联合检测血清NGAL、KIM-1和SCr可有效提高慢性肾病分期诊断

为了探讨中性粒细胞明胶酶相关脂质运载蛋白(neutrophil gelatinase-associated lipocalin, NGAL)和肾损伤分子-1 (kidney injury molecule-1, KIM-1)以及血肌酐(serum creatinine, SCr)联合检测对慢性肾病(chronic kidney disease, CKD)的早期诊断价值,本研究收集260例肾病患者和85例健康体检者,检测其血清NGAL、KIM-1和SCr水平。依据肾功能分级标准,CKD患者分为CKD 1期(53例),CKD 2期(68例),CKD 3期(71例),CKD 4期(46例)和CKD 5期(22例),并分析以上指标在各组间的含量差异,及其联合测定对CKD早期的敏感性。与健康对照组相比较,CKD 1期、CKD 2期、3期、4期和5期患者的NGAL、KIM-1水平均明显升高(p<0.001)。血清SCr含量在CKD 3期、4期和5期组较健康对照组显著增加(p<0.001)。以上3项指标均随着CKD严重程度增加而升高。各组指标阳性率分析显示,3项联合检测阳性率高于单项检测阳性率。ROC曲线分析NGAL、KIM-1、SCr对CKD诊断的AUC值F分别是为0.824、0.805、0.856。相关性分析结果显示,GFR和NGAL、KIM-1、SCr相关系数分别是r=-0.784、-0.756、-0.728 (p<0.05)。NGAL与KIM-1、SCr的相关系数分别是r=0.932、0.764 (p<0.05);KIM-1与SCr的相关系数r分别是0.791 (p<0.05)。本研究初步得出结论:血清NGAL、Kim-1可作为CKD早期诊断的重要指标,联合检测血清NGAL、Kim-1、SCr可有效提高CKD早期肾损伤诊断的敏感度,对CKD的分期诊断和治疗具有极其重要的临床价值。     

Urine as a source for clinical proteome analysis: From discovery to clinical application

The success of clinical proteome analysis should be assessed based on the clinical impact following implementation of findings. Although there have been several technological advancements in mass spectrometry in the last years, these have not resulted in similar advancements in clinical proteomics. In addition, application of proteomic biomarkers in clinical diagnostics and practical improvement in the disease management is extremely rare. In this review, we discuss the relevant issues associated with identification of robust biomarkers of clinical value. Urine appears to be an ideal source of biomarkers, for theoretical, methodological, and practical reasons. Therefore, this review is focused on the search for biomarkers in urine within the last decade. Urine can be used for non-invasive assessment of a variety of diseases including those affecting the urogenital tract and also other pathologies such as cardiovascular disease or appendicitis. We also discuss the importance of data validation, an essential step in translating biomarkers into the clinical practice. Furthermore, we examine several examples of apparently successful proteomic biomarker discovery studies and their implications for disease diagnosis, prognosis, and therapy evaluation. We also discuss some current challenges in this field and reflect on future research prospects. This article is part of a Special Issue entitled: Biomarkers: A Proteomic Challenge.     

Association study of CD36 single nucleotide polymorphisms with essential hypertension in the Northeastern Han Chinese

We found that cluster determinant 36 (CD36) gene is up-regulated in essential hypertension (EH) patients in our former research, but the association between CD36 gene variations and EH has not yet been clearly demonstrated. The relationship between CD36 gene single nucleotide polymorphisms (SNPs) and EH in the northeastern Han Chinese was examined in the present study through direct sequencing and genotype-detection. A total of 589 unrelated northeastern Han Chinese including 276 with EH and 313 controls were studied. SNPs in exon 7, exon 13 and intron 4 were detected using PCR-sequencing. The genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). + 216T/C, + 273A/G, + 132C/T, + 217T/C, + 212T/G and + 233T/C polymorphisms were identified. Distributions of genotypes AA, GA and GG of + 273A/G polymorphism were significantly different between EH group and the control group (χ²: 9.056, p = 0.011) and G allelic frequency was higher in EH (p = 0.006, OR = 1.629, 95% CI [1.224–2.168]). Logistic regression analysis showed that + 273A/G polymorphism was closely associated with blood pressure (BP) after adjusting for ages. When subclassified by sex, the genotype distribution of + 273A/G (p = 0.011) and allelic frequency of G allele (p = 0.006) were significantly different between EH participants and controls in males, but not in females. Subgroup analysis performed by body mass index (BMI) suggested that the genotype distribution of + 273A/G and allelic frequency were significantly different in non-obese group and non-obese men, but the associations were not significant (non-obese group: p = 0.016, OR = 1.664, 95% CI [1.459–2.409]; non-obese men: p = 0.073, OR = 1.898, 95% CI [1.033–3.487]). + 273A/G polymorphism in CD36 gene was associated with EH, and + 273G could be an independent predictor.     

Discovery of 1-(4-((3-(4-methylpiperazin-1-yl)propyl)amino)benzyl)-5-(trifluoromethyl)pyridin-2(1H)-one,an orally active multi-target agent for the treatment of diabetic nephropathy

Oxidative stress, inflammation and fibrosis can cause irreversible damage on cell structure and function of kidney and are key pathological factors in Diabetic Nephropathy (DN). Therefore, multi-target agents are urgently need for the clinical treatment of DN. Using Pirfenidone as a lead compound and based on the previous research, two novel series (5-trifluoromethyl)-2(1H)-pyridone analogs were designed and synthesized. SAR of (5-trifluoromethyl)-2(1H)-pyridone derivatives containing nitrogen heterocyclic ring have been established for in vitro potency. In addition, compound 8, a novel agent that act on multiple targets of anti-DN with IC₅₀ of 90 μM in NIH3T3 cell lines, t_1/2 of 4.89 ± 1.33 h in male rats and LD₅₀ > 2000 mg/kg in mice, has been advanced to preclinical studies as an oral treatment for DN.     

血液中肾损伤分子-1(KIM-1)和血清肌酐(SCr)对AKI的生物标志物作用

为了探讨血液中肾损伤分子-1 (KIM-1)和血清肌酐(SCr)的表达对外科术后急性肾损伤(AKI)的早期诊断价值,本研究选取医院内2018年3月至2019年3月进行外科手术的患者48例,分为AKI组患者即实验组12例,非AKI组患者即对照组36例,收集所有患者手术后0、3 h、6 h、9 h、12 h、24 h、48 h和72 h的血液样本,检测各个时间点血液中KIM-1和血清肌酐SCr水平,将血液中KIM-1与血清肌酐SCr水平进行相关统计学分析,绘制受试者工作特征曲线(ROC),探究并对比血液中KIM-1和血清肌酐的表达对外科手术后患者发生AKI的早期诊断价值。本研究数据显示,AKI组患者在手术后(3 h, 6 h, 9 h, 12 h)血液中KIM-1水平都高于0 h基准值,并且在6 h达到最大值;与此同时,AKI组患者手术后(0, 3 h, 6 h, 9 h)血液中KIM-1水平明显高于非AKI组患者。AKI组患者手术后血液中KIM-1 (0, 3 h, 6 h, 9 h)水平和手术后24 h的血清肌酐SCr水平呈正相关。本研究表明,3~9 h血液中KIM-1水平升高对患者外科手术后AKI的发生具备较高的诊断价值,血液中KIM-1可以作为早期诊断患者外科手术后发生AKI的一项生物标志物,且血清肌酐SCr的观测效率明显低于血液中KIM-1,可作为辅助诊疗手段。