Blood Kidney Injury Molecule-1 Is a Biomarker of Acute and Chronic Kidney Injury and Predicts Progression to ESRD in Type I Diabetes

Currently, no blood biomarker that specifically indicates injury to the proximal tubule of the kidney has been identified. Kidney injury molecule-1 (KIM-1) is highly upregulated in proximal tubular cells following kidney injury. The ectodomain of KIM-1 is shed into the lumen, and serves as a urinary biomarker of kidney injury. We report that shed KIM-1 also serves as a blood biomarker of kidney injury. Sensitive assays to measure plasma and serum KIM-1 in mice, rats, and humans were developed and validated in the current study. Plasma KIM-1 levels increased with increasing periods of ischemia (10, 20, or 30 minutes) in mice, as early as 3 hours after reperfusion; after unilateral ureteral obstruction (day 7) in mice; and after gentamicin treatment (50 or 200 mg/kg for 10 days) in rats. In humans, plasma KIM-1 levels were higher in patients with AKI than in healthy controls or post-cardiac surgery patients without AKI (area under the curve, 0.96). In patients undergoing cardiopulmonary bypass, plasma KIM-1 levels increased within 2 days after surgery only in patients who developed AKI (P<0.01). Blood KIM-1 levels were also elevated in patients with CKD of varous etiologies. In a cohort of patients with type 1 diabetes and proteinuria, serum KIM-1 level at baseline strongly predicted rate of eGFR loss and risk of ESRD during 5–15 years of follow-up, after adjustment for baseline urinary albumin-to-creatinine ratio, eGFR, and Hb1Ac. These results identify KIM-1 as a blood biomarker that specifically reflects acute and chronic kidney injury.     

肾移植患者他克莫司血药浓度与肝肾毒性分析

目的分析我院肾移植患者他克莫司血药浓度的控制情况,探讨他克莫司血药浓度与肝肾功能之间的关系,以期为临床的合理用药提供依据。方法收集我院2011年11月至2013年4月96例肾移植患者他克莫司血药浓度的数据,及血药浓度测定当天的生化检测结果。根据他克莫司血药浓度（A）测定结果,将其分为4组（I组,A≤6 ng/mL;II组,6〈A≤10 ng/mL;III组,10〈A≤15 ng/mL;IV组,A〉15 ng/mL）,对4组中的各项生化指标及不良反应比例进行统计分析。结果红细胞（P=0.57）,血红蛋白（P=0.60）,血小板（P=0.12）,总胆红素（P=0.58）,谷氨酰基转移酶（P=0.46）,天门冬氨酸氨基转移酶（P=0.98）和丙氨酸氨基转移酶（P=0.40）在4组之间没有统计学意义;而白细胞（P=0.007）,碱性磷酸酶（P=0.004）和血尿素氮（P=0.007）在4组之间差异有统计学意义。当患者的他克莫司血药浓度维持在6-15 ng/mL 时,其肾小球滤过率估计值（estimated glo-merular filtration rate,eGFR）（70.2 mL/min）要明显高于≤6 ng/mL（58.2 mL/min）和〉15 ng/mL （66.2 mL/min）。同时,感染及中重度贫血的风险也较低,但他克莫司血药浓度与肝功能异常比例之间未发现显著的相关性。结论他克莫司血药浓度维持在6-15 ng/mL有利于患者肾功能的维持,同时能够降低感染和中重度贫血的风险,这一结果将有利于他克莫司的临床使用。     

Naringin ameliorates gentamicin-induced nephrotoxicity and associated mitochondrial dysfunction,apoptosis and inflammation in rats: Possible mechanism of nephroprotection

Gentamicin-induced nephrotoxicity has been well documented, although its underlying mechanisms and preventive strategies remain to be investigated. The present study was designed to investigate the protective effect of naringin, a bioflavonoid, on gentamicin-induced nephrotoxicity and to elucidate the potential mechanism. Serum specific renal function parameters (blood urea nitrogen and creatinine) and histopathology of kidney tissues were evaluated to assess the gentamicin-induced nephrotoxicity. Renal oxidative stress (lipid peroxidation, protein carbonylation, enzymatic and non-enzymatic antioxidants), inflammatory (NF-kB [p65], TNF-α, IL-6 and MPO) and apoptotic (caspase 3, caspase 9, Bax, Bcl-2, p53 and DNA fragmentation) markers were also evaluated. Significant decrease in mitochondrial NADH dehydrogenase, succinate dehydrogenase, cytochrome c oxidase and mitochondrial redox activity indicated the gentamicin-induced mitochondrial dysfunction. Naringin (100 mg/kg) treatment along with gentamicin restored the mitochondrial function and increased the renal endogenous antioxidant status. Gentamicin induced increased renal inflammatory cytokines (TNF-α and IL-6), nuclear protein expression of NF-κB (p65) and NF-κB-DNA binding activity and myeloperoxidase (MPO) activity were significantly decreased upon naringin treatment. In addition, naringin treatment significantly decreased the amount of cleaved caspase 3, Bax, and p53 protein expression and increased the Bcl-2 protein expression. Naringin treatment also ameliorated the extent of histologic injury and reduced inflammatory infiltration in renal tubules. U-HPLS-MS data revealed that naringin co-administration along with gentamicin did not alter the renal uptake and/or accumulation of gentamicin in kidney tissues. These findings suggest that naringin treatment attenuates renal dysfunction and structural damage through the reduction of oxidative stress, mitochondrial dysfunction, inflammation and apoptosis in the kidney.     

Nephroprotective effect of astaxanthin against trivalent inorganic arsenic-induced renal injury in wistar rats

Inorganic arsenic (iAs) is a toxic metalloid found ubiquitously in the environment. In humans, exposure to iAs can result in toxicity and cause toxicological manifestations. Arsenic trioxide (As₂O₃) has been used in the treatment for acute promyelocytic leukemia. The kidney is the critical target organ of trivalent inorganic As (iAs^III) toxicity. We examine if oral administration of astaxanthin (AST) has protective effects on nephrotoxicity and oxidative stress induced by As₂O₃ exposure (via intraperitoneal injection) in rats. Markers of renal function, histopathological changes, Na⁺-K⁺ ATPase, sulfydryl, oxidative stress, and As accumulation in kidneys were evaluated as indicators of As₂O₃ exposure. AST showed a significant protective effect against As₂O₃-induced nephrotoxicity. These results suggest that the mechanisms of action, by which AST reduces nephrotoxicity, may include antioxidant protection against oxidative injury and reduction of As accumulation. These findings might be of therapeutic benefit in humans or animals suffering from exposure to iAs^III from natural sources or cancer therapy.     

利用1H-NMR技术研究大黄素染毒后大鼠内源性代谢物的改变

目的 采用¹H NMR的代谢组学技术揭示大黄素的肾毒性机制,寻找肾脏损害的早期生物标志物.方法 雄性SD大鼠20只,随机分为溶剂对照,大黄素170、500、1 500 mg/(kg·d)3个剂量组,连续给药16 d,给药结束后收集24 h尿液,血浆及肾组织,测定¹H NMR谱,并进行血浆生化指标测定和肝脏组织病理学检查.结果 1 500 mg/(kg·d)大黄素服用16 d可引起大鼠血肌酐下降,大黄素可导致肾细胞胞浆中出现明显的空泡化改变.代谢成分的改变主要表现为血液中乳酸、糖、氨基酸和脂肪酸成分下降;尿液中乳酸、糖和氨基酸成分增加;肾脏组织中醋酸盐和肌酐/肌酸明显升高,乳酸和胆碱/磷酸卵磷脂水平下降,饱和与不饱和脂肪酸及磷脂的成分比例明显改变.结论 代谢组学分析在识别药物诱导代谢成分改变方面较传统技术更灵敏;脂肪和能量代谢紊乱参与了大黄素的肾毒性,尿液中氨基酸、葡萄糖氧化三甲胺(TMAO)及肌酐可作为大黄素诱导肾组织损害的潜在生物标志物.     

Effect of renal angioembolization on post-traumatic acute kidney injury after high-grade renal trauma: A comparative study of 52 consecutive cases

Background

Acute kidney injury (AKI) is associated with unfavourable outcomes and higher mortality after trauma. Renal angioembolization (RAE) has proved efficiency in the management of high-grade renal trauma (HGRT), but inevitably expose to unavoidable ischaemic areas or contrast medium nephrotoxicity which may impair renal function in the following hours. The aim of this study was to assess the potential acute impact of RAE on renal function in a consecutive series of HGRTs treated nonoperatively.

Materials and methods

Of 101 cases of renal trauma admitted to our Regional Trauma Center between January 2005 and January 2010, 52 cases of HGRT were treated nonoperatively; they were retrospectively classified into 2 groups according to whether RAE was used. Incidence and progression of AKI (RIFLE classification), maximum increase in serum creatinine (SCr), level since admission and recovery of renal function at discharge were compared between the groups. Multivariable analysis was performed to determine the role of RAE as an independent risk factor of AKI.

Results

RAE was performed in 10 patients within the first 48 h. The RAE and no RAE groups were comparable in terms of severity score, renal injury grade, and level of SCr on admission. AKI incidence (RIFLE score Risk or worse) after 48 and 96 h was 33% and 10%, respectively and did not differ significantly between groups at 48 h (p = 1.00) or 96 h (p = 1.00). The median maximum increase in SCr was significantly higher in no RAE than RAE group (30.4% vs. 6.9%, p = 0.04). RAE was not found to be a significant variable in a multiple linear regression analysis predicting maximum SCr rise (p = 0.34). SCr at discharge was >120% of baseline in only 5 patients, with no difference according to RAE (p = 0.24).

Conclusion

In a population of nonoperatively treated HGRT, the incidence of AKI decreased from almost 30% to 10% at 48 h and 96 h. RAE proceeding did not seem to affect significantly the occurrence and course of AKI or renal recovery. The decision to use RAE should probably not be restricted by fear of worsening renal function.     

Ameliorative effect of ferulic acid against renal injuries mediated by nuclear factor-kappaB during glycerol-induced nephrotoxicity in Wistar rats

The pathogenesis of glycerol-induced myoglobinuric acute renal failure involves ischemia, vascular congestion and reactive oxygen metabolites. In this study, we have investigated for the first time, the role of ferulic acid in attenuating glycerol-induced nephrotoxicity. Male Wistar rats were injected intramuscularly with 8?mL/kg body weight of 50% glycerol, glycerol?+?ferulic acid at the dose of 5, 10, 15, 20 and 25?mg/kg body weight. After 24?h, the rats were sacrificed and the kidneys were removed for histological and immunohistochemical studies. Furthermore, determinations of lipid peroxidation (LPO) as well as antioxidant enzymes were also analyzed; blood, urine samples were collected in order to quantify renal function and nitric oxide generation, respectively. Glycerol-induced rats showed a significant increase in the level of urinary markers assessed in serum as well as kidney and these were reversed upon ferulic acid treatment. A significant increase in urine nitric oxide, serum as well as kidney LPO, decrease in activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase and reduced glutathione were observed in glycerol-induced rats. Immunohistochemical study in glycerol-induced rats demonstrated an increase in the level of nuclear factor-kappaB (NF-κB). All these effects induced by glycerol were reduced upon treatment with ferulic acid in a dose-dependent manner. To conclude, ferulic acid enhances antioxidants and decreases NF-κB, thereby protecting the cells against stress induced by glycerol.     

Mechanochemical prepared ibuprofen-Polygonatum sibiricum polysaccharide drug delivery system for enhanced bioactivity with reduced renal injury induced by NSAIDs

Ibuprofen (IBU) was a widely used NSAID (a type of nonsteroidal anti-inflammatory drug) worldwide, and many drug deliveries had been reported to enhance bioavailability. However, higher bioavailability would increase the danger of renal injury caused by oxidative stress. This study prepared IBU-Polygonatum sibiricum polysaccharide (IBU-PSP) drug delivery system via mechanochemical method. Due to drug delivery and renal protection effect of Polygonatum sibiricum polysaccharide (PSP), the solubility of IBU-PSP was increased 8.22 times, and the bioavailability was increased 2.52 times compared with IBU, carrageenin-induced rat paw edema test also increased. Meanwhile, short-term and long-term renal injuries induced by IBU were notable decreases. In conclusion, IBU-PSP was a multifunctional drug delivery system with superior anti-inflammatory and renal protection effects. It will benefit from developing high-efficiency NADIs preparations with safer clinical applications while providing an efficient and energy-saving technology for polysaccharide drug delivery.     

Beagle犬药物诱导急性肾损伤模型的研究

目的 建立顺铂诱导的Beagle犬急性肾损伤模型,为开展肾毒性生物标志物研究奠定基础.方法 通过对Beagle犬单次静脉注射3、4和5 mg/kg顺铂,探讨采用顺铂建立急性肾小管损伤模型的给药方案.密切观察动物给药后临床症状,测定不同时间点的传统血清及尿液新型肾损伤生物标志物的动态变化,在试验结束时解剖动物并进行肾脏组...