 1.97 to 1.93 L, P < 0.01) Hemodialysis did not affect the FEV₁/FVC ratio or number of subjects with airflow limitation indicative of COPD (113 vs. 120, P = 0.324; n = 242). COPD is a frequent and underdiagnosed comorbidity in patients on chronic hemodialysis. Spirometry should be considered in all patients on dialysis in order to address dyspnea adequately. Hemodialysis induced a small fall in mean FEV₁ and FVC, which was more pronounced in patients with little or no fluid removal, but the FEV₁/FVC ratio and the number of subjects with airflow limitation indicative of COPD were not affected by dialysis.     

Xenobiotic Metabolism: The Effect of Acute Kidney Injury on Non-Renal Drug Clearance and Hepatic Drug Metabolism

Acute kidney injury (AKI) is a common complication of critical illness, and evidence is emerging that suggests AKI disrupts the function of other organs. It is a recognized phenomenon that patients with chronic kidney disease (CKD) have reduced hepatic metabolism of drugs, via the cytochrome P450 (CYP) enzyme group, and drug dosing guidelines in AKI are often extrapolated from data obtained from patients with CKD. This approach, however, is flawed because several confounding factors exist in AKI. The data from animal studies investigating the effects of AKI on CYP activity are conflicting, although the results of the majority do suggest that AKI impairs hepatic CYP activity. More recently, human study data have also demonstrated decreased CYP activity associated with AKI, in particular the CYP3A subtypes. Furthermore, preliminary data suggest that patients expressing the functional allele variant CYP3A5*1 may be protected from the deleterious effects of AKI when compared with patients homozygous for the variant CYP3A5*3, which codes for a non-functional protein. In conclusion, there is a need to individualize drug prescribing, particularly for the more sick and vulnerable patients, but this needs to be explored in greater depth.     

Recombinant Long-Acting Thioredoxin Ameliorates AKI to CKD Transition via Modulating Renal Oxidative Stress and Inflammation

An effective strategy is highly desirable for preventing acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Thioredoxin-1 (Trx), a redox-active protein that has anti-oxidative and anti-inflammatory properties, would be a candidate for this but its short half-life limits its clinical application. In this study, we examined the renoprotective effect of long-acting Trx that is comprised of human albumin and Trx (HSA-Trx) against AKI to CKD transition. AKI to CKD mice were created by renal ischemia-reperfusion (IR). From day 1 to day 14 after renal IR, the recovery of renal function was accelerated by HSA-Trx administration. On day 14, HSA-Trx reduced renal fibrosis compared with PBS treatment. At the early phase of fibrogenesis (day 7), HSA-Trx treatment suppressed renal oxidative stress, pro-inflammatory cytokine production and macrophage infiltration, thus ameliorating tubular injury and fibrosis. In addition, HSA-Trx treatment inhibited G2/M cell cycle arrest and apoptosis in renal tubular cells. While renal Trx protein levels were decreased after renal IR, the levels were recovered by HSA-Trx treatment. Together, HSA-Trx has potential for use in the treatment of AKI to CKD transition via its effects of modulating oxidative stress and inflammation.     

Ochratoxin a in pig kidney determined by enzyme-linked immunosorbent assay (elisa)

An indirect, double antibody enzyme-linked immunosorbent assay (ELISA) has been validated for application to pig kidney. The specificity of the anti-ochratoxin A antiserum employed is such that minimal sample preparation is required prior to assay, with consequent beneficial effects on sample throughput. Kidneys (303) obtained in the UK as being unsuitable for human consumption were examined for ochratoxin A content by ELISA. Of these, 191 (63%) contained no detectable toxin (the detection limit was 0.5 ng g^?1). Only eight samples (2.6%) contained more than 5 ng g^?1 ochratoxin A, and only two were above 10 ng g^?1 (at 11.5 and 12.4 ng g^?1). The significance of these findings is discussed.     

基于线粒体损伤机制的药物性急性肾损伤研究进展

药物性肾损伤约占急性肾损伤发病率的20%,易发展为肾衰竭。目前临床除了肾脏替代疗法,尚无有效的治疗措施。越来越多的证据表明线粒体结构和功能损伤在药物性急性肾损伤的发生发展中发挥了重要作用。本文就药物性急性肾损伤领域中线粒体损伤的相关机制、潜在的生物标志物以及可能的干预靶点的研究进展作一综述,以期为临床上药物性急性肾损伤的早期诊断和治疗提供新的思路。     

微创经皮肾镜取石术对肾血流动力学的影响

目的探讨微创经皮肾镜取石术（MPCNL）对肾血流动力学的影响。方法采用彩色多普勒血流显像（CDFI）观察并分析52例肾结石患者单通道MPCNL术前及术后1、3个月肾主动脉、段间动脉、叶间动脉收缩期峰值流速（S）与舒张期末流速（D）的比值（S/D）和阻力指数（RI）。结果术前肾主动脉、段间动脉、叶间动脉RI值分别为0.60±0.13、0.62±0.12、0.62±0.16;术后1个月肾主动脉、段间动脉、叶间动脉RI值分别为0.61±0.14、0.61±0.15、0.61±0.18;术后3个月肾主动脉、段间动脉、叶间动脉RI值分别为0.61±0.17、0.61±0.09、0.62±0.13。术前与术后1、3个月肾主动脉、段间动脉、叶间动脉S/D、RI值比较,差异均无统计学意义（P均〉0.05）。结论微创经皮肾镜取石术对肾血流动力学无影响,是治疗肾结石的一种安全的方法。     

庆大霉素诱导急性肾损伤大鼠模型肾损伤分子-1的表达

目的探讨庆大霉素(Gentamycin,GM)诱导急性肾损伤大鼠模型肾损伤分子-1(Kidney injury molecule-1,KIM-1)的表达。方法建立GM诱导大鼠急性肾损伤模型;检测各组大鼠血、尿各项生化指标;取大鼠肾组织,进行病理组织学观察;ELISA法检测各组大鼠尿液中KIM-1的分泌;RT-PCR法检测各组大鼠肾组织KIM-1mRNA的表达;免疫组织化学SP法检测各组大鼠肾组织KIM-1、α-平滑肌肌动蛋白(α-SMA)、波形蛋白(Vimentin)的表达。结果与对照组比较,模型组大鼠血、尿各项生化指标及病理组织学观察均出现不同程度的病变;ELISA检测显示,大鼠尿液中KIM-1的含量显著增高(P<0.05);RT-PCR检测显示,肾组织KIM-1mRNA表达上调(P<0.05),且呈时间依赖性;免疫组化法检测显示,KIM-1表达量随肾损伤加重而显著升高,且呈时间依赖性。结论 KIM-1具有良好的敏感性和特异性,可作为GM所致肾小管损伤的早期诊断标志物。     

Extracellular Vesicles as a Therapeutic Tool for Kidney Disease: Current Advances and Perspectives

Extracellular vesicles (EVs) have been described as important mediators of cell communication, regulating several physiological processes, including tissue recovery and regeneration. In the kidneys, EVs derived from stem cells have been shown to support tissue recovery in diverse disease models and have been considered an interesting alternative to cell therapy. For this purpose, however, several challenges remain to be overcome, such as the requirement of a high number of EVs for human therapy and the need for optimization of techniques for their isolation and characterization. Moreover, the kidney’s complexity and the pathological process to be treated require that EVs present a heterogeneous group of molecules to be delivered. In this review, we discuss the recent advances in the use of EVs as a therapeutic tool for kidney diseases. Moreover, we give an overview of the new technologies applied to improve EVs’ efficacy, such as novel methods of EV production and isolation by means of bioreactors and microfluidics, bioengineering the EV content and the use of alternative cell sources, including kidney organoids, to support their transfer to clinical applications.     

Dialysis patients treated with Epoetin α show improved exercise tolerance and physical function: A new analysis of the Canadian Erythropoietin Study Group trial

The risks/benefits of anemia treatment in dialysis patients have been redefined in the US Epoetin α label. This analysis was carried out to determine if increasing hemoglobin (Hb) levels improve exercise tolerance and physical function in anemic dialysis patients. This is a new analysis of the Canadian Erythropoietin Study Group trial, a double‐blind, randomized, placebo‐controlled trial in dialysis patients. Subjects were 18 to 75 years old, on hemodialysis for >3 months, and had a baseline Hb <9.0 g/dL. Patients with a history of diabetes mellitus, ischemic heart disease, or severe/uncontrolled hypertension were excluded. Patients were randomized to receive Epoetin α to a target Hb of 9.5 to 11.0 g/dL (n=40) or a target of 11.5 to 13.0 g/dL (n=38), or receive placebo (n=40). Results from patients in the Epoetin‐α–treated arms were combined for this analysis. Hb level, exercise tolerance (Treadmill Stress Test and 6‐Minute Walk Test) and patient‐reported physical function measures (Physical Summary domain from the Kidney Disease Questionnaire, and 4 domains from the Sickness Impact Profile) were reported at baseline and months 2, 4, and 6. Differences in measures were statistically significant for exercise tolerance (Treadmill Stress, P=0.0001) and patient‐reported physical function (Kidney Disease Questionnaire Physical, P=0.0001; Sickness Impact Profile Physical, P=0.0015) across all time points for Epoetin‐α–treated patients compared with placebo. Improvements were seen at 2 months and were maintained through months 4 and 6. Dialysis patients receiving Epoetin α showed improved exercise tolerance and physical function. These findings should be considered as physicians weigh the risks and benefits of treatment.