Kidney disease models:tools to identify mechanisms and potential therapeutic targets

Acute kidney injury （AKI） and chronic kidney disease （CKD） are worldwide public health problems affecting millions of people and have rapidly increased in prevalence in recent years. Due to the multiple causes of renal failure, many animal models have been developed to advance our understanding of human nephropathy. Among these experimental models, rodents have been extensively used to enable mechanistic understanding of kidney disease induction and progression, as well as to identify potential targets for therapy. In this review, we discuss AKI models induced by surgical operation and drugs or toxins, as well as a variety of CKD models （mainly genetically modified mouse models）. Results from recent and ongoing clinical trials and conceptual advances derived from animal models are also explored.

Severe mental disorders following anti-retroviral treatment in a patient on peritoneal dialysis: A case report and literature review

BACKGROUND Antiviral drugs are widely used in populations with viral infection caused by immunologic inadequacy.Because these drugs are mainly metabolized by the kidneys,patients with renal failure undergoing renal replacement therapy are prone to drug adverse effects and poisoning.Severe neurotoxicity caused by antiviral drugs is a rare but life-threatening complication.CASE SUMMARY This study reported one male patient on peritoneal dialysis who suffered from severe mental disorders after receiving an overdose of acyclovir and valacyclovir for the treatment of herpes zoster.The literature review suggested that hemodialysis is better than peritoneal dialysis to clear acyclovir from the circulation.The patient died after his consciousness deteriorated despite peritoneal dialysis and continuous blood purification.CONCLUSION This case emphasizes cautiousness when using anti-retroviral drugs in patients with uremia.Hemodialysis is optimal method to remove the drugs.

Can sacubitril/valsartan become the promising drug to delay the progression of chronic kidney disease?

1 Introduction Chronic kidney disease(CKD)often coexists with or is a complication of cardiovascular disease.Previous studies have shown that CKD increases the risk of cardiovascular death and all-cause death and was considered to be a risk equivalent of coronary heart disease.[1,2]Adjusted for confounders,decreased glomerular filtration rate(GFR)and increased albuminuria are both independent risk factors for cardiovascular events.[3,4]The risk for cardiovascular death linearly increases with the decline of GFR in a certain range(<70 mL/min per 1.73 m^2)and the increase of albuminuria without a threshold effect[3].

Influence of Peritoneal Transport Characteristics on Nutritional Status and Clinical Outcome in Chinese Diabetic Nephropathy Patients on Peritoneal Dialysis

Background： High peritoneal transport status was previously thought to be a poor prognostic factor in peritoneal dialysis （PD） patients. However, its effect on diabetic nephropathy PD patients is unclear in consideration of the adverse impact of diabetes itself. The purpose of this study was to investigate the influence of peritoneal transport characteristics on nutritional status and clinical outcome in diabetic nephropathy patients on PD. Methods： One hundred and two diabetic nephropathy patients on PD were enrolled in this observational cohort study. According to the initial peritoneal equilibration test result, patients were divided into two groups： Higher transport group （HT, including high and high average transport） and lower transport group （LT, including low and low-average transport）. Demographic characteristics, biochemical data, dialysis adequacy, and nutritional status were evaluated. Clinical outcomes were compared. Risk factors for death-censored technique failure and mortality were analyzed. Results： Compared with LT group （n = 37）, serum albumin was significantly lower and the incidence of malnutrition by subjective global assessment was significantly higher in HT group （n = 65） （P 〈 0.05）. Kaplan-Meier analyses showed that death-censored technique failure and mortality were significantly increased in HT group compared with that in LT group. On multivariate Cox analyses, higher peritoneal transport status and lower residual renal function （RRF） were independent predictors of death-censored technique failure when adjusted for serum albumin and total weekly urea clearance （Kt/V）. Independent predictors of mortality were advanced age, anemia, hypoalbuminemia, and lower RRF, but not higher peritoneal transport status. Conclusions： Higher peritoneal transport status has an adverse influence on nutrition for diabetic nephropathy patients on PD. Higher peritoneal transport status is a significant independent risk factor for death-censored technique failure, but not for mortality in diabetic nephropathy patients on PD.

雷帕霉素对小鼠百草枯中毒导致肺纤维化的治疗作用(英文)

目的:评估雷帕霉素(RAPA)对小鼠百草枯(PQ)中毒导致肺纤维化的治疗作用,并初步探讨其作用机制。创新点:首次在小鼠PQ中毒的模型中证明RAPA可明显抑制肺纤维化,且此作用与转化生长因子-β1(TGF-β1)的抑制相关。方法:将C57BL/6J雄鼠分为对照组(腹腔注射生理盐水)和实验组(腹腔注射10 mg/kg PQ)。实验组根据采用的治疗不同,可分为以下四组:PQ组、PQ+RAPA组、PQ+MP(甲强龙)组和PQ+MP+RAPA组。用苏木精-伊红染色法(H&E)和马松(Masson)三色染色法观察肺组织病理结构变化,用酶联免疫吸附测定(ELISA)试剂盒检测肺组织中的羟脯氨酸(HYP)含量,用免疫组化和免疫印迹的方法检测TGF-β1和α-平滑肌肌动蛋白(α-SMA)的表达水平。结论:本实验中小鼠的肺组织病理染色结果显示,RAPA治疗能缓解肺纤维化导致的病理改变(图3)。ELISA实验结果显示,RAPA治疗28天后可显著降低肺组织中HYP的含量(图4)。免疫组化和免疫印迹实验结果显示,RAPA治疗能明显下调肺组织中TGF-β1和α-SMA的高表达(图5和6)。综上所述,RAPA在治疗PQ中毒导致的肺纤维化中有重要价值。

使用斑马鱼模型比较山豆根不同有效部位的毒性(英文)

目的:利用斑马鱼模型评价和比较山豆根不同提取方法提取的有效部位的体内毒性。创新点:首次在斑马鱼模型中证明山豆根提取方法不同,有效部位的毒性有明显差异。研究结果有助于指导山豆根的新药开发与临床应用。方法:用五种不同的溶剂(去碱水、乙醇、正丁基乙醇、二氯甲烷和乙醚)提取山豆根,然后通过高效液相色谱法(HPLC)检测有效部位,将AB品系斑马鱼分为对照组(养鱼水处理)和实验组(山豆根提取物)。实验组根据采用的提取溶剂不同,分为以下六组:去碱水提取组、乙醇沉提取组、正丁基乙醇提取组、二氯甲烷提取组和乙醚提取组以及山豆根总组分组(对照),观察各种山豆根提取物对斑马鱼的急性毒性与毒性靶器官。结论:山豆根乙醚提取组诱发斑马鱼心血管毒性(图1);山豆根去碱水提取组、乙醇沉提取组以及山豆根总组分组诱发斑马鱼肝脏毒性(图3和图4);而山豆根正丁基乙醇提取组和二氯甲烷提取组诱发斑马鱼心血管毒性(图1和图2)和肝脏毒性(图3和图4)。

Complex Precipitation Sequences of Al-Cu-Li-(Mg)Alloys Characterized in Relation to Thermal Ageing Processes

The A1-Cu-Li-（Mg） alloy is a high-performance lightweight material strengthened by complex coexisting precipitates that form in the alloy upon thermal ageing. Using high-resolution （scanning） transmission electron microscopy in association with first-principles energy calculations, we systematically studied the complex coexisting precipitates in the alloys and correlated their precipitation sequences with thermal ageing processes applied. The principal results are the following： （1） eight types of precipitates can be observed in the alloy; （2） of these precipitates, the Tl-phase is most stable. The S-phase precipitates with segregated Li atoms at their interfacial edges are unexpectedly more stable than the a-phase; （3） the Tl-phase has a characteristic precursor that plays the key role in its nucleation and growth.

霉酚酸酯联合糖皮质激素诱导治疗过敏性紫癜性肾炎的回顾性研究（英文）

目的：合并中等量蛋白尿的过敏性紫癜性肾炎的诱导治疗尚无确切方案，本研究通过回顾性比较分析了霉酚酸酯联合糖皮质激素的疗效与安全性。创新点：首次对霉酚酸酯联合糖皮质激素诱导治疗过敏性紫癜性肾炎进行了回顾性研究。方法：回顾性分析2007年1月至2013年6月间在浙江大学附属第一医院肾脏病中心接受‘肾穿刺活检，且经过3个月以上血管紧张素转换酶抑制剂（ACEI）／血管紧张素受体拮抗剂（ARB）治疗后蛋白尿为1．0-3．5g／24h的过敏性紫癜性肾炎患者95例。根据治疗方案分为3组，霉酚酸酯组（33例）在原剂量ACEFARB的基础上加用霉酚酸酯联合低剂量糖皮质激素，糖皮质激素组（31例）在原剂量ACEFARB的基础上加用全剂量糖皮质激素，对照组（31例）维持单用ACEFARB治疗，但可提高其剂量。患者随访观察6～78月（中位观察时间28月），霉酚酸酯组、糖皮质激素组与对照组的蛋白尿缓解率分别为72．7％、64．5％与45．2％（图1），发生副作用分别为17例、30例与6例，糖皮质激素组高脂血症与高血压发生率较高（表3）。结论：霉酚酸酯联合低剂量糖皮质激素可有效诱导缓解过敏性紫癜性肾炎，其缓解率与全剂量糖皮质激素治疗相当，且副作用较少。

Revisiting the Hierarchical Microstructures of an Al-Zn-Mg Alloy Fabricated by Pre-deformation and Aging

Pre-deformation before aging has been demonstrated to have a positive effect on the mechanical strength of the 7N01 alloy in our previous study,which is rather different from the general negative effects of pre-deformation on high-strength 7XXX aluminum alloys.In order to explain the strengthening mechanism relating to the positive effect,in the present study,the microstructure of the aged 7N01 alloy with different degrees of pre-deformation was investigated in detail using advanced electron microscopy techniques.Our results show that,without pre-deformation,the aged alloy is strengthened mainly by the η′type of hardening precipitates.In contrast,with pre-deformation,the aged alloy is strengthened by the hierarchical microstructure consisting of the GP-η′type of precipitates formed inside sub-grains,the ηp type of precipitates formed at small-angle boundaries,and the dislocation introduced by pre-deformation(residual work-hardening effect).By visualizing the distribution of theηp precipitates through three-dimensional electron tomography,the 3 D microstructures of dislocation cells are clearly revealed.Proper combinations of ηp precipitates,GP-η′precipitates and residual dislocations in the alloy are responsible for the positive effect of pre-deformation on its mechanical properties.

吲哚美辛对小鼠肾缺血再灌注损伤的保护作用(英文)

研究目的:在小鼠模型中利用吲哚美辛阻断COX-1/2通路,探讨非甾体类抗炎药对肾缺血再灌注损伤的保护作用。创新要点:非甾体类抗炎药被认为具有肾毒性,本研究首次在小鼠模型中探讨非甾体类抗炎药对肾缺血再灌注损伤的保护作用。研究方法:小鼠左侧肾蒂夹闭后,通过腹腔注射不同剂量的吲哚美辛,在肾缺血再灌注损伤24小时后,获取血液和肾脏标本。利用酶联免疫(ELISA)试剂盒测定血清肌酐和细胞因子浓度来评估肾功能,肾组织样本进行苏木精-伊红染色和免疫组化分析。重要结论:腹腔注射吲哚美辛5 mg/kg组的小鼠血清肌酐值与对照组相比显著降低,肾小管损伤也显著减轻(见图1和2);腹腔注射5和7 mg/kg吲哚美辛组的小鼠血清肾肿瘤坏死因子-α和白介素-6的浓度显著降低(见图3a和3b);腹腔注射3和5 mg/kg吲哚美辛组的小鼠血清血栓素B2与6-酮前列腺素F1α的比值明显降低(见图3c);腹腔注射5 mg/kg吲哚美辛组小鼠肾组织COX-1和COX-2染色较弱(见图4)。因此,吲哚美辛对小鼠肾缺血再灌注损伤的作用与其剂量相关,在某个特定的剂量范围内具有肾保护作用。吲哚美辛对小鼠肾缺血再灌注损伤的保护作用与阻断COX-1/2有关。

0.9%盐水既不正常也不生理（英文）

本文旨在客观评价0.9%氯化钠溶液(盐水)的生物化学和病理生理学特性,并深入探讨静脉输注该盐水对机体酸碱平衡和肾脏血流动力学的影响。研究表明多数临床医生对电解质平衡的认识有限,对静脉输注盐水所引起的血浆电解质变化认识不足。而错误地应用盐水会增加患者的患病率和死亡率。健康成人大剂量(>2L)输注盐水会导致高氯血症并进而引起代谢性酸中毒、高钾血症和负氮平衡。总之,盐水是一种高度酸化的液体,用于治疗呕吐或上消化道减压引起的低氯性代谢性碱中毒和容量不足较为合适。临床上不加区分地应用盐水对患者特别是对重症患者可能导致不必要的并发症,应注意避免。临床医生对于盐水相关作用和电解质管理的认识亟需增强。

Synergistic Effect of Alloying Atoms on Intrinsic Stacking-Fault Energy in Austenitic Steels

Intrinsic stacking-fault energy is a critical parameter influencing the various mechanical performances of aus- tenitic steels with high Mn concentrations. However, quantitative calculations of the stacking-fault energy （SFE） of the face-centered cubic （fcc） Fe, including the changes in concentrations and geometrical distribution of alloying atoms, cannot be obtained by using previous computation models. On the basis of the interaction energy model, we evaluated the effects of a single alloying atom （i.e., Mn, A1, Si, C and N）, as well as its aggregates, including the Mn-X dimer and Mn2-X trimer （X = A1, Si, C and N） on the SFE of the fcc Fe via first-principle calculations. Given low concentrations （〈10 wt%） of alloying atoms, dimers and trimers, theoretical calculations reveal the following： （1） Alloying atom Mn causes a decrease in the SFE, whereas A1, Si, C and N significantly increase the SFE; （2） combination with other alloying atoms to form the Mn-X dimer （X = A1, Si, C and N） exerts an effect on SFE that, to a certain extent, is close to that of the corresponding single X atom; （3） the interaction between Mnz-X and the stacking fault is stronger than that of the corresponding single X atom, inducing a significant increase in the SFE of fcc Fe. The theoretical results we obtained demonstrate that the increase in SFE in high-Mn steel originates from the synergistic effect of Mn and other trace alloy atoms.

Optimized Combinatorial Properties of an AlMgSi(Cu) Alloy Achieved by a Mechanical-Thermal Combinatorial Process

Enhancing combinatorial properties,such as excellent corrosion resistance,high strength and good ductility combined,is an important issue for manufacturing high-quality AlMgSi(Cu)alloys.Here,we show that this can be achieved by optimizing a combinatorial process consisting of pre-ageing,cold-rolling and post-ageing to tailor the hierarchical microstructures of the alloy.Transmission electron microscopy analysis reveals that the enhanced combinatorial properties of corrosion resistance,strength and ductility are owing to modification of grain boundary microstructure in good association with changes of precipitate microstructures and a more homogenous distribution of solute atoms,as compared with the microstructures of the alloy processed by thermal ageing only.

PI-3 kinase pathway can mediate the effect of TGF-β1 in inducing the expression of SHARP-2 in LLC-PK1 cells

We aim to investigate the effect of transforming growth factor (TGF)-β1 on the expression of enhancer of split- and hairy-related protein-2 (SHARP-2) messenger RNA (mRNA) and its signaling pathway. In this study, several cell lines including LLC-PK1 (a porcine kidney tubular epithelial cell line), MDCK (Madin-Darby canine kidney) and CTLL-2 (cytotoxic T-lymphocyte line) were treated with recombinant human TGF-β1, and a series of experiments were carried out, involving Northern blot analysis of total RNA from these cells. Further, several specific chemical inhibitors were applied before TGF-β1 treatment to probe the signaling pathway. The results showed that TGF-β1 can significantly up-regulate SHARP-2 mRNA expression in the LLC-PK1 cell line. The peak level of induction was found 2 h after TGF-β1 stimulation. While one phospho-inositide 3-kinases (PI-3) kinase inhibitor, LY294002, completely blocked the effect of TGF-β1 on SHARP-2 mRNA expression in LLC-PK1 cells at a low concentration, other inhibitors, including PD98059, staurosporine, AG490, wortmannin, okadaic acid and rapamycin, had no effect. The effect of LY294002 was dose-dependent. We conclude that, in LLC-PK1 cells at least, TGF-β1 can effectively induce the SHARP-2 mRNA expression and that the PI-3 kinase pathway can mediate this effect.

Elastic Properties and Stacking Fault Energies of Borides, Carbides and Nitrides from First-Principles Calculations

Owing to the excellent elastic properties and chemical stability,binary metal or light element borides,carbides and nitrides have been extensively applied as hard and low-compressible materials.Researchers are searching for harder materials all the time.Recently,the successful fabrication of nano-twinned cubic BN(Tian et al.Nature 493:385–388,2013)and diamond(Huang et al.Nature 510:250–253,2014)exhibiting superior properties than their twin-free counterparts allows an efficient way to be harder.From this point of view,the borides,carbides and nitrides may be stronger by introducing twins,whose formation tendency can be measured using stacking fault energies(SFEs).The lower the SFEs,the easier the formation of twins.In the present study,by means of first-principles calculations,we first calculated the fundamental elastic constants of forty-two borides,seventeen carbides and thirty-one nitrides,and their moduli,elastic anisotropy factors and bonding characters were accordingly derived.Then,the SFEs of the{111}<112>glide system of twenty-seven compounds with the space group F43 m or Fm3m were calculated.Based on the obtained elastic properties and SFEs,we find that(1)light element compounds usually exhibit superior elastic properties over the metal borides,carbides or nitrides;(2)the 5 d transitionmetal compounds(ReB2,WB,OsC,RuC,WC,OsN2,TaN and WN)possess comparable bulk modulus(B)with that of cBN(B=363 GPa);(3)twins may form in ZrB,HfN,PtN,VN and ZrN,since their SFEs are lower or slightly higher than that of diamond(SFE=277 mJ/m^2).Our work can be used as a valuable database to compare these compounds.

Quantitative Electron Tomography for Accurate Measurement of Precipitates Microstructure Parameters in Al–Cu–Li Alloys

Mechanical theories show that properties of alloys are strongly dependent on the morphological parameters oftheir strengthening precipitates.However,accurate measurement of precipitates microstructure parameters is still a challenging task.In this article,we develop a quantitative electron tomography method by combining computer vision technology to accurately characterize the three-dimensional microstructure parameters,such as volume fractions,sizes and distributions,of the T_(1) and δ’/θ’/δ’ precipitates in Al-Cu-Li(-Mg) alloys.Since they have extremely large aspect-ratios in shape and large numbers in density upon formation in the Al matrix,these thin plate-like precipitates are difficult to be characterized quantitatively without the assistance of computer vision technology.It is shown that the property difference between two peak-aged states of the alloy can be well explained with the quantitative precipitate parameters correctly measured.Using these correct precipitate data,we also tested the validity of current mechanical models for projecting the contribution of precipitates to the strengths of the alloy,demonstrating that quantitative relations between strength and micro structure parameters still need to be refined.

Application of the Peierls–Nabarro Model to Symmetric Tilt Low-Angle Grain Boundary with Full Dislocation in Pure Magnesium

Three types of symmetric （1120） tilt low-angle grain boundaries （LAGBs） with array of basal, prismatic, and pyramidal edge full 〈a〉 dislocations in pure Mg have been studied by using the improved Peierls-Nabarro model in combination with the generalized stacking fault energy curve. The results show that with decreasing distance between the dislocations in all the three types of tilt LAGBs, the stress and strain fields are gradually suppressed. The reduction extent of the stress and strain fields decreases from the prismatic to basal to pyramidal dislocations. The variation of dislocation line energy （DLE） for all tilt LAGBs is divided into three stages： DLE changes slightly and linearly when the distance is larger than 300 A, - 10%; DLE declines exponentially and quickly when the distance goes from 300 to 100 A, ,- 70%; and finally, the descent speed lowers when the distance is smaller than 100 A and the dislocation core energy is nearly half of the DLE. The grain boundary energy （GBE） decreases when the tilt angle of LAGB increases from1 ° to 2° for all cases. The tilt LAGB consists of pyramidal dislocations always has the largest GBE, while that with array of prismatic dislo- cations has the smallest one in the whole range. The Peierls stress of dislocation in tilt LAGB is nearly unchanged, the same as that of single dislocation. This work is useful for further study of dissociated dislocation, solute segregation, precipitate nucleation in tilt LAGB and its interaction with single dislocations.

多囊肾患者行腹膜透析的预后分析（英文）

目的:探讨多囊肾致终末期肾病患者行腹膜透析治疗的预后情况。创新点:分析国内最大一组单中心样本关于多囊肾患者行腹膜透析治疗的预后研究,进一步证实多囊肾并非腹膜透析的禁忌症。方法:回顾性分析2007年7月1日至2014年7月31日于我院置管并开始维持性腹膜透析的30例多囊肾致终末期肾病患者,选择30例年龄及性别与多囊肾组匹配的非多囊肾患者作为对照组。记录患者一般资料、透析初始资料、并发症、生存时间、退出透析或死亡等治疗结局。采用Kaplan-Meier法和log-rank检验进行生存分析。结论:多囊肾组3年病人生存率和技术生存率分别为90.6%和89.2%,对照组为86.3%和74.3%,差异无统计学意义(图1和2)。两组患者的腹膜炎发生率分别为0.19次/病人年和0.21次/病人年(表3)。两组患者腹透液渗漏、疝气、心脑血管事件发生率之间的差异均无统计学意义(表4)。综上所述,通过合理的病人筛选和评估,多囊肾不是腹膜透析的禁忌症。

Double-Shelled L1_(2) Nano-structures in Quaternary Al–Er–Sc–Zr Alloys: Origin and Critical Significance

The formation of highly coherent double-shelled L1_(2) nano-precipitates in dilute Al–Er–Sc–Zr alloys was investigated with the combined use of Cs-corrected transmission electron microscopy characterization and first-principles energetics calculations. The double-shelled nano-precipitates are primarily featured with an Er-rich core surrounded by a Sc-rich inner shell and a Zr-rich outer shell. First-principles energetics analyses based on the classic homogenous nucleation theory suggested that once forms, this double-shell structure can be thermally stable. The predominant formation of this double-shell structure has thus both profound kinetic and thermodynamic origins. Its formation and stability preference to all other possible L1_(2) nano-structures would become more pronounced as its size increases, no matter what the solute ratio and aging temperature of interest.

端粒缺陷相关因子和人类IgA肾病的关系(英文)

研究目的:分析在中国人群中,端粒缩短以及相关衰老因子与人类IgA肾病发生进展的关系。创新要点:目前的研究发现,端粒功能缺陷是限制分裂增殖、细胞衰老的重要分子机制。它不仅仅与衰老相关,而且在疾病的发生、进展过程中都有直接影响。肾脏的正常衰老过程伴随端粒逐渐缩短,端粒功能缺陷可以加速慢性肾脏疾病进程,并伴随相关衰老因子cathelin相关抗菌肽(CRAMP)、延长因子-1α(EF-1α)、几丁质酶(chitinase)和微管不稳定蛋白(stathmin)等表达增加。本项研究首次在中国人群中,揭示端粒缩短以及相关衰老因子与人类IgA肾病发生进展的关系。研究方法:采用双盲法,以IgA肾病患者(n=177)为实验组,以狼疮肾炎(n=50)、糖尿病肾病(n=30)和局灶节段性肾小球硬化(n=30)病人以及健康人(n=83)为对照组,通过定量荧光原位杂交(qFISH)检测了肾脏组织的端粒长度,并通过酶联免疫吸附试验(ELISA)检测了血液、尿液中的CRAMP、EF-1α、stathmin的含量,运用几丁质酶试剂盒(CS1030)检测了血液、尿液中几丁质酶的酶活性,运用免疫荧光染色检测了组织中CRAMP的表达情况。重要结论:端粒缩短和相关炎症蛋白与IgA肾病的发生发展有关,并为IgA肾病的特异性诊断和及预后评估提供可靠的研究基础。