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Objective:To define more information for familial hematuria by genetic screening in a pedigree with familial hematuria.Methods:This was a 4 generation pedigree included 20 family members. The clinical data and laboratory manifestations of the family members were reviewed and collected from medical records. Meanwhile, the peripheral blood samples of 11 family members of the pedigree were collected, and then DNA samples were extracted by salting out method for genetic analysis. For genetic analysis, firstly, three family members including the proband were selected for whole exome sequencing, and the genetic variations were screened according to the sequence variation interpretation guidelines from the American College of Medical Genetics and Genomics (ACMG) for diagnostic sequence interpretation. Then PCR and Sanger sequencing were used to verify the identified pathogenic variants in all family members in the pedigree.Results:In the pedigree, 6 female members had persistent hematuria. Among them, 2 died due to end-stage renal disease, 2 died due to non-renal diseases, and 2 maintained stable renal function. One of the two members with stable renal function was diagnosed as IgA nephropathy by renal biopsy. Moreover, diffuse basement membrane lesions were identified in her renal biopsy sample after the electron microscope examination, which resulted in the suspected diagnosis of Alport syndrome. Genetic testing in this pedigree revealed two novel mutations in COL4A4 gene (NM_000092), c.G446T:p.G149V in exon 7 and c.G1249A:p.G417R in exon 20. Conclusion:Two novel mutations of COL4A4 gene (c.G446T:p.G149V in exon 7 and c.G1249A:p.G417R in exon 20) in a hematuria pedigree are related with phenotype of familial hematuria.
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Objective:To evaluate the clinicopathological characteristics and prognosis of IgA nephropathy (IgAN) patients with microangiopathy lesions and with no hypertension.Methods:Adult IgAN patients without hypertension were selected from Peking University First Hospital. All kidney biopsies were independently reviewed by 2 investigators. Patients were divided into three groups (microangiopathy group, simple arterio/arteriolosclerosis group and normal vascular group) by renal arteriolar lesions. Composite kidney end point event defined as a ≥30% reduction in estimated glomerular filtration rate (eGFR) and end-stage kidney disease. Cox regression analysis was used to test the association between microangiopathy lesions and the outcomes.Results:A total of 420 patients were included in this study, of which 37(8.8%) patients had renal arteriolar microangiopathy lesions, 134 (31.9%) patients had simple arterio/ arteriolosclerosis, and the others had no vascular lesion. Compared with simple arterio/arteriolosclerosis group or non-vascular lesion group, patients with renal arteriolar microangiopathy lesions had more severe urine protein ( P=0.002), worse renal function ( P<0.001), higher proportion of segmental glomerulosclerosis and/or balloon adhesion (S1), tubular atrophy/interstitial fibrosis (T1/2), cellular/fibrocellular crescents (C1/2) (all P<0.05). During the follow-up, 20(54.1%) patients with microangiopathy lesions, 45(33.6%) patients with simple arterio/arteriolosclerosis and 82(32.9%) patients without vascular lesion reached the composite kidney end points ( χ2=6.491, P=0.039). In a multivariable Cox regression model, the presence of microangiopathy lesions was an independent risk factor for kidney disease progression in IgAN patients ( HR=1.872, 95% CI 1.044-3.357, P=0.035), and simple arterio/arteriolosclerosis was not a risk factor for kidney disease progression. Conclusion:It is not uncommon for non-hypertensive patients with IgAN having microangiopathy lesions, which suggests that hypertension is not the sole risk factor for microangiopathy lesions.
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In this retrospective cohort study, we aim to evaluate the effect of endocapillary hypercellularity (E) lesions on the renal prognosis and response to immunosuppressive therapy, especially diffuse endocapillary hypercellularity lesion in IgA nephropathy (IgAN). A total of 365 patients with IgAN and E lesions and 31 patients with diffuse E lesions and over 12-month follow-up period were included in this study. We performed an 1∶1 propensity score to identify controls with matched clinical and pathological features from 769 IgAN patients without E lesions. The end-point was defined as a 30% decrease in estimated glomerular filtration rate (eGFR) or end-stage kidney disease. The kidney survival of the two groups was compared by Kaplan-Meier analysis. During median follow-up period of 41 months, kidney survival rates in patients with E lesions were 96.0% at 1 year, 83.6% at 3 years, 67.7% at 5 years; while they were 96.9% at 1 year, 83.6% at 3 years, and 68.7% at 5 years in patients without E lesions ( P=0.265).The HRof immunosuppressive therapy was 1.038 (95% CI 0.749-1.440) and 1.113 (95% CI 0.770-1.609) in patients not receiving immunosuppressive therapy ( P=0.781). (2) During median follow-up period of 52.5 months, the kidney survival rates in patients with diffuse E-lesion were 100.0% at 1 year, 96.2% at 3 years, 74.5% at 5 years; while they were 96.2% at 1 year, 82.3% at 3 years, and 63.7% at 5 years in patients without E-lesion ( P=0.158). The HR of immunosuppressive therapy was 0.625 (95% CI 0.213-1.839) and 0.447 (95% CI 0.028-7.191) in patients not receiving immunosuppressive therapy ( P=0.825). E lesion or diffuse E lesion may not be associated with prognosis or response to immunosuppressive therapy.
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Objective To evaluate the clinicopathological characteristics and outcomes of IgA nephropathy (IgAN) with acute tubulointerstitial nephropathy (ATIN).Methods Patients who were diagnosed as IgAN with ATIN and IgAN without ATIN by renal biopsy in Peking University First Hospital were enrolled.There were 74 cases of IgAN with ATIN,and seventy-four cases of IgAN without ATIN were enrolled based on stratified sampling (chosen by 1∶ 1).The two groups were well matched with age,gender,follow-up time,mesangial hypercellularity(M),endocapillaryhypercellularity (E),segmental glomerulosclerosis(S),tubular atrophy/interstitial fibrosis(T) and cellular/fibrocellular crescent(C).The clinicopathological characteristics and outcomes of two groups were retrospectively analyzed.A composite end point,defined as 30％ or 50％ estimated glomerular filtration rate (eGFR)decline and end stage renal disease (ESRD) was used.Renal function and proteinuria during follow-up were observed.Renal survival was calculated by Kaplan-Meier survival analysis and risk factors of progression were analyzed by using univariate and multivariate Cox regression models.Results Seventy-four cases of IgAN with ATIN and seventy-four cases of IgAN without ATIN were enrolled.Serum creatinine [(185.6±83.2) μmol/L vs (146.3 ±69.2) μmol/L,P=0.010] and incidence of acute kidney disease (AKD) (31.1％ vs 5.4％,P ＜ 0.001) were higher in IgAN with ATIN group than those in IgAN without ATIN group.Patients in ATIN group received more immunosuppressive treatment (86.5％vs 58.1％,P＜ 0.001).During 1 year after biopsy,mean eGFR increased significantly in IgAN with ATIN group [(39.7+ 14.6) ml· min-1· (1.73 m2)-1 vs (47.2+ 19.9) ml· min-1· (1.73 m2)-1,P=0.017],but mean eGFR was not statistic different in IgAN without ATIN group [(60.0±30.5) ml· min-1· (1.73 m2)-1 vs (59.0±31.7) ml· min-1· (1.73 m2)-1,P=0.567].Median follow-up was 23.0 months in IgAN with ATIN group,and Median follow-up was 30.0 months in IgAN without ATIN group.Incidence of composite end point had no significant differences between two groups.IgAN with ATIN was not the independent risk factor for end point.IgAN patients with ATIN were divided into two groups (with AKD and without AKD),then renal survival rate was higher (Log-rank test,x2=5.293,P=0.021) and the risk for composite end point decreased by 79.2％ (HR=0.208,95％CI 0.046-0.939,P=0.041) in the group with AKD.Conclusions In IgAN,there is a subgroup of patients with the specific pathological phenotype combined with ATIN.Compared with those without AKD,the risk for composite end point of IgAN patients with ATIN and AKD showed a 79.2％ decrease.
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Objective To establish the measurement of IgA1 O-glycan-specific antiglycan autoantibodies in patients with IgA nephropathy (IgAN),and evaluate their role in the development and progression of IgAN.Methods In the IgAN regular follow-up cohort of Peking University Institute of Nephrology from January 2006 to December 2015,170 patients drawn by stratified randomization were enrolled in this study.Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of plasma galactose-deficient IgA1 (Gd-IgA1) and antiglycan autoantibody (IgG and IgA1).The correlation between antiglycan autoantibodies and clinicopathological parameters was analyzed by linear correlation and multiple linear regression analysis.The receiver operating characteristic curve (ROC) was used to evaluate the value of plasma anti glycide antibodies in the diagnosis of IgAN.Results IgG and IgA1 antiglycan antoantibodies that specifically recognized Fab-hinge region (Fab-HR) antigens could be detected in both IgAN and healthy control group.Agglutinin inhibition test showed that the specific antigen epitope was N-acetylgalactosamine (GalNAc) residue exposed to galactose deficiency in IgA1 hinged region.There was no significant difference in the absolute levels of plasma IgG antiglycan autoantibodies between IgAN and healthy controls (P=0.963).After adjustment of the plasma level of IgG,the normalized antiglycan autoantibody (ln[IgG antiglycan antibody/IgG]) in patients with IgANwas significantly higher than that in healthy controls (0.58±0.31 vs 0.37±0.11,P ＜ 0.01).The normalized level of IgG antiglycan autoantibody in IgAN patients was positively correlated with 24 h urine protein level during renal biopsy (Spearman r=0.183,P ＜ 0.05),and was also significantly correlated with 24 h urinary protein level after adjusting for baseline clinical and pathological factors (β=0.713,95％CI 0.323-1.102,P ＜ 0.01).The area under ROC curve (AUC) of normalized IgG antiglycan autoantibody in the diagnosis of IgAN was 0.764 (95％ CI 0.682-0.845,P ＜ 0.05).Using the cut-off value of 0.396,the sensitivity and specificity of normalized IgG antiglycan autoantibody for IgAN were 0.729 and 0.700 respectively.There was no significant difference in the absolute or normalized levels of IgA1 antiglycan autoantibodies between IgAN patients and healthy controls.Conclusions Gd-IgA1-specific antiglycan autoantibodies can be detected both in IgAN patients and healthy controls.They are elevated in some patients with IgAN and possibly involved in the development of IgAN.
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Objective To explore the inhibitory effects of lobaplatin and cisplatin and their regulation of apoptosis-related genes in ovarian cancer cells in nude mice.Methods SKOV3 cells were implanted into nude mice.In monotherapy treatment study,the nude mice bearing human SKOV3 cells were randomly divided into control,lobaplatin,and cisplatin groups,with 7 mice in each group.The mice in each group were received corresponding treatment.The volume of tumor and the weight of nude mice were measured three times per week,respectively.Tumor inhibitory rate was calculated.The protein expressions of bax and bcl-2 were detected by flow cytometry.Results The growth inhibitory rate was 47.2％ in lobaplatin group and 42.8％ in cisplatin group,without significant difference between two groups (P ＞ 0.05).The expression of bcl-2 was decreased but the bax was increased in lobaplatin and ciaplatin groups compared to the control group.Conclusions Lobaplatin can significantly inhibit the growth of ovarian cancer cells,induce apoptosis by down-regulation of bcl-2 and up-regulation of bax.
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Objective To investigate the blood pressure circadian rhythm in patients with IgA nephropathy by ambulatory blood pressure monitoring and explore its role in the disease progression. Methods A cross sectional study was carried out.Blood pressure rhythm was studied by ambulatory 24-hour monitoring with a portable oscillometric recorder in selected patients with primary IgA nephropathy.The term dipper was described as blood pressure during night dropped at least 10％ below daytime blood pressure.The term non-dipper referred to those in whom the nocturnal decline in blood pressure was less than 10％.Clinicopathological indices between dipper and non-dipper groups were compared. Results Ninety-three patients completed ambulatory blood pressure monitoring among whom 68 (73％) patients were non-dipper.The frequency of non-dipper was 70％,70％ and 81％ in the patients at chronic kidney disease stage 1,2 and 3 or more.The frequency did not differ among these three group patients (P=-0.587).77％ of patients with hypertension and 69％ of patients with normotension were non-dipper (P=0.373).The disappearance of blood pressure circadian rhythm in IgA nephropathy was not influenced by age,gender,blood pressure,proteinuria,renal function and renal pathology lesions.Among the patients who were followed up regularly for more than 12 months (n=54),patients in the dipper group had a trend of slower eGFR decline rate than those in non-dipper group albeit the difference was not significant (P=0.329).Subgroup analysis revealed that in patients with hypertension and non-dipper (n=29),the eGFR decline rate was much faster than that in dipper group[(-6.79±11.58 )vs (-0.34±1.74) ml ·min-1 ·(1.73 m2)-1·year-1,P=0.019]. Conclusions Most patients with IgA nephropathy present disappearance of blood pressure circadian rhythm,even among those at an early stage or without hypertension.The loss of blood pressure rhythm may be associated with a rapid renal function decline rate in those with hypertension.
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ObjectiveTo investigate the clinical significance and histological origin of glomerular epithelial proliferative lesion in patients with focal segmental glomerulosclerosis (FSGS). MethodsSeventy-four patients with idiopathic FSGS hospitalized in Peking University First Hospital from Jan. 2000 to Dec.2005 were enrolled in this study. Patients were classified into two groups according to with or without glomerular epithelial proliferative lesion. Estimation of active and chronic pathological scores was carried out using a semi-quantitative grade system by two pathologists. Clinical and pathological characteristics were compared between two groups. Immunohistochemical studies were performed to analyze the histological origin of glomerular epithelial proliferative lesion. ResultsThirty-one patients with glomerular epithelial proliferative lesion showed shorter interval from presentation to biopsy (P<0.05), higher percentage of nephrotic syndrome (NS) (P<0.05), higher frequency of segmental glomerulosclerosis(P<0.05), higher pathological active scores (P<0.05) and lower pathological chronic scores (P<0.05)as compared to 43 patients without glomerular epithelial proliferative lesion. Twenty-nine patients were followed up and renal survival rate in patients with glomerular epithelial proliferative lesion (39.7%) was significantly lower than that in patients without glomerular epithelial proliferative lesion (83.3%) (P=0.049). The frequency of glomerular epithelial proliferative lesion and the serum creatinine (Scr) level at biopsy were independent predictors of ESRD (OR value was 1.204, 1.008 respectively ). Glomerular epithelial proliferative lesion did not express mature podocyte markers including WT-1 and pedocalyxin, but stained positive for PCNA, PAX-2 and CK-8. ConclusionsGlomerular epithelial proliferative lesion represents the pathological change of acute stage and active lesion of FSGS, and also may be the pathological marker of severe clinical presentation and worse renal survival. Glomerular epithelial proliferative lesion may be derived from proliferation of parietal epithelial proliferation or de-differentiated podocytes.