红细胞生成素(erythropoietin,EPO)的调节是机体低氧适应的重要病理生理过程,对这一现象的深入探究发现了机体的氧感应调适系统.氧感知调适系统的发现为EPO缺乏相关疾病的治疗提供了理论基础.靶向机体氧感受器—脯氨酰羟化酶(prolyl hydroxylase domain,PHD)研发的低氧诱导因子稳定剂(hypoxia inducible factor-prolyl hydroxylase inhibitor,HIF-PHI)将这一理论基础转化为临床应用.目前,HIF-PHI主要用于肾性贫血的治疗,而HIF-PHI使用对肾脏病以及相关疾病的影响尚不十分清楚.本文主要总结了HIF-PHI对贫血、各种肾脏病以及慢性肾脏病心血管疾病的潜在作用.

Objective To observe the expression of SIRT1 gene and explore its role during the renal development of mice.Methods Genotyping was used to observe the impact of SIRT1 knockout on the survival of mice.Immunohistochemistry and immunofluorescence staining were used to examine the location of SIRT1 protein at fetal age of 14 days.Real-time quantitative PCR was used to semi-quantitatively measure the expression level of SIRT1 mRNA in the developing mice kidney at fetal age of 15,16,17 and 18 days,and also 0,5,9,23 days after birth.Effects of SIRT1 knockout on size of mice kidney was observed at fetal age of 17,18 days and also 4,10 days after birth.Kidneys were cultured in vitro to observe the effects of SIRT1 knockout on ureter bud branching.Immunohistochemical and real-time quantitative PCR were used to observe the effects of SIRT1 knockout on kidney PCNA expression levels.Results Most of SIRT1(-/-) mice could still be alive during pregnancy,but died shortly after birth.Immunohistochemistry and immunofluorescence staining showed that the expression of SIRT1 protein could be detected in the early stage of kidney development and could be fully expressed in the metanephric mesenchyme of the developing kidney,but weakly expressed in the ureteric bud.Real-time quantitative PCR analysis revealed that SIRT1 was highly expressed in embryonic kidney at fetal age of 17 days,while the expression level declined quickly thereafter and maintained at low level after birth.Absence of SIRT1 gene resulted in smaller kidney specimens of mice and further microscopic observation showed the glomerular area was smaller and the glomerular number was lesser(P ＜ 0.01).Absence of SIRT1 gene also resulted in decreased ureteral bud branching and declined PCNA expression level of kidney(P ＜ 0.01).Conclusion SIRT1 plays an important role in the nephron development in mice by regulating the expression of PCNA.

Objective To investigate the protective effect of res-veratrol（RSV）on 5/6 nephrectomized rats and its mechanism.Methods Fifty male SD rats were randomly divided into three groups:sham operated（Sham,n=10）

<正>糖尿病发生率在我国甚高,同时有越来越增加的趋势。高血压和肾脏损害等是糖尿病主要合并症,由此导致的心血管、肾脏病变如脑卒中、心肌梗死以及肾功能衰竭等,不但造成患者严重损伤,同时增加了社会负担。预防和控制糖尿病发生、发展,严格控制血压,

<正>肾上腺皮质激素和免疫抑制剂为肾病最常用的治疗武器,它们在免疫性肾脏疾病及肾移植等方面起到十分重要的作用。然而在不少非免疫性肾脏疾病中,以及某些肾脏病虽以免疫为起始但之后免疫过程已不再起主导地位的时期,其他多种非特异性免疫机制也参与肾脏病的进展组成慢性肾脏病(chronic kidney disease,CKD)进展机制的一部分,充分注意干预此部分机制显然也是肾脏病治疗中重要的一部分。

>1研究背景营养不良在维持性血液透析(maintenance he-modialysis,MHD)患者中相当普遍,且与患者的预后及生存质量密切相关。国内尽管已意识到营养不良的危害,但对营养治疗并未重视。很多患者总蛋白质摄入过多而优质蛋白质摄入不足,热量、脂肪分配不合理,致使营养不良、高磷血症、代谢性酸中毒、高脂血症、胰岛素抵抗等问题接踵而至,成

Objective To evaluate the role of nutritional parameters in prognosis,especially in the early and late mortality of hospital-acquired acute kidney injury (AKI) patients.Methods This study was a prospective cohort study conducted in a hospital comprising 1500 beds in Shanghai, China. One hundred ninety-four patients with hospital-acquired AKI, as determined using the RIFLE staging criteria,were enrolled as subjects after obtaining informed consent.Patients with AKI caused by postrenal obstruction,glomerulonephritis,interstitial nephritis or vasculitis were excluded.Nutritional evaluation,including subjective global assessment (SGA),anthropometric and laboratory examination,was conducted. Other laboratory measurements and clinical data were recorded.The primary outcome was early mortality (≤ 7 days) and late mortality (8-28 days) after enrolling into the study. Results AKI patients at enrollment were characterized by a high prevalence of malnutrition as determined by SGA, anthropometric and laboratory examination.Univariate analysis showed that the SGA,the serum levels of prealbumin,cholesterol and total lymphatic cells, and the Maastricht index were significantly different among early mortality,late mortality and survival groups.The serum prealbumin and cholesterol levels in the early death group were significantly lower than those in the survival and late death groups (P＜0.05).Multivariate analysis revealed that SGA,albumin,prealbumin and cholesterol remained independently and significantly associated with early mortality after adjusting for age,sex,dialysis,ventilation,hemoglobin,platelets,bilirubin,and Glasgow coma score.The areas under the receiver operating characteristic curve to predict early mortality for albumin,prealbumin and cholesterol were 0.591,0.736 and 0.603,respectively,with that of prealbumin significantly higher than others (P＜0.05). Conclusion Low levels of serum prealbumin,albumin and cholesterol at enrollment are independtly associated with increased early mortality in hospital-acquired AKI patients.

Objective To elucidate the malnutrition in patients with hospital-acquired acute kidney injury (AKI), and to examine the association between subjective global assessment (SGA) and prognosis. Methods Adult patients with hospital-acquired AKI were prospectively enrolled in this cohort study.Nutritional evaluations, including SGA, anthropometric and serum nutritional markers were conducted at enrollment.Overall survival at 90 days among different SGA scores was analyzed using Kaplan-Meier methods, and differences were tested using the log-rank test.The Cox model was used to analyze the relationship between SGA scores and all-cause mortality after adjusting for confounders.Results A total of 170 patients were enrolled.The prevalence of moderate malnutrition (SGA B) and severe malnutrition (SGA C) was 51.8％ and 22.9％ respectively, while patients with normal nutrition (SGA A) accounted for 25.3％.After 90 days follow-up, all-cause mortality was 9.8％ in SGA A group, 34.9％ in SGA B group and 56.8％ in SGA C group respectively. After adjusting for age, sex, dialysis, ventilation, hemoglobin, platelets and bilirubin, the hazard ratio (HR) of 90 days all-cause mortality was 4.0(95％ CI 1.42-11.22, P=0.008) in malnutrition group (SGA B group and SGA C group) compared with SGA A group.The Kaplan-Meier curve also revealed that the worse the SGA score was, the lower the cumulative survival became (P＜0.01). Conclusion SGA score is an independent risk factor for all-cause mortality within 90 days in patients with hospital-acquired acute kidney injury.

Objective To observe the influence of low protein diet with α-keto acid on kidney sclerosis and renin-angiotensin system in renal ablation rats. Methods Chronic renal failure rat model was established by renal ablation in 30 male SD rats,then the animals were randomly assigned to the following diet groups:normal protein group (NPD:18%casein protein),low protein group (LPD:6%casein protein) and supplemented low protein group (LK:5%casein protein+1%α-keto acids).Ten male SD sham-operated rats received 18%casein protein as control.All the rats were killed at the end of the 12th week.Pathologic changes were assessed by PAS staining.Ang II in homogenate and plasma were measured by radioimmunoassay and ELISA respectively.Immunohistochemistry and Western blotting were used to detect the protein expression of TGF-β1,renin and AT1R.Real-time PCR was used to detect the gene expression of renin and ATla,the main subtype of AT1 receptor. Results Body weight,total protein and serum albumin had not significant difference among the four groups(all P>0.05).Serum creatinine and proteinuria of nephrectomized rats were significantly higher compared to the control group (all P<0.05).Proteinuria of the LK group was lower than that of NPD and LPD groups (all P<0.05).Pathological results indicated fibrosis indices were significantly improved after LPD and LK intervention.Expressions of renin,Ang II and AT1R in LK group were significantly lower than those in NPD group (all P<0.05). Conclusions Low protein diet with α-keto acids supplement therapy exhibits renal protective effects of reducing urine protein excretion and improving renal fibrosis,which might be related to the attenuation of local renin-angiotensin system in activity nephrectomized rats.

Objectives To evaluate the effect of the selective cytopheretic device (SCD) on outcome of severe acute kidney injury (AKI) requiring renal replacement therapy, and to observe the occurrence of adverse events from application of the device. Methods In this study, acute kidney injury was defined as ischemic or nephrotoxic acute tubular necrosis by clinic diagnosis, with at least one nonrenal organ failure or presence of sepsis at the same time. All subjects received standard intensive care treatment with continuous veno-venous hemofiltration (CVVH) in addition to the SCD treatment. Patients enrolled in the trial were compared with the historical casematched controls from PICARD study with respect to age and Sequential Organ Failure Assessment (SOFA) score. The primary endpoint was in-hospital all cause mortality. Other observation index included urine output change and the occurrence of adverse events. After adjusting for confounders, the Cox model was used to analyze whether SCD combined with CVVH treatment was better than routine CVVH. Results A total of 9 patients were enrolled. In-hospital all cause mortality of SCD combined with CVVH treatment group was 22.2%, significantly lower than historical case-matched control group (77.8%) (x2=5.247,P=0.027). Multiple regression analysis identified treatment with SCD as the only significant variable affecting mortality among age, SOFA score, and average change in urine output (SCD vs. CVVH historical cohort,(T=-2.596,P=0.0222). Mean total urine output in the 9 subjects receiving SCD treatment increased from a baseline of approximately 500 ml/d to more than 2,000 ml/d by day 7 of treatment. In this study, only a few mild adverse events occurred, and no serious adverse events were reported.Conclusion SCD can regulate the immune response by deactivating leukocytes, and therefore improve in-hospital mortality of patients with AKI. The safety of SCD is favorable.

<正>前言肾间质纤维化的病理为多种细胞外基质(ECM)成分的积聚。大量体内和体外实验发现,多种细胞因子和生长因子与ECM合成及代谢的调节密切相关,参与了肾间质纤维化的发展过程,其中转化生长因子β1(TGF-β1)的地位尤为突出,被认为是所有进行性肾脏纤维化疾病中导致

Objective To observe the changes of renin-angiotensin system (RAS) in cultured mesangial cells by serum from 3/4 nephrectomized rats feeding with low protein diet and α-keto acid. Methods Thirty male SD rats received 3/4 nephrectomy (Nx) were placed on 18%normal protein diet (NPD,n=10),6% low protein diet(LPD,n=10) or 5% low protein plus 1%α-keto acid diet (LK,n=10) flor 12 weeks.Ten male SD sham-operated rats fed with 18% normal protein diet were used as control (sham group).In addition,mesangial cells were cultured in sera (10%) collected from above animals treated with or without losartan (0.02 mmol/L)for 48 hours.ELISA was applied to detect the level of Ang II,TGF-β1 and fibronectin (FN) in cell medium.Westem blotting was used to determine the protein level of ATI receptor (AT1R)and real-time PCR was used to detect the mRNA level of AT1R,TGF-β1 and FN. Results (1) Nutritional indices including body weight,total protein and albumin had no significant difference in each group. (2) Serum creatinine and 24 h pruteinuria were significantly inceased in nephrectomized groups compared to sham group(P<0.05,respectively).24 h proteinuria was greatly lower in LK group than that in NPD and LPD groups(P<0.05,respectively).(3)LK greatly decteased the level of Ang II[NPD(12.70±0.12)mg/g protein;sham(8.04±0.62)mg/g protein]in supernatant as well as the protein and mRNA expression of AT1R in cultured mesangial cells (P<0.05).(4)NPD serum directly induced higher secretion[FN:sham(20.58±0.46)g/g protein,NPD (39.84±0.06)g/g protein;TGF-β1:sham(10.12±O.56)mg/g protein,NPD(83.85±3.58)mg/g protein] and mRNA expression of FN and TGF-β1 compared with sham group (P<0.05).LPD decreased these increment (P<0.05) and LK showed stronger inhibitory effect (P<0.05). (5)Losartan application sharply reduced FN and TGF-β1 production both in supematant and in mRNA expression in NPD serum treated cells (P<0.05,respectively). Conclusion Low protein diet with α-keto acids supplement directly inhibits the RAS in mesangial cells which may contribute to its beneficial effect on the kidney.

>肾素-血管紧张素系统(RAS)已被发现多年,对其功能的传统认识是维持血压、保持体液特别是钠盐平衡。近年研究证实还有许多血流动力学以外的作用,并发现RAS除传统成分以外,还包括其他一些重要成分,例如血管紧张素转化酶(ACE)2及其产物血管紧张素(Ang)1-7与受体、前肾素

Objective To study the level of NT-pro brain natriuretic peptide(NT-proBNP) and its correlation with heart remodeling and function in maintenance hemodialysis(MHD) patients. Methods NT-proBNP level was determined in 117 MHD patients before a regular 4-hour hemodialysis(HD).Echocardiography was performed on a non-dialysis day.The clinical and biochemical characteristics of MHD patients were collected.The MHD patients were divided into four sub-groups according to their NT-proBNP levels. Results All of the patients had pre-dialysis concentration of NT-proBNP above the cut-off values for HF.There were differences in age,interdialysis bodyweight gain,ultrafiltration volume,systolic blood pressure(SBP),hemoglobin,heamatocrit,left atrial diameters(LAD) and left ventricle mass index(LVMI) between the higher level NT-proBNP group and lower level group(P0.01 or P0.05).The marker levels positively correlated with systolic blood pressure(SBP)(r=0.348,P0.01),left atrial diameters(LAD)(r=0.312,P=0.01)and left ventricle mass index(LVMI)(r=0.529,P0.01).Strong inverse correlation was found between NT-proBNP and hemoglobin(r=-0.210,P=0.006),hematocrit(r=-0.201,P=0.030) and pre-albumin as well(r=-0.377,P0.01).In the multiple regression model,higher SBP(β=0.370,P=0.001),lower serum pre-albumin(β=-0.459,P0.001) and greater LVMI(β=0.251,P=0.025) were significant independent influential factors for increased NT-proBNP level.The elevated NT-proBNP level also positively correlated with ACC/AHA heart failure stages(r=0.553,P0.01). Conclusions NT-proBNP level is markedly elevated in MHD patients.Higher SBP,lower serum pre-albumin and greater LVMI are significant independent influential factors for increased NT-proBNP level which may reflect heart remodeling and function in MHD patients.

Podocyte injury is a feature of glomerulopathies associated with proteinuria, which in turn has been used as a clinical prognostic factor for glomerular diseases. The goal of this study is to investigate the relationship between podocyte injury found in biopsied renal tissue and change of proteinuria in IgA nephropathy (IgAN). In all, 35 patients with biopsy-proven IgAN and proteinuria (>1.0 g per 24 h) were enrolled in the IgAN group, while 8 patients with excision of renal harmatoma or carcinoma served as kidney controls (Control). Immunohistochemistry was applied to detect the expression of nestin, cell-cycle regulatory protein p27, as well as complement C5b-9 and complement receptor 1 (CR1). Podocyte foot process width (FPW) and podocyte population in renal biopsied samples were measured by morphometric analysis. On the basis of the podocyte density (Nv), the IgAN patients were divided into podocytopenic group (n=17, Nv<57.10 /μm3 × 106) and normopodocytic group (n=18, Nv≥57.10 /μm3 × 106). Changes of proteinuria were followed for 18 months after biopsy. Compared with the Control, IgAN glomeruli had reduced podocyte expression of p27 and nestin along with decreased podocyte number. IgAN glomeruli also showed activation of C5b-9 in mesangial and subepithelial areas with decreased CR1 expression in podocytes. The C5b-9 positivity was inversely correlated with the number of WT-1-positive podocytes. Although the magnitude of proteinuria at biopsy correlated with podocyte FPW (P<0.05), the change in the amount of proteinuria expressed as proteinuria progression rate significantly correlated with the podocyte density. Thus, the normopodocytic group showed significantly lower proteinuria progression rate than the podocytopenic group regardless the comparable clinical features at biopsy and treatment regimen between the two groups. The results of this study indicate that, in IgAN, podocyte injury is involved in development of proteinuria and loss of podocytes predicts progression of the proteinuria. Complement activation may contribute to podocyte damage in IgAN.

Objective To observe the growing shape and function of Madin-Darby canine kidney (MDCK) cells implanted on the polysilicon nanopore membrane by micro-electro-mechanical system (MEMS). Methods The polysilicon nanomembrane was made by silicon film processed via whirling photoresist, wet etching, electroplating and so on, and then it was coated by extracellular matrix and implanted with MDCK cells. The cell growth shape and function was observed or examined by scanning electron microscope or MTT test and Trypan Blue staining.Results The nanomembrane with regular slit pores was successfully fabricated. Extracellular matrix-coated nanomembrane, especially for collagen Ⅳ coating, was more suitable for MDCK cells to adhere and proliferate without membrane injury. The polysilicon nanomembrane coated with extracellular matrix did not induce the cell death and also not stimulate cells releasing the cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α). Under scanning electron microscope, MDCK cells formed a flat single-cell fusion with tight junction on the surface of polysilicon nanomembrane and there was a large number of microvillus on the top of cells.Conclusion The collagen-coated polysilicon nanomembrane made by MEMS techniques, with no cytotoxicity and good biocompatibility, is valuable to frame the artificial glomerular filtration membrane

Objective:To investigate the effect of plasmadiafiltration(PDF) with different operating parameters on the sieving coefficients and clearance rates of different molecular weight substance in an in vitro sepsis model.Methods: In vitro sepsis model was constructed by exposure of human whole blood to bacterial lipopolysaccharide.PDF was performed with a filter named Evacure 2A and the operating parameters which would be combined in turn were set as following: fixed blood flow rate 150 mL·min-1;dialysate flow rate 2 000,4 000 mL·h-1;replacing fluid flow rate 400,800 mL·h-1;net ultra filtration rate 0,300,600 ml/h.After 0,1,2 hours′ PDF with different combination of operating parameters,samples were taken from the blood and ultrafiltration circuit to test the sieving coefficient and clearance rate of inflammatory factors.Results: Most sieving coefficients did not change with replacing fluid flow rate,dialysate flow rate,and ultrafiltration rate.Sieving coefficients of different solutes ranged from 0.1 to 1.0 at first,decreased 10%~60% after 1 hour′s PDF,and then kept stable.Concentrations of most solutes decreased more than 50% after 1 hours′ PDF,meanwhile the reduction rate of serum creatinine was 91.54%±5.40%.After 2 hours′ PDF,total clearance rate of tumor necrosis factor-α(TNF-α),interleukin-2(IL-2),interleukin-6(IL-6) and creatinine could still be maintained at 56.75 ± 8.65 mL·min-1,66.54±8.20 mL·min-1,11.46±2.45 mL·min-1,117.50±10.61 mL·min-1,respectively.Total clearance rate of albumin was 2.02±1.39 mL·min-1 at baseline,and then reduced to 0.28±0.15 mL·min-1 after 2 hours′ PDF.Conclusions: PDF with Evacure 2A plasma separator can remove almost all of the inflammatory mediators commonly seen in sepsis.It can provide an acceptable balance between high cytokine and low albumin clearances.

Objective To evaluate the value of the three general scoring systems (SOFA, APACHE Ⅱ and SAPS Ⅱ), the AKI-specific scoring system (Liano), and the RILFE criteria for predicting prognosis in acute kidney injury (AKI) patients. Methods In this prospective and single center study, AKI patients with different causes and hospitalized in this hospital from December 2008 to November 2009 were enrolled. AKI was diagnosed based on the serum creatinine of RIFLE criteria. Patients were excluded from this study if the AKI was due to obstructive uropathy, interstitial nephritis, primary or secondary glomerulonephritis. The primary end point of the study was the mortality after 28 days. Scores from RIFLE classification, SOFA, APACHE Ⅱ, SAPS Ⅱ and Liano scoring systems were compared between the survival and non-survival patients. Receiver operating characteristic (ROC) curve for predict- ing death was used for the evaluation of scoring systems with and without stratification based on RIFLE classification. Results A total of 194 AKI patients were enrolled in this study. No significant differences were found in RIFLE classification, cause of AKI and dialysis between survivor and death groups. However, ventilation therapy, and scores from SOFA, APACHE Ⅱ, SAPS Ⅱ and Liano systems were significantly different between survivors and non-survivors. Area under ROC (AUROC) curves for predicting death by SOFA, APACHE Ⅱ, SAPS Ⅱ and Liano scores were 0.900, 0.885, 0.888 and 0.875, respectively (P<0.001), which were all higher than the AUROC of RIFLE (0.566, P > 0.05). Stratification of AKI based on RIFLE classification revealed that patients in the failure group had higher AUROC of the 4 scoring systems, especially the AUROC of Liano scoring system. Conclusions General or AKI-specific scoring systems including SOFA, APACHE Ⅱ, SAPS Ⅱ and Liano systems are superior to RIFLE criteria for predicting prognosis in AKI patients.

钙通道阻滞药(CCB)具有良好的降压作用,其在心血管领域中讨论很多,而在肾脏病领域相对较少,甚至由于其对肾血流动力学的作用特点,还常常被误认为是对肾病不利的降压药.