Adenine‐induced chronic kidney disease in rats

Many animal models have been developed to study the causes and treatments of chronic kidney disease (CKD) in humans, an insidious disease resulting from kidney injury and characterized by persistent functional decline for more than 3 months, with or without evidence of structural deficit. The eventual outcome of CKD may be end‐stage kidney disease (ESKD), where patients need dialysis or transplantation to survive. Cardiovascular disease is accelerated in patients with CKD and contributes to increased mortality, with the relationship between CKD and cardiovascular disease being bi‐directional. Most animal models do not mimic the complexity of the human disease as many do not develop CKD‐associated cardiovascular disease. The adenine diet model of CKD in rodents is an exception. The original adenine diet model produced rapid‐onset kidney disease with extensive tubulointerstitial fibrosis, tubular atrophy, crystal formation and marked vessel calcification. Since then, lower adenine intake in rats has been found to induce slowly progressive kidney damage and cardiovascular disease. These chronic adenine diet models allow the characterization of relatively stable kidney and cardiovascular disease, similar to CKD in humans. In addition, interventions for reversal can be tested. Here the key features of the adenine diet model of CKD are noted, along with some limitations of other available models. In summary, the data presented here support the use of chronic low‐dose adenine diet in rats as an easy and effective model for understanding human CKD, especially the links with cardiovascular disease, and developing potential therapeutic interventions.     

慢性肾脏病患者血栓调节蛋白与动脉粥样硬化的相关性

目的 探讨慢性肾脏病(CKD)患者血栓调节蛋白（Tm）水平与动脉粥样硬化（AS）的相关性。 方法 以北京朝阳医院肾内科住院的96例CKD患者为对象,其中血液透析32例,非透析64例;30例健康志愿者为对照。参试者均于清晨空腹采静脉血,分别测定Scr、胆固醇、三酰甘油、高密度脂蛋白、低密度脂蛋白、C反应蛋白、血红蛋白及血栓调节蛋白。应用彩色多普勒超声检测颈动脉内膜中层厚度（IMT）。对血栓调节蛋白与IMT及相关参数进行相关分析。 结果 CKD患者血栓调节蛋白为（12.15±3.04） mg/L,显著高于健康对照组的（3.12±0.23） mg/L（P < 0.01）。血液透析组血栓调节蛋白为（16.89±3.35） mg/L,显著高于非透析组的（9.78±2.49） mg/L（P < 0.01）。血液透析组IMT值为（1.13±0.31） mm,斑块检出率为48.5%,均显著高于非透析治疗组的（0.95±0.33） mm和28.7%（均P < 0.05）。96例CRF患者的Tm水平与IMT呈正相关（r = 0.335,P < 0．01）。动脉病变程度越重者,血浆Tm水平越高。多元逐步回归分析结果显示,Tm（OR=1.13,95%CI 1.010~1.121）、SBP（OR=1.09,95%CI 1.009~1.114）、CRP（OR=1.22,95%CI 1.216~2.007）分别与CKD患者IMT独立相关。 结论 CKD患者Tm水平与IMT独立相关。血管内皮细胞损伤与CKD患者动脉粥样硬化并发症密切相关。Tm有可能成为血管内皮细胞损伤或功能紊乱的标志物。     

Estrogen and estrogen receptors in kidney diseases

Acute kidney injury (AKI) and chronic kidney disease (CKD) are posing great threats to global health within this century. Studies have suggested that estrogen and estrogen receptors (ERs) play important roles in many physiological processes in the kidney. For instance, they are crucial in maintaining mitochondrial homeostasis and modulating endothelin-1 (ET-1) system in the kidney. Estrogen takes part in the kidney repair and regeneration via its receptors. Estrogen also participates in the regulation of phosphorus homeostasis via its receptors in the proximal tubule. The ERα polymorphisms have been associated with the susceptibilities and outcomes of several renal diseases. As a consequence, the altered or dysregulated estrogen/ERs signaling pathways may contribute to a variety of kidney diseases, including various causes-induced AKI, diabetic kidney disease (DKD), lupus nephritis (LN), IgA nephropathy (IgAN), CKD complications, etc. Experimental and clinical studies have shown that targeting estrogen/ERs signaling pathways might have protective effects against certain renal disorders. However, many unsolved problems still exist in knowledge regarding the roles of estrogen and ERs in distinct kidney diseases. Further research is needed to shed light on this area and to enable the discovery of pathway-specific therapies for kidney diseases.     

普乐布考治疗慢性肾脏疾病的疗效观察

目的观察普罗布考对以肾小动脉硬化为主要病变的慢性肾脏疾病（CKD）的治疗作用。方法采用回顾性对比分析．观察52例病因为为高血压肾病和糖尿病肾脏病的CKD患者服用普罗布考的疗效。并设对照组49例。两组基础疾病及基本治疗相似,对照组未用普罗布考,观察9个月。应用硫代巴比妥酸比色法测定血清丙二醛（malondialdehyde,MDA）;常规生化疗法检测尿蛋白定量、肾功能（GFR、BUN、SCr）及血脂（TC、TG）;用Friedwald公式计算低密度脂蛋白胆固醇（LDLC）.采用方差分析及t检验进行统计学处理。结果观察9个月后,治疗组MDA、TC、TG、LDL-C、均下降,尿蛋白定量减少,CIFR、BUN及SCr等指标改善。对照组MDA、血脂无变化。结论普罗布考能够通过抗氧化应激及降脂作用减轻高血压肾脏病和糖尿病肾病的肾脏损伤,延缓CKD进展。     

Correlation of kidney size with kidney function and anthropometric parameters in healthy subjects and patients with chronic kidney diseases

Abstract

Background/Aim: Echosonography is a simple, noninvasive method of kidney visualization. The objective of this study was to compare the kidney echosonograpic characteristics with the kidney function and anthropometric characteristics in healthy subjects and patients with the chronic kidney disease (CKD). Methods: The study involved 49 patients (21 men; 46.02?±?14.27 years) with CKD and the control group of 46 healthy persons (20 males; 45.45?±?18.48 years). Physical examination, kidney echosonography and laboratory analyses including creatinine clearance (Ccr; 24?h and calculated by Cockroft--Gault (C--G) formula) were done in all persons. Results: There was no significant difference in age and sex between two groups but serum creatinine concentration was significantly higher (218.8 vs. 84.5?μmol/L) and Ccr significantly lower (66.44 vs. 94.20?mL/min, C--G) in patient group. The left kidney was larger in both groups, but the only significant difference was in kidney depth (p?<?0.01). There was significant correlation between all measured kidney dimensions, volume, parenchymal thickness and serum creatinine concentration and Ccr (C--G) in patient group. In the controls, there was no significant correlation between the kidney size and function, but there was a significant correlation between the kidney width, depth, volume and patients’ age and anthropometric parameters. On the contrary, all analyzed parameters of kidney size, except volume, did not correlate significantly with the anthropometric parameters of patients. Conclusion: Kidney size of patients with CKD correlated significantly with kidney function, while correlation with anthropometric parameters, which is otherwise present in healthy subjects, was lost in patients with CKD.     

慢性肾脏病患者骨骼肌萎缩与自噬间关系的初步探讨

目的 观察慢性肾脏病(CKD)患者骨骼肌萎缩现象,并初步探讨自噬在骨骼肌萎缩中的可能作用.方法 对2012年本市4家医院确诊为CKD5期的22例尿毒症患者在腹膜透析置管术中行腹直肌活检.将8例诊断为子宫腺肌病并拟行经腹全子宫切除术患者及6例确诊为腹壁疝并拟行腹壁疝修补术患者设为对照组,于手术时留取少许腹直肌标本.所有标本行HE染色,观察肌纤维形态并计算肌纤维横截面积,透射电子显微镜检测骨骼肌自噬小体.采用RT-PCR法及Western印迹法分别检测自噬相关基因微管相关蛋白1轻链3B(LC3B)、Beclin-1及Bcl2-腺病毒E1B结合蛋白3(Bnip3)的mRNA及蛋白表达情况.结果 CKD患者腹直肌肌纤维的横截面积显著小于对照组[(2982.20± 629.42) μm2比(3928.01±836.9)μm2,t=-2.86,P＜0.05],LC3B、Beclin-1及Bnip3的mRNA表达量显著高于对照组(t=2.23、3.50、6.76,均P＜0.05),且LC3B(Ⅰ及Ⅱ型)、Beclin-1、Bnip3的蛋白表达量亦显著高于对照组(t=3.51、3.97、2.46、2.49,均P＜0.05).电镜检查发现CKD患者腹直肌中存在大量的自噬小体,而对照组少见.结论 CKD患者存在骨骼肌萎缩及自噬活化现象,推测自噬活化可能参与了CKD患者骨骼肌萎缩的发生.     

成纤维细胞生长因子23与慢性肾脏病中晚期患者冠状动脉钙化的关系

目的 探讨慢性肾脏病（CKD）中晚期患者血成纤维细胞生长因子23（FGF23）水平与冠状动脉钙化的关系。 方法 2010年4月至12月我院肾脏科病房、腹透中心、血透中心的CKD非透析（CKD 3~5期）、腹膜透析和血液透析患者共150例为对象;年龄、性别匹配的25例健康体检者为对照。收集患者临床和相关生化指标资料。采用酶联免疫法测定血清全段FGF23水平。对入选患者进行冠脉多层螺旋CT（MSCT）检查。分析FGF23水平与CKD中晚期患者冠脉钙化的关系。 结果 CKD中晚期患者血清FGF23水平显著高于健康对照组[196.46（83.09,355.02） ng/L比27.17（21.63,51.20） ng/L,P < 0.01];透析患者的FGF23水平显著高于非透析患者（P < 0.01）;血透患者的FGF23水平显著高于腹透患者[6048.29 （1129.08,34807.45） ng/L比1625.80（602.83,7521.78） ng/L,P < 0.01]。CKD中晚期患者冠脉钙化发生率较高（74/130,56.9%）,血清FGF23水平与冠脉钙化分数（CaS）呈正相关（r = 0.177,P < 0.05）。Logistic回归分析显示年龄（β = 0.091,OR = 1.095,P < 0.01）、透析龄（β = 2.013,OR = 7.483,P < 0.05）和FGF23水平（β = 0.838,OR = 2.311,P < 0.05）是CKD中晚期患者发生冠脉钙化的独立危险因素。冠状动脉钙化的ROC曲线显示,FGF23曲线下面积为0.705（P < 0.01）,当检测的截点为786.73 ng/L时,其敏感度和特异性分别为62.5%和75.9%;碱性磷酸酶（AKP）的曲线下面积为0.626（P = 0.017）,当检测的截点为79.75 U/L时,其敏感度和特异性分别为84.5%和41.5%。血磷在诊断冠脉钙化时没有统计学意义。 结论 血清FGF23水平与CKD中晚期患者冠脉钙化发生相关。FGF23作为诊断冠脉钙化的参考指标,其敏感度低于AKP,特异性优于AKP。     

血浆不对称二甲基精氨酸对慢性肾脏病患者心脏结构及功能的预测价值

目的 探讨血浆不对称二甲基精氨酸(ADMA)水平对慢性肾脏病(CKD)患者心脏结构及功能的预测价值.方法 选取100例非透析CKD患者为研究对象.依照K-DOQI指南的分期标准,将患者分为5组.选取年龄匹配的健康体检者20例为健康对照组.用高效液相色谱法检测血浆ADMA水平和超声心动图检测心脏结构及功能.结果 CKD患者血浆ADMA水平(μmol/L)随着肾功能的减退而增高.CKD3、4、5期患者血浆ADMA水平(1.3318±0.4684、1.5712±0.4210、2.1093±0.7714)显著高于健康对照组(0.4611±0.1615)及CKD1、2期患者( 0.4387±0.2575、0.4809±0.2846)(均P＜0.01);而CKD5期患者血浆ADMA又高于CKD3、4期患者.CKD4、5期患者左心室心肌质量指数(LMVI)( 140.24±40.52、150.21±46.23)显著高于健康对照组及CKD1 ～3期患者(均P＜0.01).ADMA与LMVI呈正相关(r=0.476,P=0.028),与心脏射血分数(EF)呈负相关(r=-0.327,P=0.041).多因素逐步回归分析结果显示血浆ADMA是EF降低的独立危险因素(OR=0.984,P＜0.01).结论 CKD患者血浆ADMA水平在CKD3期开始升高,并随着肾功能的减退而增加.血浆ADMA与左心室肥厚呈正相关,且是EF降低的独立危险因素,对心血管并发症有预测价值.     

自噬和ASPPs在老年大鼠急性肾损伤早期的表达

目的观察自噬相关蛋白和p53凋亡刺激蛋白(ASPPs)在肾损伤早期的表达变化,初步探讨自噬相关蛋白和ASPPs是否可能成为老年大鼠AKI早期生物标志物。 方法建立顺铂致AKI青年与老年大鼠模型。雄性SD老年大鼠随机分为假手术组(Sham),顺铂模型组,同时设数量匹配的雄性SD青年大鼠为对照;模型组大鼠一次性腹腔注射顺铂4 mg/kg,Sham组相同途径注射生理盐水4 ml/kg;在给药12 h、1 d、3 d、5 d、7 d时检测大鼠Scr、BUN;光镜观察大鼠肾脏病理变化;透射电镜观察大鼠肾小管上皮细胞超微结构变化及自噬体的情况;免疫印迹法检测肾脏组织Beclin 1、溶酶体相关膜蛋白2(LAMP2)、p62、p53及ASPP抑制物(iASPP)和ASPP1表达情况。 结果顺铂诱导12 h后,与Sham组比较,青年与老年大鼠Scr无明显变化(P>0.05);电镜观察到大鼠肾小管上皮细胞自噬体出现而且数量显著增多;老年大鼠肾组织Beclin 1、p62、LAMP-2和p53表达水平明显升高(P<0.05),iASPP表达水平明显降低(P<0.05),并且老年大鼠肾组织Beclin 1、LAMP-2和p53变化时间早于青年大鼠(P<0.05)。 结论自噬和ASPPs在老年大鼠AKI发生早期即可出现,在Scr开始升高前,反应性自噬已经启动。自噬相关蛋白和ASPPs有望成为AKI早期的损伤标志物,可能是AKI早期干预的新靶点,但仍需更深入的研究。     

Monogenic causes of chronic kidney disease in adults

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Better recovery of kidney function in patients with de novo chronic kidney disease after partial nephrectomy compared with those with pre‐existing chronic kidney disease

We compared kidney functional recovery between patients with pre‐existing chronic kidney disease, those with de novo chronic kidney disease and those with normal kidney function, after partial nephrectomy. A total of 311 patients who underwent partial nephrectomy at Tokyo Women's Medical University Hospital, Tokyo, Japan, between January 2004 and July 2011 with sufficient kidney functional data participated in the study. Patients with pre‐existing chronic kidney disease (group1: 78 patients) were defined as those with estimated glomerular filtration rate under 60 mL/min/m² before partial nephrectomy. Patients with de novo chronic kidney disease (group 2: 49) were defined as those with estimated glomerular filtration rate over 60 mL/min/m² before surgery and who developed estimated glomerular filtration rate under 60 mL/min/m² 3 months after partial nephrectomy. Normal patients (group 3: 184) were defined as those with estimated glomerular filtration rate over 60 mL/min/m² both before and after partial nephrectomy. Group 1 was associated with older age and higher comorbidity, including hypertension and diabetes mellitus, compared with other groups. R.E.N.A.L. score was not significantly different between the groups. Although the percent change of estimated glomerular filtration rate between the preoperative period and 3 months after partial nephrectomy in group 2 was significantly decreased compared with that in other groups (group 1: ?6.8%, group 2: ?18%, group 3: ?7.3%), the renal functional recovery between 3 and 12 months after partial nephrectomy in group 2 was better than that in other groups (group 1: ?0.5%, group 2: 5.6%, group 3: ?0.4%). Patients with de novo chronic kidney disease had better kidney functional recovery than the other two groups, which might suggest that they were surgically assaulted and developed chronic kidney disease in the early postoperative period, and were essentially different from those with pre‐existing chronic kidney disease.     

多学科协作联合移动医疗用于慢性肾脏病患者管理

目的提高慢性肾脏病(CKD)非透析患者自我管理能力,延缓疾病进展。方法将420例CKD非透析患者随机分为两组各210例。对照组行常规肾内科门诊复诊与随访;观察组在此基础上采取多学科专业团队联合移动医疗实施患者管理,包括设计CKD患者管理App,建立患者电子档案,多学科协作团队同时出诊,线上线下咨询与指导等。实施12个月后评价效果。结果完成全程研究者观察组208例、对照组200例。干预6个月、12个月时,观察组自我管理行为评分,收缩压达标率显著高于对照组(均P0.01);肾小球滤过率、血肌酐值显著优于对照组(均P0.01)。结论采用多学科协作联合移动医疗针对CKD非透析患者进行持续管理,有利于培养患者自我管理能力,延缓疾病进展。     

Pro- and anti-fibrotic effects of vascular endothelial growth factor in chronic kidney diseases

Renal fibrosis is the inevitable common end-point of all progressive chronic kidney diseases. The underlying mechanisms of renal fibrosis are complex, and currently there is no effective therapy against renal fibrosis. Renal microvascular rarefaction contributes to the progression of renal fibrosis; however, an imbalance between proangiogenic and antiangiogenic factors leads to the loss of renal microvasculature. Vascular endothelial growth factor (VEGF) is the most important pro-angiogenic factor. Recent studies have unraveled the involvement of VEGF in the regulation of renal microvascular rarefaction and fibrosis via various mechanisms; however, it is not clear whether it has anti-fibrotic or pro-fibrotic effect. This paper reviews the available evidence pertaining to the function of VEGF in the fibrotic process and explores the associated underlying mechanisms. Our synthesis will help identify the future research priorities for developing specialized treatments for alleviating or preventing renal fibrosis. Abbreviation: VEGF: vascular endothelial growth factor; CKD: chronic kidney disease; ESKD: end-stage kidney disease; ER: endoplasmic reticulum; VEGFR: vascular endothelial growth factor receptor; AKI: acute kidney injury; EMT: epithelial-to-mesenchymal transition; HIF: hypoxia-inducible factor; α-SMA: α smooth muscle actin; UUO: unilateral ureteral obstruction; TGF-β: transforming growth factor-β; PMT: pericyte-myofibroblast transition; NO: nitric oxide; NOS: nitric oxide synthase; nNOS: neuronal nitric oxide synthase; iNOS: inducible nitric oxide synthase; eNOS: endothelial nitric oxide synthase; sGC: soluble guanylate cyclase; PKG: soluble guanylate cyclase dependent protein kinases; UP R: unfolded protein response     

上海市脑血管疾病住院患者慢性肾脏病调查研究

目的 调查上海城市脑血管疾病住院患者的慢性肾脏病（CKD）发生情况及其并发症,从而有助高危人群中CKD的早发现、早诊断和早治疗。 方法 收集上海市瑞金医院、第九人民医院、新华医院、解放军第八五医院、仁济医院5家医院神经内科2007年6月至2008年2月间住院的脑血管疾病患者的临床资料。所有患者均分别经脑CT、脑血管CT（CTA）、磁共振成像（MRI）、脑血管MRI（MRA）及经颅多普勒超声（TCD）确诊。对患者进行肾脏损伤指标（Scr、尿常规+沉渣镜检、尿微量白蛋白/肌酐比值）及相关危险因素（血压、空腹血糖、餐后2 h血糖、血脂、胸部X线片、心电图等）的检测。Scr检测统一在瑞金医院检验中心进行。采用MDRD复杂公式估算GFR,并根据K/DOQI指南进行CKD分期。 结果 共调查脑血管疾病住院患者1014例,男性559例,女性455例,平均年龄（68.56±12.17）岁。病因依次为缺血性脑血管疾病（708例）、出血性脑血管疾病（197例）和短暂性脑缺血发作（TIA）（109例）。11.2%的患者伴有微量白蛋白尿(MAU),而24.8%患者为显性蛋白尿。脑血管疾病患者的CKD患病率为47.7%;CKD 1~5期分别占该人群的6.90%、14.69%、21.60%、2.56% 和1.97%。多因素Logistic回归提示,影响脑血管疾病患者短期（30 d）预后的危险因素为蛋白尿（OR = 1.69,P = 0.0005）、空腹血糖升高（OR = 1.67,P = 0.0005）和贫血（OR = 1.37,P = 0.04）。 结论 首次在我国进行脑血管疾病人群中肾功能情况调查分析,报道了上海脑血管疾病人群中CKD流行病学数据。脑血管疾病住院患者中CKD的发生率为47.7%。对该人群进行CKD评估,尤其是在早期进行尿微量白蛋白/肌酐比值（ACR）筛查尤为重要。     

The porcine remnant kidney model of chronic renal insufficiency

BACKGROUND: The purpose of the present study was to develop and characterize a porcine model of chronic renal insufficiency created by renal artery embolization. METHODS: The model was created using 42 castrated juvenile male pigs (7-8 months old) in two parts (pilot (N = 10) group, definitive (N = 26) group, and control group (N = 6). In the pilot group, the embolization procedure was optimized with respect to the size of polyvinyl acrylide (PVA) particles, coils, and amount of kidney embolized. The animals were followed serially for 4 weeks after the embolization procedure to determine the renal function and hypertensive response. In the definitive group, these results were extended to later time points and a left total nephrectomy and a right partial nephrectomy (remnant) were performed and these animals were followed for 28 to 84 days. RESULTS: The kidney function after the embolization was characterized by acute deterioration in renal function, followed by improvement, and "stable" chronic renal insufficiency with statistically significant elevation in creatinine and BUN being observed until day 42. The mean arterial blood pressure remained significantly elevated until day 7 after which it began to decrease to pre-embolization value. The remnant kidney developed fibrosis in the tublointerstitial compartment as it hypertrophied and increased its weight which remained significantly elevated after embolization. CONCLUSIONS: A reproducible remnant kidney model of chronic renal insufficiency in pigs was developed. In this model, stable renal insufficiency develops by 4 weeks that lasts until 12 weeks.