Tissue-specific expression of renin-angiotensin system components in IgA nephropathy

BACKGROUND: The renin-angiotensin II system (RAS) has been implicated in the development of glomerulonephritis. The aims of this study were to determine (1) the expression of RAS components, angiotensin (Ang II)-forming enzymes [angiotensin-I-converting enzyme (ACE) and chymase], and Ang II receptors, and (2) the correlation between RAS expression and severity of tissue injury in IgA nephropathy (IgAN). METHODS: The expression levels of ACE, chymase, and Ang II type 1 and type 2 receptor (AT1R and AT2R) mRNAs were determined by in situ hybridization in renal specimens from 18 patients with IgAN, 5 patients with non-IgA mesangial proliferative glomerulonephritis (non-IgAN) and 10 patients with nonmesangial proliferative glomerulonephritis (minimal change nephrotic syndrome, n = 5, and membranous nephropathy, n = 5). Normal portions of surgically resected kidney served as control. RESULTS: In normal kidney, a few mesangial cells and glomerular and tubular epithelial cells weakly expressed ACE, chymase and AT1R mRNAs. In IgAN and non-IgAN samples, ACE, chymase, AT1R and AT2R mRNAs were expressed in resident glomerular cells, including mesangial cells, glomerular epithelial cells and cells of Bowman's capsule. The glomerular expressions in IgAN were stronger than in minimal change nephrotic syndrome and membranous nephropathy. In IgAN, the expressions in glomeruli correlated with the degree of mesangial hypercellularity, whereas the expression levels were weaker at the area of mesangial expansion. IgAN with severe tubulointerstitial injury showed expression of ACE, chymase, AT1R and AT2R mRNAs in atrophic tubules and infiltrating cells and such expression correlated with the degree of tubulointerstitial damage. CONCLUSION: Our results suggest that renal cells can produce RAS components and that locally synthesized Ang II may be involved in tissue injury in IgAN through Ang II receptors in the kidney.     

少量蛋白尿IgA肾病患者镜下血尿与病理指标的相关性分析

目的探索少量蛋白尿IgA肾病(IgAN)患者镜下血尿发生与病理指标的相关性。 方法回顾性分析2007年1月1日至2012年12月31日在解放军总医院经肾穿刺活检首次诊断的原发性IgAN、尿蛋白<0.5 g/24 h且无肉眼血尿患者。采集患者肾穿刺活检前1周内的血压、尿蛋白定量、尿红细胞形态及计数、肾功能等指标。肾活检后的病理指标按照IgAN牛津分型更新版评价,采用Poisson回归分析镜下血尿水平与病理指标的相关性。 结果共纳入尿蛋白<0.5 g/24 h的IgAN患者88例,其中无镜下血尿组22例,非满视野镜下血尿组58例,满视野镜下血尿组8例。Poisson回归分析显示在校正患者的尿蛋白和肾功能(eGFR)水平后,新月体形成(OR 6.55,95%CI 2.68～15.98)和系膜细胞增殖(OR 4.92,95%CI 1.75～13.83)与IgAN患者镜下血尿水平相关,系膜细胞增殖病变与节段硬化或球囊粘连病变存在交互作用(OR 3.82,95%CI 1.30～11.25)。 结论在蛋白尿少于0.5 g/d的IgAN患者中,患者镜下血尿水平相关的病理因素主要是增殖性病变,包括系膜细胞增殖和新月体形成。系膜细胞增殖病变合并节段硬化和(或)球囊粘连病变,与镜下血尿水平的相关性显著增加。     

Validation of some pathophysiological mechanisms of the CKD progression theory and outcome prediction in IgA nephropathy

Background: The "remnant kidney" chronic kidney disease (CKD) progression theory based on hemodynamic, proteinuric and inflammatory mechanisms consequent to nephron loss has not been confirmed in a human disease. The aim of this study was to evaluate whether some of these mechanisms are present in IgA nephropathy (IgAN) and predict functional outcome. Methods: In 132 IgAN patients (68 untreated, 64 angiotensin-converting enzyme inhibitor [ACEi]-treated) fractional excretion of IgG (FEIgG) and alpha1-microglobulin, proteinuria/day and beta-NAG excretion were divided by percentage of nonglobally sclerotic glomeruli ("surviving glomeruli" [SG]) to assess the effective glomerular loss and tubular load of proteins in surviving nephrons. Proteinuric markers were compared between 4 SG groups: group 1: <=50%; group 2: >50% and <80%; group 3: >=80% and <100%; and group 4: 100%. The outcome prediction (estimated glomerular filtration rate [eGFR] improvement and stability, progression) was assessed comparing low- and high-risk groups for each marker. Results: Proteinuric markers showed increasing values in parallel with reduction of percentages of SG (p<0.0001). FEIgG/SG, 40-fold higher in patients with SG <=50% vs. SG=100% (0.00040 ± 0.00039 vs. 0.00001 ± 0.00002, p<0.0001), was the most powerful outcome predictor: in ACEi-untreated patients, FEIgG/SG less or greater than 0.00010 predicted eGFR improvement and stability (88% vs. 12%, p<0.0001) and end-stage renal disease (ESRD) + eGFR reduction >=50% (2% vs. 87.5%, p<0.0001); ACEi treatment reduced ESRD+eGFR reduction >=50%: 36% vs. 87.5% (p=0.002). In patients with FEIgG/SG <0.00010 the eGFR increase is significantly higher in ACEi-treated for >=70 months versus ACEi-untreated with follow up >=70 months (+35% ± 23% vs. +13% ± 8%, p=0.004). Conclusions: In IgAN, progressive nephron loss is associated with an increase of proteinuric markers of glomerular and tubular damage. FEIgG/SG is the best outcome predictor. These data represent the first validation in a human disease of some pathophysiological mechanisms of CKD progression theory.     

儿童原发性肾病综合征中血管生成素样蛋白3的表达

目的 研究血管生成素样蛋白3 (angiopoietin-like 3 protein，ANGPTL3)在儿童原发性肾病综合征(PNS)患者肾组织中表达分布及其参与蛋白尿发生的机制。方法 ANGPTL3分别与足细胞核标记抗原(WT1)、基底膜标记抗原类肝素硫酸蛋白多糖perlecan进行双标记法免疫荧光染色。应用免疫组化的方法检测ANGPTL3和perlecan在不同病理类型的69例PNS及血尿患儿，包括微小病变(MCD)31例、膜性肾病(MN)6例、局灶节段硬化性肾小球肾炎(FSGS)6例、IgA肾病16例、薄基底膜肾病(TBMN)10例以及2例正常对照肾组织中表达，并以IMS彩色图像分析系统量化为免疫组化指数。在MCD病例中将尿蛋白肌酐比值分别与肾组织中ANGPTL3和perlecan肾小球内染色强度及电镜下平均足突宽度(FWP)进行相关分析。对不同病理诊断时间(发病至肾穿刺)分组患儿肾小球ANGPTL3和perlecan的表达进行比较。结果 (1)ANGPTL3在正常肾组织呈现微弱的沉积，而在不同病理类型的肾病综合征患儿的肾组织的肾小球和肾小管存在不同程度的表达。肾小球内ANGPTL3表达量在MCD(7.49±1.96)、MN(6.27±0.98)中显著高于正常对照(0.02±0.001)、TBMN(0.02±0.001)及FSGS(3.14±0.49)(均P < 0.05)。在IgA肾病(系膜增生型)中，蛋白尿组肾小球中ANGPTL3表达量显著高于单纯血尿组(1.90±0.81比0.03±0.01， P < 0.05)。(2) 在MCD肾组织中，WT1及perlecan荧光双标记染色显示， ANGPTL3在足细胞胞浆及沿肾小球血管袢表达。(3) ANGPTL3在肾小球表达量分别与尿蛋白肌酐比值及电镜下平均足突宽度正相关(r为0.86、0.84，P均<0.05)，并与perlecan在肾小球内表达量负相关(r为-0.83，P < 0.05)。(4)不同发病年限的MCD患儿肾组织中肾小球ANGPTL3及perlecan的表达无显著性差异。结论 在不同程度的蛋白尿及不同足突融合程度的肾组织中存在ANGPTL3的表达差异。在MCD中，ANGPTL3主要在足细胞胞浆表达，肾小球中ANGPTL3的表达与蛋白尿程度及足细胞融合程度呈正相关。     

Mesangial changes in IgA nephropathy in children

The mesangial changes in 92 renal biopsy specimens from 81 children with IgA nephropathy were correlated with the clinical and the other renal biopsy findings. Three types of mesangial changes were identified: mesangial hypercellularity was predominant compared with the increase in matrix in 34 biopsy specimens (type A), the degrees of mesangial hypercellularity and matrix increase were similar in 36 (type B) and matrix increase was predominant in 22 (type C). The interval between the onset of disease and biopsy was significantly shorter in biopsies with type A mesangial changes (P less than 0.01) and significantly longer in those with type C (P less than 0.01). Serial pathologic observations revealed that predominant mesangial hypercellularity was almost exclusively seen in the initial biopsy but predominant matrix increase was usually seen in the follow-up biopsy. The percentage of glomeruli showing sclerosis was significantly higher in biopsies with type C mesangial changes (P less than 0.05). At the latest follow-up, 58% of the patients showing type A and 57% showing type B lost their proteinuria, whereas only 9% showing type C lost their proteinuria (P less than 0.01). These findings suggest that predominant mesangial hypercellularity is characteristic of the early lesion of childhood IgA nephropathy, and progression of disease leads to gradual decrease of mesangial cellularity and increase of matrix with sclerosis.     

Cell proliferation and regulation of apoptosis in human glomerulonephritis

Summary: We examined the expression of the protein products and mRNA of protooncogenes associated with cell proliferation and inhibition of apoptosis (bcl-2, c-fos, c-myc, and p53) in normal renal tissues and biopsy specimens from patients with glomerulonephritis. Bcl-2 was up-regulated in the glomeruli of several forms of human glomerulonephritis. Bcl-2 expression was significantly correlated with mesangial hypercellularity and proteinuria, c-myc and c-fos expression is associated with mesangial proliferation and matrix expasion in human glomerulonephritis and may predict subsequent progression.     

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.     

Analysis of association between segmental glomerulosclerosis and renal function decline in IgA nephropathy

Objective To explore the relationship between segmental glomerulosclerosis and the change of renal function in IgA nephropathy (IgAN). Methods It was a single-center retrospective cohort study. The patients with biopsy-proven primary IgAN who were hospitalized in Shenzhen Second People's Hospital from January 1, 2011 to December 31, 2018 were included. Participants with a secondary cause of IgAN, without baseline serum creatinine or renal pathology data for Oxford classification, baseline estimated glomerulofiltration rate (eGFR)＜30 ml?min-1?(1.73 m2)-1, follow-up time＜6 months, or less than three times measurements of followed-up serum creatinine were excluded. The clinical data, laboratory tests and renal pathology data and so on were collected. Patients were divided into absence of segmental glomerulosclerosis (S0) group and segmental glomerulosclerosis (S1) group according to the Oxford classification. The generalized additive mixed model was used to analyze the associations of segmental glomerulosclerosis and longitudinal renal function decline (Renal function was evaluated by using the eGFR). Results There were 280 patients included in this study, with 199 patients in S0 group, and 81 patients in S1 group. Compared with S0 group, patients in S1 group exhibited higher levels of triglyceride, serum uric acid as well as 24-hour urinary protein, and a lower level of eGFR, and had higher proportions of tubular atrophy and interstitial fibrosis (T) (all P＜0.05). After adjusting for age, gender, mean arterial pressure, 24-hour urinary protein, mesangial hypercellularity (M), endocapillary hypercellularity (E), T and crescent (C) in the generalized additive mixed model, the effect value of S1 (the difference of baseline eGFR between S1 group and S0 group) was -14.09 ml?min-1?(1.73 m2)-1. For every additional year, the eGFR of S0 group decreased 1.29 ml?min-1?(1.73 m2)-1 (95% CI 0.47-2.12, P=0.002) in average, and eGFR decline in S1 group had 2.85 ml?min-1?(1.73 m2)-1 more than that in S0 group [95%CI 1.05-4.64, P=0.002]. Conclusion Segmental glomerulosclerosis is independently associated with the longitudinal decrease in renal function in patients with IgAN, which suggests therapies targeted for improving the early damages of segmental glomerulosclerosis may be essential to delay the renal function decline progression.     

Characteristics of patients with coexisting IgA nephropathy and membranous nephropathy

Background: Coexistence of IgA nephropathy (IgAN) and membranous nephropathy (MN) in the same patient is rare. Few studies have reported the clinical and pathological features of patients with combined IgAN and MN (IgAN–MN).

Methods: The clinico-pathological features, levels of galactose-deficient IgA1 (Gd-IgA1) and autoantibodies against M-type transmembrane phospholipase A₂ receptor (anti-PLA₂R) in sera were compared among IgAN–MN, IgAN, and MN patients.

Results: Twenty-six patients with biopsy-proven IgAN–MN were enrolled. The mean age at biopsy was 43.6?±?15.9?years, and 65.4% were male. Proteinuria and estimated glomerular filtration rate (eGFR) levels in patients with IgAN–MN were similar to that of MN patients. Compared with the IgAN patients, IgAN–MN patients showed a higher median proteinuria level (4.3 vs. 1.2?g/day, p?2, p?p?=?.801). Percentage of IgAN–MN patients with detectable serum levels of anti-PLA₂R was lower than that of MN patients (38.5% vs. 68.6%, p?=?.011).

Conclusions: IgAN–MN patients display similar clinical features to MN patients and milder pathological lesions than IgAN patients. IgAN–MN patients have similar levels of Gd-IgA1 to those of IgAN patients, and a lower proportion of anti-PLA₂R than MN patients.     

68例伴有肾组织乙肝病毒抗原沉积的肾炎患者临床和病理分析

目的：探讨血清乙肝病毒（HBV）标志物与肾组织HBV抗原沉积、肾病理之间的关系，了解乙肝病毒相关性肾炎（HBV—GN）的临床和病理特点。方法：收集成人肾组织中检测到HBsAg和／或HBcAg沉积的肾炎患者68例（以下称沉积阳性组）。随机抽取同期肾穿合并有慢性乙型肝炎但肾组织中不伴HBsAg和／或HBcAg沉积的肾炎患者24例作为对照组（以下称沉积阴性组）。两组均采用间接免疫荧光法检测肾活检组织冰冻切片中HBsAg和HBcAg，荧光定量PCR法检测血清HBV—DNA水平。结果：（1）两组患者在血压、血尿和蛋白尿程度以及肾功能水平均无统计学差异；（2）沉积阳性组肾病理以IgA肾病（IgAN，占51．5％）和不典型膜性肾病（MN，占38．2％）为主；沉积阴性组则以系膜增生性肾炎（MsPGN，占50％）为主；（3）68例患者中13例血清HBV标志物阴性或仅有HBsAb阳性，血HBV—DNA病毒载量〈100拷贝／ml的患者肾组织中检测到HBsAg和俄HBcAg沉积，且免疫荧光显示免疫球蛋白和补体沉积均在3种以上，满堂亮者7例（53．8％）：光镜显示不典型MN9例（69．2％），IgAN3例，MPGN1例。结论：对于成年人依据临床难作出HBV—GN诊断。成人HBV—GN病理表现具有多样性，以IgAN和不典型MN为主，其次为MPGN和MsPGN，FSGS少见；肾组织HBV抗原沉积现象可以出现在血清HBV标志物阴性或仅HBsAb阳性的患者，提示应重视肾组织HBV抗原检测，尽可能降低HBV—GN的漏诊率，尤其是血清HBV标志物阴性的患者。     

Histological differences in new-onset IgA nephropathy between children and adults.

BACKGROUND: It is suggested that IgA nephropathy (IgAN) manifests differently in children vs adults on the basis of biopsy findings. However, this has been difficult to establish owing to the uncertainty of the timing of disease onset in adult IgAN. We addressed this question by comparing both histology and leucocyte accumulation in biopsies of recently diagnosed childhood and adult IgAN. METHODS: Biopsies taken within 2 years from the onset of renal abnormalities in 33 childhood (10 +/- 3 years of age) and 38 adult (35 +/- 6 years) cases of IgAN were examined for histological changes (cellularity in mesangial, endocapillary and extracapillary areas, matrix expansion, adhesions/crescents and interstitial damage), glomerular deposition of immunoglobulin and complement, and the presence of macrophages, activated macrophages and T cells by immunohistochemistry. RESULTS: Glomerular hypercellularity owing to increased cells in mesangial area was prominent in paediatric IgAN and significantly greater than in adult IgAN. In contrast, glomerular matrix expansion, crescent formation and interstitial damage were more severe in adults compared to paediatric IgAN. Indeed, glomerular hypercellularity correlated with proteinuria in paediatric but not in adult IgAN, whereas glomerular matrix correlated with proteinuria and renal function in adult but not in paediatric IgAN. The degree of C3c deposition was significantly greater in paediatric IgAN, while deposition of fibrinogen was greater in adult IgAN. Glomerular and interstitial CD68+ macrophages and a subset of sialoadhesin (Sn)+ activated macrophages were identified in both paediatric and adult IgAN, being significantly greater in number in adult IgAN. Glomerular leucocyte infiltration correlated with proteinuria while interstitial leucocyte infiltration correlated with interstitial damage in both groups. However, only the subset of Sn+ macrophages gave a significant correlation with renal function, glomerular hypercellularity and glomerular matrix. CONCLUSIONS: This study has demonstrated significant differences in the early glomerular lesions of IgAN in children vs adults. Furthermore, Sn+ activated macrophages are implicated in the pathogenesis of IgAN in both patient groups. The prognostic significance of these findings warrants further study.     

Study on glomerular microvascular injury and repair in patients with IgA nephropathy and its relationship with intermedin

Objective To investigate the glomerular microvascular injury and repair in patients with IgA nephropathy (IgAN) as well as its relationship with intermedin (IMD). Methods Eighty cases of renal tissue taken from patients first diagnosed as IgAN in Shanxi Provincial People's Hospital Affiliated to Shanxi Medical University and 15 cases of normal renal tissue were detected by the expression of glomerular IMD, CD31, and VE-cadherin through immunohistochemical method. ELISA method was used to detect VEGF and IMD of plasm from 31 normal subjects and 36 cases chosen from the IgAN patients. Their changes and internal relationship were analyzed according to Lee's and chronic kidney disease (CKD) classification. Results (1) Compared with the control group the expressions of CD31, IMD, and VE-cadherin in IgAN patients were statistically significant (P＜0.01). Compared with the control group the levels of IMD and VEGF in plasma of IgAN patients in early stage of CKD group and late stage of CKD group were statistically significant (P＜0.01). (2) Correlation analysis: the expression of glomerular CD31 and Lee's classification were negatively correlated (r=-0.232, P＜0.05); glomerular IMD was negatively correlated with Lee's classification (r=-0.241, P＜0.05), while positively correlated with glomerular VE-cadherin (r=0.417, P＜0.01). VEGF in plasma of IgAN patients was positive correlated with CKD classification, BUN (r=0.458, 0.409, P＜0.05), and negatively correlated with serum ALB (r=-0.532, P＜0.01). Conclusion Microvascular injury exists in patients with IgAN. The expression of VE-cadherin and IMD are positively correlated, suggesting that IMD may be involved in the progression of vascular protection and angiogenesis in IgAN. The contents of IMD and VEGF in plasma of IgAN patients increase, indicating that they may play a role in the progression of IgAN.     

Tubular and interstitial expression of ICAM-1 as a marker of renal injury in IgA nephropathy

BACKGROUND: The upregulated renal expression of intercellular adhesion molecule 1 (ICAM-1) is associated with glomerular and interstitial infiltration of leukocytes. AIM: To test the hypothesis that renal expression of ICAM-1 may be predictive in the highly variable IgA nephropathy (IgAN). METHODS: ICAM-1 (CD54) in tubular epithelium and interstitial leukocytes, macrophages (CD14), and T cells (CD3) were assessed using avidin-biotin-peroxidase in renal biopsy specimens from 45 patients with IgAN and from 29 patients with no glomerulonephritis. RESULTS: In IgAN, tubular ICAM-1+ was seen in 25 of 45 (55%) biopsy specimens, associated with glomerular hypercellularity, glomerulosclerosis involving less than 50% of the glomerular area, interstitial cellular infiltration, tubular atrophy, and proteinuria (U = 44, p = 0.005). Interstitial ICAM-1+ leukocytes were correlated with glomerulosclerosis involving less and more than 50% of the glomerular area, tubular atrophy, interstitial fibrosis, and serum creatinine concentration (r = 0.6343, p < 0.001). In patients with an increase of 50% in the serum creatinine concentration, interstitial ICAM-1+ leukocytes and CD14+ and CD3+ cells were significantly more numerous than in patients with a stable creatinine concentration. In patients with no glomerulonephritis, tubular ICAM-1+ was seen in 7 of 29 (24%) biopsy specimens, inversely correlated with the number of normal glomeruli and associated with glomerulosclerosis covering more than 50% of the glomerular area, tubular atrophy, and creatinine. CONCLUSIONS: Tubular and interstitial expression of ICAM-1 can be a marker of tubulointerstitial disturbance in IgAN. Interstitial ICAM-1 may be an adverse predictor of disease progression.     

Intraglomerular synthesis of complement C3 and its activation products in IgA nephropathy

BACKGROUND: Complement activation is thought to be pathologically important in IgA nephropathy (IgAN). Although C3 deposition in the mesangium is found in IgAN, the origin of C3 is not clear. We recently demonstrated intraglomerular C3 synthesis in the human kidney; however, the activation and pathological role of locally synthesized C3 remains unclear. Here we performed nonradioactive in situ hybridization for C3 mRNA and immunohistochemistry for C3 and its activation products, such as C3d and membrane attack complex (MAC), to determine whether locally produced C3 in glomeruli was activated in IgA nephropathy. METHODS: Renal samples from 14 patients with IgAN and 5 with minimal change nephrotic syndrome (MCNS) were examined. Uninvolved portions of surgically removed kidneys with tumors served as normal controls. RESULTS: C3 mRNA was not detected in glomeruli in control tissue and MCNS, but was strongly expressed in resident glomerular cells of IgAN, including mesangial cells, glomerular epithelial cells and the cells of Bowman's capsule. Examination of serial sections disclosed that more than 70% of cells positive for C3 mRNA were also stained for C3 protein, C3d, and MAC. Double staining for in situ hybridization and immunohistochemistry also revealed that those C3 mRNA signals were present in intraglomerular cells positive for C3. The expression of C3 mRNA and MAC in glomeruli correlated significantly with the degree of mesangial matrix expansion. CONCLUSIONS: Our results demonstrated that locally synthesized C3 is activated in the glomeruli of IgAN and that its expression correlated with the severity of mesangial matrix expansion. These findings suggest that activation of C3 may be involved in tissue injury in IgAN through the formation of membrane attack complex.     

Complexes of IgA with FcalphaRI/CD89 are not specific for primary IgA nephropathy

BACKGROUND: The presence of IgA together with the myeloid IgA-receptor FcalphaRI/CD89 in the circulation of patients with IgA nephropathy (IgAN) has been suggested as a specific pathogenic factor for mesangial deposition. However, in a recent study we found these complexes also in serum samples from healthy subjects. To investigate whether these circulating complexes are specific for IgAN, the levels and characteristics of IgA-CD89 complexes were analyzed in patients with IgAN and healthy controls. METHODS: Specific ELISAs with different poly- and monoclonal antibodies and a sensitive dot-blot method were used to measure IgA-CD89 levels in serum and purified IgA samples obtained from healthy volunteers (N = 30) and patients with IgAN (N = 35). Fractionated samples of purified IgA were used to compare the size characteristics of the IgA-CD89 complexes. RESULTS: Almost all CD89 in serum of patients with IgAN and controls was associated with high molecular weight IgA. Quantitative analysis of IgA-CD89 complexes in purified IgA revealed no significant difference between patients with IgAN and controls. No correlation was found between levels of IgA-CD89 complexes and clinical parameters associated with progressive IgAN. CONCLUSIONS: CD89 in the circulation is found mainly linked to high molecular weight IgA. The presence of these complexes is not specific for IgAN. Therefore, if IgA-CD89 complexes are involved in the pathogenesis of primary IgA nephropathy, additional factors are required to explain the IgA-CD89 complex-mediated renal inflammation.     

Evaluation on the effect of steroid therapy for the outcome of IgA nephropathy in adults on the basis of histological scoring: A clinicopathologic study of 104 cases

Application criteria of steroid therapy for the patients of IgA nephropathy (IgAN) have not yet been established. The purpose of the present study was to establish retrospectively the clinical and pathological criteria for the steroid therapy by using a histological scoring on 104 adult patients of IgAN. Steroid therapy was designated as an administration of prednisolone in the amount of more than 30 mg per day in the period of more than 4 weeks within 1 year of kidney biopsy.
We developed our own scoring system for the following main glomerular and tubulointerstitial changes as shown in Table 1 . The histological scoring was expressed by evaluating semiquantitatively the extent of glomerular and tubulointerstitial lesions in terms of activity index (AI) and chronicity index (CI). Activity index is the sum of graded score according to the extent of glomeruli with mesangial hypercellularity, intracapillary macrophagic infiltration and cellular crescent as well as to the extent of interstitial inflammation and tubulitis. Chronicity index is the sum of graded score according to the extent of glomeruli with global sclerosis, increase of extracellular matrices or periglomerular fibrosis, and tuft adhesion or fibrous (or fibrocellular) crescent as well as to the extent of interstitial fibrosis ( Table 1 ).  

  Table 1.   Histological scoring     

17.

Serum visfatin concentration and endothelial dysfunction in chronic kidney disease.     

Mahmut Ilker Yilmaz  Mutlu Saglam  Juan Jesus Carrero  Abdul Rashid Qureshi  Kayser Caglar  Tayfun Eyileten  Alper Sonmez  Erdinc Cakir  Mujdat Yenicesu  Bengt Lindholm  Peter Stenvinkel  Jonas Axelsson 《Nephrology, dialysis, transplantation》2008,23(3):959-965

BACKGROUND: Endothelial dysfunction (ED) is common in patients with moderate to advanced chronic kidney disease (CKD). Recently, visfatin, a protein with insulin-mimetic properties, was shown to be associated with sVCAM-1. Thus, we hypothesised that visfatin may be a marker of ED in CKD. METHODS: We studied 406 patients with different stages of non-diabetic CKD (50% males, 46 +/- 12 years), testing the relationship between flow-mediated dilatation (FMD), assessed by high resolution brachial ultrasonography, and plasma adiponectin and visfatin concentrations. Eighty healthy volunteers (50% males, 46 +/- 11 years) served as matched controls. RESULTS: Compared to healthy controls, ED was observed in all stages of CKD (Stages 1-5) and correlated strongly with the reduction in estimated glomerular filtration rate (eGFR). Whereas visfatin concentrations were found to be increased in all but CKD stages 1 and 2, adiponectin levels were found to be increased in all patients but CKD stage 1. Visfatin and adiponectin levels were strongly correlated with eGFR (rho = -0.62 and rho = -0.72, respectively, P < 0.001 for both). FMD levels were negatively correlated with both visfatin and adiponectin levels (rho = -0.53 and, rho = -0.57, respectively, P < 0.001 for both). In a multiple regression model, eGFR levels (Beta = 0.74, P < 0.001), visfatin (Beta = -0.15, P < 0.001), age (Beta = 0.06, P < 0.01), adiponectin (Beta = 0.09, P < 0.05), HOMA-IR (Beta = 0.07, P < 0.05) and hsCRP (Beta = -0.08, P < 0.05) were all found to be significantly related to FMD. CONCLUSIONS: We conclude that the circulating levels of visfatin and adiponectin are associated with ED in all stages of CKD, independently of inflammation and insulin resistance.     

18.

Mesangial factor V expression colocalized with fibrin deposition in IgA nephropathy   总被引：2，自引：0，他引：2  

Liu N  Ono T  Suyama K  Nogaki F  Shirakawa K  Maeda M  Kawamura T  Kamata T  Oyama A  Muso E  Sasayama S 《Kidney international》2000,58(2):598-606

BACKGROUND: Factor V in its active form (Va) plays a key role at the termination of the intrinsic coagulation pathway, serving as a membrane-bound cofactor for the conversion of prothrombin to thrombin by factor Xa. Cross-linked fibrin (XFb) is often observed in mesangial areas in active types of human glomerulonephritis. In this study, to clarify contribution of factor V in intramesangial coagulation, mesangial factor V expression and its relationship to mesangial proliferation and fibrin deposition in IgA nephropathy (IgAN) were investigated. METHODS: Twenty-two patients with IgAN were studied. XFb was detected in renal biopsy specimens using anti-d-dimer antibody combined with plasmin exposure, and factor V was detected with rabbit antibody against human factor V. Double-labeling immunohistochemistry was used to investigate the relationship of the glomerular distribution of factor V to XFb. The relationship of factor V staining to the activity index or XFb deposition was evaluated. The expression of factor V mRNA was assessed by in situ hybridization in relationship to the antigen staining of alpha-smooth muscle actin (alpha-SMA). The ultrastructural distribution of factor V in glomeruli was studied by immunoelectron microscopy. RESULTS: XFb and factor V were observed in the mesangium and along capillary loops in seven and nine specimens, respectively. Factor V had intense, frequent expression in the proliferating and necrotizing areas, showing a significant relationship to XFb (P < 0.05). Furthermore, XFb deposition and factor V expression were markedly correlated with disease activity (P = 0.005 and P = 0.008, respectively). By double-labeling experiments, XFb and factor V were often seen colocalized in mesangial areas of the glomeruli, which showed necrotizing lesions and/or intense cellular proliferation. By in situ hybridization, factor V mRNA was detected mainly in the mesangial cells, which were positive for alpha-SMA, and partly in the endothelial cells. By immunoelectron microscopy, factor V presence was confirmed in the mesangium and endothelium. CONCLUSION: The present findings suggest that factor V is strongly expressed in mesangial cells in active IgAN accompanied with mesangial proliferation and may exert procoagulant activity, leading to intramesangial coagulation.     

19.

Immunoglobulin a nephropathy: Pathological markers of renal survival in paediatric patients          下载免费PDF全文

Rafaela Cabral Gonçalves Fabiano  Sérgio Veloso Brant Pinheiro  Stanley de Almeida Araújo  Ana Cristina Simões e Silva 《Nephrology (Carlton, Vic.)》2016,21(12):995-1002

IgA nephropathy (IgAN) is one of the leading causes of glomerulonephritis characterized by the findings of IgA and IgG immune deposits in the mesangium of kidney biopsies from patients with persistent microscopic haematuria. IgAN is frequently detected among adolescents and young adults. IgAN presents a highly variable course that includes a spectrum from a very mild disease to end‐stage renal disease (ESRD). There are several clinical and histological factors that strongly determined the final outcome of patients with IgAN. Pathological variables associated with unfavorable outcomes are mesangial hypercellularity, segmental glomerulosclerosis, endocapillary hypercellularity and interstitial fibrosis/tubular atrophy, according to the Oxford classification. Moreover, some studies also suggest a role for complement activation in the pathogenesis of IgAN. In this regard, staining for C4d may be an independent risk factor for the development of ESRD in IgAN. Despite the growing number of studies assessing IgAN risk factors, this kind of investigation in paediatric patients is still very limited. The aim of this article is to revise pathological markers related to deterioration of renal function in paediatric patients with IgAN, particularly those that can independently affect renal survival.     

20.

Relationship between insulin resistance and increased carotid artery intima-media thickness in non-diabetic kidney disease patients     

Wang Qianqian  Peng Hui  Wang Cheng  Liu Xun  Zhang Jun  Li Yuanqing  Zhong Meirong  Lou Tanqi. 《中华肾脏病杂志》2014,30(11):825-832

Objective To evaluate the relationship of insulin resistance (IR) and carotid artery intima-media thickness (CA-IMT), plaque status in non-diabetic non-dialysis chronic kidney disease (CKD) patients with different stages. Methods One hundred and seventeen non-diabetes non-dialysis CKD patients were enrolled into this cross-sectional observational study. Insulin resistance index (HOME-IR) was assessed by the homeostasis model assessment. Patients with HOME-IR≥1.73 were defined as insulin resistance. And patients with CA-IMT≥0.9 mm were defined as thickening. The blood pressure measurement, heart Doppler ultrasound, bilateral carotid artery ultrasound examination, blood biochemistry and urine protein test were performed, eGFR was calculated by EPI formula. Results The prevalence of IR was 47.01% in 117 non-diabetic non-dialysis CKD patients, and it was 35.71%, 50.00% and 54.55% in eGFR≥60ml•min-1•(1.73 m2)-1 group, 30≤eGFR＜60ml•min-1•(1.73 m2)-1 group, and eGFR＜30ml•min-1•(1.73 m2)-1 group separately. In eGFR＜30ml•min-1•(1.73 m2)-1 group, cystain C, homocysteine, parathyroid hormone, Scr, BUN, uric acid, interventricular septal thickness, left ventricular dimension, left ventricular posterior wall thickness were significantly higher than that in the other two groups (P＜0.01), while the level of hemoglobin was significantly lower (P＜0.01); then the levels of serum albumin and systolic pressure were higher than that in the eGFR≥60ml•min-1•(1.73 m2)-1 group, however, the levels of total cholesterol and low-density lipoprotein-cholesterol were lower than that in the eGFR≥60ml•min-1•(1.73 m2)-1 group. Correlation analysis showed that insulin resistance index was significantly correlated with CA-IMT (r=0.444, P=0.006）in the eGFR＜30ml•min-1•(1.73 m2)-1 group, however, there wasn’t correlation in other two groups. And although insulin resistance wasn’t correlated with soft plaque, it was significantly correlated with hard plaque (χ2=6.476, P=0.011) in the eGFR＜30ml•min-1•(1.73 m2)-1 group. The Logistic regression analysis results displayed aging increase was the independent risk factor of the CA-IMT thickening for non-diabetes non-dialysis CKD patients but not insulin resistance. Conclusions HOMA-IR is correlated with CA-IMT and hard plaque when eGFR＜30ml•min-1•(1.73 m2)-1 in non-diabetes non-dialysis CKD patients. However, the insulin resistance isn’t the independent risk factor of the CA-IMT thickening for non-diabetes non-dialysis CKD patients.     

Serum visfatin concentration and endothelial dysfunction in chronic kidney disease.

BACKGROUND: Endothelial dysfunction (ED) is common in patients with moderate to advanced chronic kidney disease (CKD). Recently, visfatin, a protein with insulin-mimetic properties, was shown to be associated with sVCAM-1. Thus, we hypothesised that visfatin may be a marker of ED in CKD. METHODS: We studied 406 patients with different stages of non-diabetic CKD (50% males, 46 +/- 12 years), testing the relationship between flow-mediated dilatation (FMD), assessed by high resolution brachial ultrasonography, and plasma adiponectin and visfatin concentrations. Eighty healthy volunteers (50% males, 46 +/- 11 years) served as matched controls. RESULTS: Compared to healthy controls, ED was observed in all stages of CKD (Stages 1-5) and correlated strongly with the reduction in estimated glomerular filtration rate (eGFR). Whereas visfatin concentrations were found to be increased in all but CKD stages 1 and 2, adiponectin levels were found to be increased in all patients but CKD stage 1. Visfatin and adiponectin levels were strongly correlated with eGFR (rho = -0.62 and rho = -0.72, respectively, P < 0.001 for both). FMD levels were negatively correlated with both visfatin and adiponectin levels (rho = -0.53 and, rho = -0.57, respectively, P < 0.001 for both). In a multiple regression model, eGFR levels (Beta = 0.74, P < 0.001), visfatin (Beta = -0.15, P < 0.001), age (Beta = 0.06, P < 0.01), adiponectin (Beta = 0.09, P < 0.05), HOMA-IR (Beta = 0.07, P < 0.05) and hsCRP (Beta = -0.08, P < 0.05) were all found to be significantly related to FMD. CONCLUSIONS: We conclude that the circulating levels of visfatin and adiponectin are associated with ED in all stages of CKD, independently of inflammation and insulin resistance.     

Mesangial factor V expression colocalized with fibrin deposition in IgA nephropathy

BACKGROUND: Factor V in its active form (Va) plays a key role at the termination of the intrinsic coagulation pathway, serving as a membrane-bound cofactor for the conversion of prothrombin to thrombin by factor Xa. Cross-linked fibrin (XFb) is often observed in mesangial areas in active types of human glomerulonephritis. In this study, to clarify contribution of factor V in intramesangial coagulation, mesangial factor V expression and its relationship to mesangial proliferation and fibrin deposition in IgA nephropathy (IgAN) were investigated. METHODS: Twenty-two patients with IgAN were studied. XFb was detected in renal biopsy specimens using anti-d-dimer antibody combined with plasmin exposure, and factor V was detected with rabbit antibody against human factor V. Double-labeling immunohistochemistry was used to investigate the relationship of the glomerular distribution of factor V to XFb. The relationship of factor V staining to the activity index or XFb deposition was evaluated. The expression of factor V mRNA was assessed by in situ hybridization in relationship to the antigen staining of alpha-smooth muscle actin (alpha-SMA). The ultrastructural distribution of factor V in glomeruli was studied by immunoelectron microscopy. RESULTS: XFb and factor V were observed in the mesangium and along capillary loops in seven and nine specimens, respectively. Factor V had intense, frequent expression in the proliferating and necrotizing areas, showing a significant relationship to XFb (P < 0.05). Furthermore, XFb deposition and factor V expression were markedly correlated with disease activity (P = 0.005 and P = 0.008, respectively). By double-labeling experiments, XFb and factor V were often seen colocalized in mesangial areas of the glomeruli, which showed necrotizing lesions and/or intense cellular proliferation. By in situ hybridization, factor V mRNA was detected mainly in the mesangial cells, which were positive for alpha-SMA, and partly in the endothelial cells. By immunoelectron microscopy, factor V presence was confirmed in the mesangium and endothelium. CONCLUSION: The present findings suggest that factor V is strongly expressed in mesangial cells in active IgAN accompanied with mesangial proliferation and may exert procoagulant activity, leading to intramesangial coagulation.     

Immunoglobulin a nephropathy: Pathological markers of renal survival in paediatric patients

IgA nephropathy (IgAN) is one of the leading causes of glomerulonephritis characterized by the findings of IgA and IgG immune deposits in the mesangium of kidney biopsies from patients with persistent microscopic haematuria. IgAN is frequently detected among adolescents and young adults. IgAN presents a highly variable course that includes a spectrum from a very mild disease to end‐stage renal disease (ESRD). There are several clinical and histological factors that strongly determined the final outcome of patients with IgAN. Pathological variables associated with unfavorable outcomes are mesangial hypercellularity, segmental glomerulosclerosis, endocapillary hypercellularity and interstitial fibrosis/tubular atrophy, according to the Oxford classification. Moreover, some studies also suggest a role for complement activation in the pathogenesis of IgAN. In this regard, staining for C4d may be an independent risk factor for the development of ESRD in IgAN. Despite the growing number of studies assessing IgAN risk factors, this kind of investigation in paediatric patients is still very limited. The aim of this article is to revise pathological markers related to deterioration of renal function in paediatric patients with IgAN, particularly those that can independently affect renal survival.     

Relationship between insulin resistance and increased carotid artery intima-media thickness in non-diabetic kidney disease patients

Objective To evaluate the relationship of insulin resistance (IR) and carotid artery intima-media thickness (CA-IMT), plaque status in non-diabetic non-dialysis chronic kidney disease (CKD) patients with different stages. Methods One hundred and seventeen non-diabetes non-dialysis CKD patients were enrolled into this cross-sectional observational study. Insulin resistance index (HOME-IR) was assessed by the homeostasis model assessment. Patients with HOME-IR≥1.73 were defined as insulin resistance. And patients with CA-IMT≥0.9 mm were defined as thickening. The blood pressure measurement, heart Doppler ultrasound, bilateral carotid artery ultrasound examination, blood biochemistry and urine protein test were performed, eGFR was calculated by EPI formula. Results The prevalence of IR was 47.01% in 117 non-diabetic non-dialysis CKD patients, and it was 35.71%, 50.00% and 54.55% in eGFR≥60ml•min-1•(1.73 m2)-1 group, 30≤eGFR＜60ml•min-1•(1.73 m2)-1 group, and eGFR＜30ml•min-1•(1.73 m2)-1 group separately. In eGFR＜30ml•min-1•(1.73 m2)-1 group, cystain C, homocysteine, parathyroid hormone, Scr, BUN, uric acid, interventricular septal thickness, left ventricular dimension, left ventricular posterior wall thickness were significantly higher than that in the other two groups (P＜0.01), while the level of hemoglobin was significantly lower (P＜0.01); then the levels of serum albumin and systolic pressure were higher than that in the eGFR≥60ml•min-1•(1.73 m2)-1 group, however, the levels of total cholesterol and low-density lipoprotein-cholesterol were lower than that in the eGFR≥60ml•min-1•(1.73 m2)-1 group. Correlation analysis showed that insulin resistance index was significantly correlated with CA-IMT (r=0.444, P=0.006）in the eGFR＜30ml•min-1•(1.73 m2)-1 group, however, there wasn’t correlation in other two groups. And although insulin resistance wasn’t correlated with soft plaque, it was significantly correlated with hard plaque (χ2=6.476, P=0.011) in the eGFR＜30ml•min-1•(1.73 m2)-1 group. The Logistic regression analysis results displayed aging increase was the independent risk factor of the CA-IMT thickening for non-diabetes non-dialysis CKD patients but not insulin resistance. Conclusions HOMA-IR is correlated with CA-IMT and hard plaque when eGFR＜30ml•min-1•(1.73 m2)-1 in non-diabetes non-dialysis CKD patients. However, the insulin resistance isn’t the independent risk factor of the CA-IMT thickening for non-diabetes non-dialysis CKD patients.