补体旁路途径过度活化在恶性高血压肾硬化中的作用

目的研究补体旁路途径(alternative complement pathway)过度活化在恶性高血压肾硬化中的作用。方法(1)选取本院经肾穿刺活检证实为恶性高血压肾硬化患者50例为病例组,零点行肾穿刺活检的供肾者25例为正常对照组,采用酶联免疫吸附法(ELISA)检测血浆及尿液中的补体旁路途径活化起始B因子、正向调节P因子、负向调节H因子及补体活化终末产物C3a、C5a水平。(2)免疫组化法检测补体活化终末产物C5b-9、C4d及凝集素途径活化产物甘露糖结合凝集素(MBL)在肾活检组织的沉积;免疫荧光双染检测C5b-9与CD34(内皮细胞标志物)在小动脉内皮及肾小球毛细血管内皮的沉积。结果(1)恶性高血压肾硬化患者血浆及尿液中补体B因子、P因子、C3a及C5a均高于正常对照组(均P<0.05),而H因子则低于正常对照组(P<0.05)。(2)恶性高血压肾硬化患者血浆中补体P因子与24 h尿蛋白量呈正相关(rs=0.465,P=0.001),而补体B因子、H因子、C3a、C5a与血肌酐及24 h尿蛋白量无明显相关性。恶性高血压肾硬化患者尿B因子/尿肌酐、尿P因子/尿肌酐、尿C3a/尿肌酐与血肌酐均呈正相关(rs=0.483,P<0.001;rs=0.352,P=0.012;rs=0.319,P=0.024),尿H因子/尿肌酐与血肌酐及24 h尿蛋白量均呈负相关(rs=-0.299,P=0.035;rs=-0.342,P=0.015),尿C5a/尿肌酐与血肌酐及24 h尿蛋白量均呈正相关(rs=0.525,P<0.001;rs=0.496,P<0.001)。(3)免疫组化显示,恶性高血压肾硬化患者C5b-9沉积于小动脉壁及肾小球毛细血管壁,而正常对照组肾组织中未见沉积。恶性高血压肾硬化患者肾脏C5b-9沉积强度评分与血肌酐及24 h尿蛋白量呈正相关(rs=0.791,P<0.001;rs=0.345,P=0.014)。双重免疫荧光标记法可见C5b-9、CD34沉积于小动脉内皮及肾小球毛细血管内皮。(4)恶性高血压肾硬化患者血浆中B因子与C3a(r=0.331,P=0.022)、P因子与C5b-9评分(rs=0.300,P=0.034)均呈正相关;尿液中补体旁路途径活化B因子与C3a、C5a及C5b-9均呈正相关(rs=0.311,P=0.028;rs=0.465,P=0.001;rs=0.428,P=0.002),P因子与C3a、C5a也均呈正相关(rs=0.307,P=0.030;rs=0.442,P=0.001)。恶性高血压肾硬化患者免疫组化可见C4d沉积于小动脉及肾小球,而未见凝集素途径活化产物MBL沉积。结论补体旁路途径过度活化可能参与恶性高血压肾硬化的发生。恶性高血压肾硬化严重程度与补体旁路途径的活化水平相关。     

Correlation between serum C3 and glomerular microthrombosis in patients with lupus nephritis

Objective To investigate the correlation between serum C3 and glomerular microthrombosis in patients with lupus nephritis (LN). Methods Patients who were diagnosed as LN by renal biopsy hospitalized in Department of Nephrology, the First Affiliated Hospital of Shenzhen University from January 2010 to February 2019 were retrospectively analyzed and they were divided into glomerular microthrombosis group (GMT group) and non-glomerular microthrombosis group (non-GMT group). The demographic data, clinical characteristics, pathology and prognosis of the two groups were compared. Logistic regression and smooth curve fitting of generalized additive mixed model analysis were used to explore the correlation between serum C3 and glomerular microthrombosis. Renal prognosis of the two groups were compared by the Kaplan-Meier survival curve. Results A total of 116 patients were enrolled, aged (32.79±11.43) years old, in which 108 cases (93.10%) were female. Thirty-seven patients (31.90%) were confirmed to be combined with GMT (GMT group) and 79 cases were not (non-GMT group). Compared with the non-GMT group, patients in the GMT group were relatively older (t=-2.876, P=0.002), with higher proportion of hypertension ( χ2=7.492, P=0.006)，higher urine protein quantitation (Z=-2.115, P=0.003), lower levels of eGFR and serum complement C3 (Z=3.469, P＜0.001; t=1.744, P＜0.001), higher systemic lupus erythematosus disease activity index (t=-2.758, P=0.007). As to the pathological characteristics, type IV LN patients were the majority (72.97%). Proportion of crescents and pathological activity indicators of the GMT group were higher (Z=-1.866, P=0.002; t=-5.005, P＜0.001), nuclear fragmentation, endothelial hyperplasia and renal tubular atrophy were more serious ( χ2=14.987, P＜0.001; χ2=15.695, P＜0.001; χ2=4.130, P=0.042). Multivariate logistic regression analysis indicated that serum complement C3 was a relational factor of the formation of GMT in LN patients (OR=0.966, 95％CI 0.938-0.995, P=0.023). Smooth curve fitting of generalized additive mixed model analysis indicated that level of complement C3 had a linear relationship with the changing trend of GMT. The Kaplan-Meier curve showed that there were statistical differences between the two groups in terms of complete remission of urine protein (Log-rank χ2=5.858, P=0.016) and doubled serum creatinine /end-stage renal disease (Log-rank χ2=3.945, P=0.047). Conclusions Serum C3 is closely related to the formation of GMT in LN patients, and statistical differences were demonstrated in the renal prognosis of GMT group and non-GMT group.     

Detection of serum and urinary lipoprotein(a) in patients with renal diseases

We measured and analysed serum and urinary lipoprotein(a) [Lp(a)] in 73 patients with various renal diseases, and 168 control subjects. The results revealed that serum Lp(a) levels were significantly elevated in patients with mesangial proliferative glomerulonephritis, membranous nephropathy, chronic renal failure and diabetic nephropathy, except patients with IgA nephropathy (IgAN) with gross haematuria. Serum Lp(a) concentrations were found to be significantly correlated with serum albumin ( r =−0.5033, P <0.001) and urinary protein excretion ( r =0.3541, P <0.005), while not with serum creatinine ( r =−0.0144, P >0.05). Patients with selective urinary protein excretion had a lower serum Lp(a) level than those with non-selective urinary protein excretion. The correlation between serum albumin and serum Lp(a) levels remained significant ( P <0.001) after adjustment for serum creatinine, urinary protein excretion and the selectivity of urinary protein by multivariate regression analysis. Urinary Lp(a) excretion was decreased and related to the serum creatinine level ( r =−0.312, P <0.01). Our conclusion is that renal patients with proteinuria and hypoalbuminemia tend to have elevated levels of Lp(a) which are more significantly correlated to serum albumin levels than other parameters such as serum 24-h urinary protein, selectivity of urinary protein and serum creatinine; while urinary Lp(a) excretion varies inversely with serum creatinine levels.     

Detection of serum and urinary lipoprotein(a) in patients with renal diseases

SUMMARY: We measured and analysed serum and urinary lipoprotein(a) [Lp(a)] in 73 patients with various renal diseases, and 168 control subjects. the results revealed that serum Lp(a) levels were significantly elevated in patients with mesangial proliferative glomerulonephritis, membranous nephropathy, chronic renal failure and diabetic nephropathy, except patients with IgA nephropathy (IgAN) with gross haematuria. Serum Lp(a) concentrations were found to be significantly correlated with serum albumin ( r =−0.5033, P <0.001) and urinary protein excretion ( r = 0.3541, P <0.005), while not with serum creatinine ( r =−0.0144, P >0.05). Patients with selective urinary protein excretion had a lower serum Lp(a) level than those with non-selective urinary protein excretion. the correlation between serum albumin and serum Lp(a) levels remained significant ( P <0.001) after adjustment for serum creatinine, urinary protein excretion and the selectivity of urinary protein by multivariate regression analysis. Urinary Lp(a) excretion was decreased and related to the serum creatinine level ( r =−0.312, P <0.01). Our conclusion is that renal patients with proteinuria and hypoalbuminemia tend to have elevated levels of Lp(a) which are more significantly correlated to serum albumin levels than other parameters such as serum 24-h urinary protein, selectivity of urinary protein and serum creatinine; while urinary Lp(a) excretion varies inversely with serum creatinine levels.     

Focal segmental glomerulosclerosis is not a sufficient predictor of renal outcome in patients with membranous nephropathy.

BACKGROUND: The course of idiopathic membranous nephropathy (iMN) is variable in untreated patients. Accurate prediction of renal outcome would allow optimal treatment decisions. We demonstrated that urinary beta2-microglobulin (beta2M) predicted prognosis in iMN with high sensitivity and specificity. It has been suggested that focal segmental glomerulosclerosis (FSGS) is a discriminative parameter with independent prognostic value. METHODS: We selected patients with iMN biopsied between 1988 and 2002. Biopsies were analysed for the presence of FSGS, interstitial fibrosis and vascular lesions. Serum creatinine, creatinine clearance, proteinuria and blood pressure were recorded at baseline. Outcome variables included remission of proteinuria, renal death (RD) defined as serum creatinine >135 micromol/l or increase of serum creatinine of >50%, or end-stage renal disease (ESRD). In a subgroup of patients, urinary beta2-microglobulin (beta2M) was measured. RESULTS: We included 53 patients (33M, 20F). Mean age was 51 years, serum creatinine 99 micromol/l, and proteinuria 7.0 g/10 mmol creatinine. FSGS was present in 22 patients. These patients were characterized by a higher serum creatinine at time of biopsy (P = 0.035), more severe interstitial fibrosis (P = 0.001) and higher stage of membranous nephropathy (P = 0.001). During follow-up 24 patients developed RD, almost equally distributed between patients with and without FSGS. Renal survival was numerically, but not significantly, lower in patients with FSGS. In Cox proportional hazard analysis, only serum creatinine at the time of biopsy was an independent predictor of RD or ESRD (P < 0.001). In patients with known urinary beta2M, there was no significant correlation with FSGS score (P = 0.174). CONCLUSION: FSGS is not an accurate prognostic marker in iMN. Histological scoring of FSGS is inferior to measurement of urinary proteins in predicting renal outcome in iMN.     

血清胱抑素C和尿微量白蛋白联合检测在人类免疫缺陷病毒感染者肾功能损伤检测中的应用价值

目的评估血肌酐和尿常规的常规检测基础上联合血清胱抑素C和尿微量白蛋白检测在人类免疫缺陷病毒（HIV）感染者肾功能损伤检测中的应用价值。 方法以2019年2～5月于首都医科大学附属北京地坛医院感染一科住院的169例HIV感染者为研究对象，完善其尿常规、尿微量白蛋白、血肌酐、血清胱抑素C检测；分析尿蛋白及尿微量白蛋白的阳性检出率及其差异，血肌酐升高及血清胱抑素C升高的比例及其差异。计算应用替诺福韦酯（TDF）及合并丙型肝炎、高血压、糖尿病、肿瘤的肾功能损伤的相对危险度。 结果169例HIV感染者中尿常规示尿蛋白阳性者5例（3.0%），尿微量白蛋白升高者17例（10.1%），两者阳性检出率差异具有统计学意义（χ² = 5.9、P = 0.007）。血肌酐升高者10例（5.9%），血清胱抑素C升高者20例（11.8%），两者阳性检出率差异具有统计学意义（χ² = 3.0、P = 0.042）。在尿常规和血肌酐检测的基础上联合检测尿微量白蛋白和血清胱抑素C的总体阳性检出率为49例（30.0%）。CD4⁺ T淋巴细胞计数< 200个/μl与≥ 200个/μl组患者血清胱抑素C水平分别为0.94（0.83，1.05）mg/L、0.85（0.77，0.95）mg/L，差异具有统计学意义（Z =-3.02、P = 0.003）。应用TDF及合并丙型肝炎、高血压、糖尿病、肿瘤的肾功能损伤的相对危险度分别为1.1、1.5、1.9、2.2和1.4。 结论HIV感染者中，单纯以尿常规为依据评估有无蛋白尿，以血肌酐水平为依据评估肾小球滤过功能会低估肾功能损伤的患病率。在常规检测血肌酐和尿常规的基础上联合检测血清胱抑素C和尿微量白蛋白在提高HIV感染者肾功能损伤检出率方面具有重要的应用价值。低CD4⁺ T淋巴细胞计数、应用TDF及合并丙型肝炎、高血压、糖尿病、肿瘤均为肾功能损伤的危险因素。     

C4d沉积在抗体介导的慢性排斥反应中的临床意义

目的 探讨移植肾肾小管周围毛细血管补体片段C4d沉积与抗体介导的慢性排斥反应的病理形态、移植肾功能及预后的关系.方法 应用免疫组织化学技术检测77例肾移植受者移植肾肾小管周围毛细血管中C4d的沉积情况,根据检测结果分为C4d阳性组(35例)和C4d阴性组(42例).检测并比较C4d阳性和阴性组受者移植肾的病理形态结构、移植肾功能及预后.结果 与C4d阴性组比较,C4d阳性组受者移植肾肾小管萎缩和肾小球基底膜增生分层的例数明显增多,差异有统计学意义(P＜0.05).C4d阳性组受者的血肌酐水平在移植肾穿刺后12个月时较C4d阴性组受者明显升高,分别为(379.1±260.2)μmol/L和(260.5±175.3)μmol/L,差异有统计学意义(P＜0.05).C4d阳性组受者移植肾穿刺明确C4d阳性后1年内移植肾存活率为62.9%(22/35),而阴性组受者为83.3%(35/42),两组比较,差异有统计学意义(P＜0.05).结论 在抗体介导的慢性排斥反应中,移植肾C4d沉积常见的病理学改变为肾小管萎缩和肾小球基底膜增生分层,C4d阳性抗体介导的体液性慢性排斥反应加快了移植肾功能丧失的进展速度,使C4d阳性受者的移植肾功能丧失率升高,导致存活率降低.     

移植肾组织中补体C4d沉积在CAN的诊断和治疗中的临床意义

目的 探讨移植肾组织中补体C4d沉积在慢性移植肾肾病(CAN)的诊断和治疗中的临床意义.方法 将2000年1月至2008年8月间诊断为CAN,且已行移植肾活检,并能收集到活检后2年以上随访资料者纳入研究.符合标准者共有86例,其中男性53例,女性33例,移植时年龄18～65岁.应用免疫组织化学染色方法检测移植肾组织活检标本C4d的表达.所有患者在行移植肾穿刺诊断为CAN后均给予了常规治疗.结果 86例患者中,C4d沉积阳性者(C4d阳性组)39例,C4d沉积阴性者(C4d阴性组)47例,两组患者在性别、年龄、供肾来源、多次移植、移植时群体反应性抗体水平等各指标的比较,差异均无统计学意义(P＞0.05).活检2年后,C4d阳性组和阴性组患者的SCr水平分别为(551.5±140.4)和(443.0±133.1)μmol/L,两组比较,差异有统计学意义(P＜0.05);并且C4d阳性组患者移植肾功能丧失率(23.1%,10/39)也显著高于C4d阴性组(8.5%,4/47),两组比较,差异有统计学意义(P＜0.05).CAN治疗前,C4d阳性组发生高血压和高血脂者多于阴性组(P＜0.05);常规治疗后,剔除移植肾功能丧失者,两组间发生高血压、高血脂、高血糖和高血尿酸者差异无统计学意义(P＞0.05).结论 C4d阳性的CAN患者提示有慢性体液排斥反应的参与,临床常规治疗预后较差,若针对体液免疫反应进行干预,能够改善移植肾长期存活.     

肾移植术后患者血清半胱氨酸蛋白酶抑制物水平与肾功能的关系

目的 探讨肾移植术后患者血清半胱氨酸蛋白酶抑制物(CyC)的水平变化与移植肾功能的相关性.方法选择193例使用他克莫司(FK506)加霉酚酸酯(MMF)加泼尼松(Pred)三联免疫抑制剂肾移植患者术后的血、尿标本,测定血清CyC和血、尿肌酐.经统计学分析,与常规的血清肌酐(SCr)浓度及尿肌酐清除率(CCr)和内生肌酐清除率(CkCCr)作相关性比较,评估CyC判断移植肾肾小球滤过功能的敏感性和特异性.结果 193例肾移植患者术后第5天血清CyC、SCr和CCr、CkCCr分别为(1.91±1.28)mg/L、(174.2±129.1)μmol/L、(67.9±27.3)ml/min、(68.1±27.8)ml/min.其中CyC浓度＜1.25 mg/L者42例,1.25～2.00 mg/L者102例,＞2.0 mg/L者49例;SCr浓度＜125/μmol/L者62例,125～200μmol/L者83例,＞200/μmol/L者48例;CkCCr＞80ml/min者52例,80～60 ml/min者96例,＜60 ml/min者45例.CyC与SCr呈正相关(r=0.886,P＜0.001),与CkCCr呈负相关(r=-0.907,P＜0.001);SCr与CkCCr呈负相关(r=-0.889,P＜0.001).非参数受试者工作特征曲线分析CyC、SCr、CCr、CkCCr曲线下面积分别为0.877、0.771、0.832、0.909,其诊断敏感性和特异性分别为91.6%、69.3%,52.2%、96.1%,67.5%、77.1%和84.6%、71.3%. 结论 肾功能轻度损害时,血清CyC比SCr先一步增高,有可能成为评定肾移植患者移植肾功能的敏感性标志物.     

Pathological variants of focal segmental glomerulosclerosis in an adult Dutch population--epidemiology and outcome.

BACKGROUND: A working group has defined five subtypes of focal segmental glomerulosclerosis (FSGS) based on light microscopic assessment (Columbia classification). Limited information is available on the prognostic and therapeutic implications of this classification in a European population. We conducted a retrospective analysis in 93 adult patients with biopsy-proven FSGS to determine the clinical features and outcome of FSGS variants. METHODS: Renal biopsy specimens of adult patients (>16 years) diagnosed with FSGS between 1980 and 2003 were reviewed according to the Columbia classification without the knowledge of clinical outcome. The medical records were reviewed for clinical data. Primary outcomes were remission rate and renal survival. RESULTS: The frequencies of the FSGS variants were: 32% NOS (FSGS not otherwise specified), 37% tip, 26% perihilar and 5% collapsing. Cellular FSGS was not found in the biopsies. The nephrotic syndrome was less frequent in FSGS NOS (57%) and perihilar FSGS (25%) compared to the tip variant (97%). Renal function was significantly better in patients with the tip variant compared to FSGS NOS (P<0.05). Glomerular sclerosis and hyalinosis was most severe in patients with perihilar FSGS, intermediate in FSGS NOS and the least severe in patients with the tip variant. Patients with perihilar FSGS were less likely to receive immunosuppressive medication. Renal survival at 5 years was significantly better for patients with the tip variant (78% for tip vs 63% and 55% for FSGS NOS and perihilar FSGS; P=0.02). Type of FSGS and serum creatinine concentration were independent predictors of renal survival. Remission rate was higher in patients with the tip variant (P=0.1). CONCLUSION: The collapsing variant was rare in our population. Renal survival and remission rates were higher in patients with the tip variant. Use of the classification scheme for FSGS may be clinically useful.     

Clinical significance of phospholipase A2 receptor 1 in patients with idiopathic membranous nephropathy

Objective To explore the role of phospholipase A2 receptor 1 (PLA2R1) in the diagnosis, differential diagnosis and evaluation of idiopathic membranous nephropathy (IMN) in adult patients. Methods A total of 242 renal disease patients diagnosed by renal biopsy from March 2015 to January 2016 were enrolled, consisting of 90 IMN, 20 secondary membranous nephropathy (SMN), 82 IgA nephropathy (IgAN), 30 minimal changed disease (MCD), 16 focal segmental glomerulosclerosis (FSGS) and 4 membranoproliferative glomerulonephritis (MPGN). Their clinical data including age, sex, serum creatinine (Scr), serum albumin and 24 h urinary protein were collected. Serum PLA2R1 was measured by enzyme linked immunosorbent assay. PLA2R and IgG subclasses in glomeruli were detected by indirect immunofluorescence assay. The positive rate of serum PLA2R1 among those groups and its correlation with clinical-pathological parameters were analyzed. Results Compared with IMN patients, SMN, MCD and FSGS patients were younger (all P＜0.01); IgAN patients were younger and had higher serum albumin and lower 24 h proteinuria (all P＜0.001); MPGN patients had higher Scr (all P＜0.01). The positive rate of serum PLA2R1 was 75.6% in IMN patients, while it was 0.0% in non-IMN patients. The distribution between serum PLA2R1 and pathological diagnosis had difference (P＜0.001), their positive coincidence rate was 100%, negative coincidence rate was 87.4%, total coincidence rate was 90.9% and their consistency was well (Kappa=0.795, P＜0.001). Among IgG subtype comparisons between IMN patients and SMN patients in the glomeruli, only moderate or more positive IgG4 had statistical differences (82.2% vs 5.0%, P＜0.001); the positive rate of glomerular PLA2R1 was 41.1% in IMN patients, higher than 10.0% in SMN patients (P=0.009); positive PLA2R1 with moderate or more positive IgG4 in glomeruli in IMN patients was more than that in SMN patients (40.0% vs 0.0%, P＜0.001), which could improve the diagnostic specificity of IMN. In IMN patients serum PLA2R1 and glomerular PLA2R1 had statistical differences (P＜0.001). Spearman rank correlation analysis showed that serum PLA2R1 of IMN patients positively correlated with 24 h proteinuria (r=0.315, P=0.002), negatively correlated with serum albumin (r=-0.228, P=0.030) and didn't correlate with Scr (r=0.199, P=0.059). Conclusions Serum PLA2R can be used as the specific indicator for diagnosis, differential diagnosis of IMN and to reflect the severity of IMN in patients.     

Mice with focal segmental glomerular sclerosis are induced by adriamycin and its mechanism

Objective To establish adriamycin-induced focal segmental glomerular sclerosis (FSGS) mice model, and observe the expressions of and relation between oxidative stress and p38 MAPK signal pathway in renal injury. Methods Eight-week-old male Balb/c mice were randomly divided into FSGS group (n=20) and control group (n=20). In FSGS group mice were intravenously injected with a single dose of adriamycin (0.01 mg/g), and mice in control group were received saline with the same dose. At day 3, 7, 14, 22 and 32, urine protein-to-urine creatinine ratio (P/C) was detected. At day 22 and 32, serum creatinine, blood urea nitrogen, nitric oxide (NO) and reactive oxygen species (ROS) in blood and urine, and ROS in kidney tissues were detected; changes of pathological morphology in renal tissue were analyzed by HE stain; the expressions of NF-κB, CD36, IL-13, BAX and Bcl-2 mRNA were detected by real time quantitative PCR; the expressions of NF-κB, p-p38 and p-ERK1/2 protein were detected by Western blotting. Results Compared with that in control group, P/C was gradually increasing in FSGS group, and peaked at day 22 (P＜0.05). At day 22 and 32, mice had higher creatinine, serum creatinine, urea nitrogen, ROS and NO in FSGS group than those in control group (all P＜0.05). There were mild hyperplasia of mesangial cells and mesangial matrix, segment with moderate exacerbations, podocytes with significant proliferation, and the capillary loops of the stenosed in the glomerular in FSGS group at day 32. Compared with those in control group, the mRNA expression of NF-κB, BAX, IL-13 and CD36, and the protein expressions of NF-κB and p-p38 MAPK were gradually increased in FSGS group, all showed statistical differences at day 32 (all P＜0.05); the expression of p-ERK1/2 was increased at day 22 (P＜0.05) but was reduced at day 32 (P＜0.05). Conclusions Adriamycin has induced FSGS in mice successfully, which may through oxidative stress activating p38, up-regulating NF-κB, increasing the inflammatory cytokines and inducing apoptosis pathways.     

Protective effect of C5a receptor 1 antagonist on ascending urinary tract infection in mice

Objective To investigate the protective effect of complement 5a receptor 1 (C5aR1) antagonist on ascending urinary tract infection in mice. Methods (1) Female C57BL/6 mice were randomly divided into experimental and control groups: 38 mice in each group, and inoculated with E. coli by urethral catheterization to set up the ascending urinary tract infection model. C5aR1 antagonist (W54011 or PMX53) and corresponding control (PBS or control peptide) were initially given either at 2 h before or 3 h after infection by intraperitoneal injection. Mice were sacrificed to assess the infection in bladder and kidney at 24 or 48 h after infection. The bacterial load of bladder and kidney tissue was measured by agar plate assay. The mRNA expression of renal inflammatory factors was detected by real-time RCR. The renal tissue injury and inflammatory cell infiltration were assessed by HE staining and pathological scores. (2) Primary cultured renal tubular epithelial cells were randomly divided into antagonist and control groups to detect and compare the bacterial adhesion to renal tubular epithelial cells in vitro. Results Compared with control groups, the initial delivery of C5aR1 antagonist (W54011 or PMX53) before E.coli inoculation reduced the bacterial load in bladder and kidney tissue 48 h after infection (all P＜0.01). In experimental group given W54011 before infection, the renal pathological scores were reduced (both P＜0.05), as well as renal inflammatory factor expressions: CXCL-1 mRNA, IL-6 mRNA and TNF-α mRNA (all P＜0.05). Compared with corresponding control groups, the initial delivery of PMX53 after E. coli inoculation could also reduce the bacterial load in bladder and kidney tissue 48 h after infection (both P＜0.01). Furthermore, C5aR1 antagonists W54011 and PMX53 could decrease bacteria adhesion to renal tubular epithelial cells in vitro, compared with control groups (both P＜0.05). Conclusions C5aR1 antagonists can significantly attenuate renal tissue injury, ameliorate renal inflammation and the adhesion of bacteria to renal epithelial cells. C5aR1 may be an effective target for the prevention and treatment of urinary tract infection.     

血清胱抑素C对肝硬化病人肾功能损害的早期诊断价值研究

目的 探讨血清半胱氨酸蛋白酶抑制剂C(Cys C)检测对肝硬化病人肾功能损害早期诊断的意义.方法 测定76例肝硬化病人24 h肌酐清除率(Ccr)以及血清肌酐(SCr)和血清Cys C水平.以CCr＜80 ml/min/1.73 m2作为肾功能损害诊断标准,采用t检验、相关性分析和ROC曲线分析探讨Cys C的诊断价值.结果 在Child分级肝损害病人的肾功能评估能力比较中,Cys C能灵敏反映CCr变化,而Scr的反映能力明显低于Cys C.SCr与CCr有着显著的负相关性(CysC:r=-0.763,P＜0.001;SCr:r=-0.571,P＜0.01),而Cys C的相关系数较高.ROC曲线分析显示Cys C的曲线下面积(AUC)值明显高于SCr(0.830比0.612).结论 与SCr比较,Cys C能更准确地早期发现肝硬化病人的肾功能损害,常规监测肝硬化病人Cys C水平,对预防肝肾综合征的发生具有积极意义.     

Renal ultrasound elastography can reflect clinical-pathological changes in chronic kidney disease patients

Objective To analyze how is the elastography of renal tissue correlated to clinical biochemical indexes and pathological changes in patients with chronic kidney disease (CKD), and to explore the potential of renal elastography to become a new noninvasive method available for the dynamic monitoring of renal disease progression, as well as its efficacy assessment and prognosis evaluation. Methods Patients admitted to the department of nephrology of the First Affiliated Hospital of China Medical University and received renal biopsy from August 2014 to January 2015 were selected. One hundred and thirteen cases of CKD patients, 61 males and 52 females were enrolled, including 23 cases of IgA nephropathy, 39 cases of membranous nephropathy, 15 cases of minimal change nephropathy and 7 cases of focal segmental glomerulosclerosis. The Young modulus of renal cortex and medulla (YMcortex and YMmedulla) were detected by Aix Plorer type full digital color Doppler ultrasound. The correlations between the YMs and clinical biochemical indicators in blood and urine, and the difference of YMs among different pathological changes in patients with CKD were analyzed by statistics. Results The YMcortex and YMmedulla in CKD patients were higher than those in the control group (all P＜0.05); and with the progression of CKD, the YMcortex and YMmedulla gradually increased. The YMcortex in CKD G5 patients was higher than that in CKD G1-3 patients (all P＜0.05). The YMmedulla in CKD G3-5 patients was higher than that in CKD G1-2 patients (all P＜0.05). The YMcortex was correlated with systolic pressure, serum creatinine, cystatin C, serum albumin, serum phosphorus, calcium and phosphorus product, uric acid, intact parathyroid hormone (iPTH), urinary NAG, estimate glomerular filtration rate (eGFR) and hemoglobin (all P＜0.05). The YMmedulla was correlated with systolic pressure, serum creatinine, serum albumin, uric acid, iPTH, urine microalbumin (MA), urinary NAG and hemoglobin (all P＜0.05). Serum cystatin C (β=0.485, P=0.018) and uric acid (β=0.418, P=0.039) were independently correlated with the YMcortex. Serum creatinine (β=0.380, P=0.019), uric acid (β=0.482, P=0.004) and smoking (β=0.337, P=0.009) were independently correlated with YMmedulla. The YMcortex and YMmedulla in different pathological types were statistically significant (P＜0.001, P=0.003). The YMcortex and YMmedulla in patients with membranous nephropathy and IgA nephropathy were higher than those in the patients with minimal change nephropathy (all P＜0.05). The YMmedulla in patients with focal segmental glomerulosclerosis was higher than that in the patients with minimal change nephropathy (P＜0.05). The YMcortex in the patients with phases Ⅳ and Ⅴ based on the Lee grading system of IgA nephropathy was higher than that in the patients with phases Ⅱ and Ⅲ (P＜0.05). According the Oxford classification for IgA nephropathy, the YMcortex and YMmedulla in the T1 and T2 patients were higher than those in the T0 patients (P＜0.05). The YMcortex and YMmedulla showed no statistically significant differences among different stages of membranous nephropathy. Conclusions The YMcortex and YMmedulla are associated with the progress of renal insufficiency, which may become new indicators for determining CKD progression. The renal ultrasound elastography may become a new non-invasive method for early diagnosing CKD, dynamic monitoring disease progression, and assessing efficacy and prognosis.     

Mesangial C3 deposition and decreased serum C3levels in patients with IgA nephropathy

Objective To explore theclinical significance of complementactivation in IgA nephropathy (IgAN) patients and provide new potential therapy targets. Methods Biopsy-proven IgAN patients admitted in our renal center were retrospectively recruited. Demographic, baseline clinical and pathological data were recorded as well as the follow-up results. Patients were divided into three groups, negative, weak positive and strong positive group, according to the intensity of C3 deposition in mesangial area of glomurili. Decreased serum C3 level was defined as C3＜85 mg/dl. Results In this study, 528 IgAN patients were recruited and meanfollow-up time was3 years. There were 119 (22.5%), 164(31.1%), 245(46.4%) patients in the negative, weak positive and strong positive group respectively; 93(21.7%) patients had decreased serum C3 level and 335(78.3%) patients had normal serum C3 level; Significant negative correlation was found between mesangial area of C3 deposition and serum level of C3(r＝-0.209, P＜0.01). Theage or sex were similar among different groups of mesangial C3 deposition. In univariate analysis, higher baselineserum creatinine,uric acid and IgAlevels, and lower estimated glomerular filtration rate(eGFR), body mass index (BMI) levels were associated with a higher grade of mesangial C3 deposition (P＜0.05). Endocapillary hypercellularity and tubular atrophy or interstitial fibrosis were more prominent in patients with higher grade mesangial deposition of C3. Compared with the patients with normal serum C3 level, patients with decreased serum C3 level had lowerwhite blood cells,hemoglobin,triglyceride, cholesterol, eGFR level and higher serum creatinine level(P＜0.05). During the follow-up,a total of 54 patients developed to end stage renal disease (ESRD), the incidence of ESRD was 23.7% in patients with decreased serum C3 level and 8.4% with normal C3 level.Kaplan-Meieranalysis showed that median outcome-free survival timeof patients with decreased serum C3 levelwas significantshorter than patients with normal serum C3 level [(145.0±22.5) months vs (150.8±17.0) months, P＜0.01]. Cox regression proportional hazards models showed that after adjusting by sex, ageand clinical indicators (MAP, eGFR, serum albumin, urine protein and hemoglobin level), decreased serum C3level (HR＝0.97, 95%CI 0.96, 0.99, P＜0.01) remained be an independent riskfactor of ESRD. Conclusions There are different levels of complement activation in patients with IgAN. Complement activation is associated with baseline renal function and clinical outcomes, and decreased serum C3level is an independent riskfactor of ESRD in IgAN patients. Complement activation may be involved in the progression of IgAN.     

Clinicopathological and prognostic analysis of children with primary IgA nephropathy with C1q deposition

Objective To investigate the clinical and pathological features and prognosis of children with IgA nephropathy with C1q deposition. Methods The children with IgA nephropathy diagnosed by renal biopsy from January 1, 2000 to December 30, 2017 were retrospectively analyzed and divided into C1q deposit group and C1q negative group according to glomerular immunofluorescence examination. Follow-up until the patient's serum creatinine doubled, glomerular filtration rate decreased by more than 50%, entering end-stage kidney disease, renal replacement therapy or death. Kaplan-Meier survival analysis was used to evaluate the renal survival rate in two groups. Univariate and multivariate Cox proportional hazard regression models were used to analyze the effect of C1q deposition on the prognosis of patients with IgA nephropathy. Results There were 60 cases in C1q deposition group and 60 cases in C1q negative group. (1) the initial eGFR and plasma albumin in C1q deposition group were lower than those in C1q negative group, while the levels of serum creatinine, serum cholesterol and 24 hour urinary protein in C1q group were higher than those in C1q negative group (all P＜0.05). (2) pathological indexes: Mesangial cell proliferation, tubular atrophy/interstitial fibrosis, and cell/fibrocytic crescein score in C1q negative group were significantly higher than those in C1q negative group (all P＜0.0.5). (3) Kaplan-Meier analysis showed that there was significant difference in renal cumulative survival rate between the two groups (Log-rank test: χ2=6.801, P=0.009). Cox proportional hazard regression model showed that the risk of renal end-point events in IgAN children with C1q deposition group was 5.772 times higher than that in C1q negative group (HR=5.772, 95%CI: 1.353-24.6211, P=0.018). Conclusion C1q deposition is an independent risk factor for the progress of renal function in IgA nephropathy children.     

Urinary epidermal growth factor excretion in children with chronic renal failure.

To investigate the excretion of urinary epidermal growth factor (EGF) in children with chronic renal failure (CRF), we have measured the urinary EGF/creatinine ratio (EGF/Cr) and the 24-hour urine EGF concentration in 19 children with CRF, 11 children with kidney disease and normal creatinine clearance, and 12 healthy children. Children with CRF had a significantly lower daily urine EGF concentration as well as urinary EGF/Cr. In contrast, children with kidney disease and normal renal function had normal daily urine EGF levels and urinary EGF/Cr. Accompanied by no difference in serum EGF between these two groups of patients, these data provide indirect evidence of the kidney as a source of human urinary EGF. There was a positive correlation of urinary EGF/Cr with creatinine clearance in all renal patients (r = 0.608, n = 30, p < 0.001). A much better correlation was found between daily urine EGF and creatinine clearance (r = 0.855, n = 30, p < 0.001). Our results implicate that there is a functional relationship between glomerular filtration and urinary EGF excretion, and that the urinary EGF/Cr may be a reliable indicator of urinary EGF excretion in children with CRF.     

原发性肾病综合征患者中性粒细胞明胶酶相关脂质运载蛋白的变化及意义

目的 探讨原发性肾病综合征(PNS)患者中性粒细胞明胶酶相关脂质运载蛋白(NGAL)的变化以及与病理类型、肾小管间质损伤程度、临床指标的关系. 方法 40例PNS患者按有无急性肾小管坏死(ATN)分急性肾损伤(AKI)组及非AKI组,按病理类型分微小病变型肾病(MCD)组、系膜增生性肾小球肾炎(MsPGN)组、局灶性节段性肾小球硬化(FSGS)组、膜增生性肾小球肾炎(MPGN)组、膜性肾病(MN)组;20例健康体检者及20例因肾肿瘤做肾切除术但远离肿瘤部位的正常肾组织作正常对照.采用酶联免疫吸附试验(ELISA)法检测血清、尿液NGAL水平,免疫组织化学染色法观察肾组织NGAL表达.结果 (1) AKI组患者血、尿NGAL水平及肾组织NGAL表达显著高于非AKI组及对照组(P＜0.05).(2)MPGN组及FSGS组患者血、尿NGAL水平及肾组织NGAL表达显著高于其他病理类型组(P＜0.05).(3)在肾小管间质发展至重度病变之前,随着肾小管间质损伤程度的加重,血、尿NGAL水平及肾组织NGAL表达逐渐升高;在肾小管间质发展至重度病变时,血NGAL水平及肾组织NGAL表达下降(P＜0.05).(4)血、尿NGAL水平及肾组织NGAL表达与血肌酐呈正相关(r值分别为0.198、0.352、0.146,P值分别为0.048、0.000、0.028),与尿素氮呈正相关(r值分别为0.199、0.278、0.325,P值分别为0.043、0.000、0.019),与血白蛋白呈负相关(r值分别为-0.384、-0.318、-0.259,P值分别为0.028、0.024、0.020),与尿渗透浓度呈负相关(r值分别为-0.250、-0.256、-0.277,P值分别为0.012、0.027、0.002).结论 NGAL可作为预测PNS患者AKI的敏感指标,在一定程度下可用于评价肾小管间质病变程度及肾功能.     

Clinical significance of serum and urine angiopoietin-like 3 and 4 in children with primary nephrotic syndrome

Objective To explore the clinical significance of the serum and urine angiopoietin (ANGPTL) 3 and 4 levels in children with primary nephrotic syndrome (PNS). Methods Serum and urine samples from 180 children with PNS admitted from September 2012 to August 2013, and from 18 healthy children as control, were analyzed. Serum and urine ANGPTL3 and 4 concentrations were detected by ELISA. Urine protein (Up), urine creatinine (Ucr), serum creatinine (Scr), blood urea nitrogen (BUN), triglyceride (TG) and total cholesterol (TC) levels were analyzed by automatic biochemical analyzer. Data were analyzed by SPSS 19.0. Results (1) Serum ANGPTL3 concentration in PNS children was higher than that in healthy children population [1210.95 (671.28-1571.87) μg/L vs 308.20 (230.05-372.26) μg/L, P＜0.01]; Urine ANGPTL4/Cr in PNS children was also higher than that in healthy children [115.57 (26.50-129.81) ng/g vs 11.26 (2.23-15.11) ng/g, P＜0.01]; Serum ANGPTL4 concentration and urine ANGPTL3/Cr in PNS children had no difference with those in healthy children population. (2) ANGPTL3 serum levels were positively correlated with age at onset (r=0.199, P=0.047), duration of disease (r=0.501, P=0.027), 24 h urine protein excretion (r=0.384, P=0.004), Up/Ucr (r=0.367, P=0.006), TG (r=0.314, P=0.021), and TC (r=0.444, P=0.001), while controlling the serum lipid level, serum ANGPTL3 level was also correlated with 24 h urine protein excretion (r=0.348, P＜0.001) and Up/Ucr (r=0.312, P＜0.001); Urine ANGPTL4/Cr was positively correlated with 24 h urine protein excretion (r=0.318, P=0.019), Up/Ucr (r=0.117, P=0.044). (3) No difference of serum and urine ANGPTL3 and 4 levels were found among steroid-sensitive, steroid-resistant, steroid-dependent PNS groups, as well as between the frequency relapse or non-frequency relapse groups, while in steroid-dependent and frequency relapse NS children, serum ANGPTL3 level could reflect the curative effect on proteinuria. (4) In PNS children with similar degree of proteinuria and lipid levels, the serum ANGPTL3 levels varied in different pathological types. Conclusions Serum ANGPTL3 level may be an important indicator of PNS incidence, disease severities, pathological types and curative effect on proteinuria in PNS. Urine ANGPTL4 level is correlated with proteinuria, which may have the clinical reference value in PNS.