Tauroursodeoxycholic acid ameliorates renal injury induced by COL4A3 mutation.

COL4A3/A4/A5 mutations have been identified as critical causes of Alport syndrome and other genetic chronic kidney diseases. However, the underlying pathogenesis remains unclear, and specific treatments are lacking. Here, we constructed a transgenic Alport syndrome mouse model by generating a mutation (Col4a3 p.G799R) identified previously from one large Alport syndrome family into mice. We observed that the mutation caused a pathological decrease in intracellular and secreted collagen IV α3α4α5 heterotrimers. The mutant collagen IV α3 chains abnormally accumulated in the endoplasmic reticulum and exhibited defective secretion, leading to persistent endoplasmic reticulum stress in vivo and in vitro. RNA-seq analysis revealed that the MyD88/p38 MAPK pathway plays key roles in mediating subsequent inflammation and apoptosis signaling activation. Treatment with tauroursodeoxycholic acid, a chemical chaperone drug that functions as an endoplasmic reticulum stress inhibitor, effectively suppressed endoplasmic reticulum stress, promoted secretion of the α3 chains, and inhibited the activation of the MyD88/p38 MAPK pathway. Tauroursodeoxycholic acid treatment significantly improved kidney function in vivo. These results partly clarified the pathogenesis of kidney injuries associated with Alport syndrome, especially in glomeruli, and suggested that tauroursodeoxycholic acid might be useful for the early clinical treatment of Alport syndrome.

Adult-Onset Focal Segmental Glomerulosclerosis With Steroid-Dependent Nephrotic Syndrome Caused by a Novel TBC1D8B Variant: A Case Report and Literature Review.

Focal segmental glomerulosclerosis (FSGS) is a histological lesion with a variety of potential causes, including rare variants of podocyte-related genes. Recently, it has been found that variants in the TBC1D8B gene on the X chromosome can lead to early-onset focal segmental glomerulosclerosis and steroid-resistant nephrotic syndrome by affecting endocytosis and recycling of nephrin. Here, we report a 19-year-old Chinese patient with nephrotic syndrome and normal kidney function. He had a complete remission of nephrotic syndrome after full-dose prednisone and cyclosporine treatment. Unfortunately, a relapse of nephrotic syndrome occurred during prednisone tapering. Focal segmental glomerulosclerosis was proven by a kidney biopsy, and a hemizygous pathogenic variant located in the TBC (Tre-2-Bub2-Cdc16) domain of TBC1D8B was detected by whole-exome sequencing. By comparing our case with reports of other patients with TBC1D8B variants, we suggest possible genotype-phenotype correlations. To our knowledge, this is the first report identifying a pathogenetic variant in the TBC domain of TBC1D8B in an adult-onset focal segmental glomerulosclerosis patient with steroid-dependent NS. With this report, we broaden the clinical and genetic spectrum of X-linked genetic FSGS.

Mutation in XPO5 causes adult-onset autosomal dominant familial focal segmental glomerulosclerosis.

BACKGROUND: Focal and segmental glomerulosclerosis (FSGS) is a histological pathology that characterizes a wide spectrum of diseases. Many genes associated with FSGS have been studied previously, but there are still some FSGS families reported in the literature without the identification of known gene mutations. The aim of this study was to investigate the new genetic cause of adult-onset FSGS. METHODS: This study included 40 FSGS families, 77 sporadic FSGS cases, 157 non-FSGS chronic kidney disease (CKD) families and 195 healthy controls for analyses. Whole-exome sequencing (WES) and Sanger sequencing were performed on probands and family members of all recruited families and sporadic FSGS cases. RESULTS: Using WES, we have identified a novel heterozygous missense variant (c.T1655C:p.V552A) in exportin 5 gene (XPO5) in two families (FS-133 and CKD-05) affected with FSGS and CKD. Sanger sequencing has confirmed the co-segregation of this identified variant in an autosomal dominant pattern within two families, while this variant was absent in healthy controls. Furthermore, the identified mutation was absent in 195 ethnically matched healthy controls by Sanger sequencing. Subsequently, in silico analysis demonstrated that the identified variant was highly conservative in evolution and likely to be pathogenic. CONCLUSIONS: Our study reports an adult-onset autosomal dominant inheritance of the XPO5 variant in familial FSGS for the first time. Our study expanded the understanding of the genotypic, phenotypic and ethnical spectrum of mutation in this gene.

First case report of PLA2R-related monotypic (IgG-κ positive) membranous nephropathy concurrent with leukocyte chemotactic factor 2 amyloidosis.

BACKGROUND: Membranous nephropathy (MN) is a major pattern of nephrotic syndrome (NS) in adults. Some MN have secondary causes and some may be accompanied with other glomerular diseases. MN patients coexisting with amyloidosis are very rare, and mostly was polytypic MN. Herein, we describe the first report which identifying monotype PLA2R-MN (κ light chain) concurrent with leukocyte chemotactic factor 2 amyloidosis (ALECT2). This rare case highlights the importance of renal pathology for diagnosis. CASE PRESENTATION: We describe a case of a 60-year-old male patient with persistent proteinuria and low serum albumin for nine months. No monoclonal component was revealed by serum and urine immunofixation electrophoresis but serum PLA2R antibody was positive. The patient was empirically treated with Leflunomide and Losartan, but edema was not improved. The diagnosis of renal pathology is PLA2R-related monotypic (IgG-κ positive) MN concurrent with ALECT2. Methylprednisolone, cyclosporine A and anticoagulant (rivaroxaban) were prescribed resulting in a complete remission of NS. CONCLUSIONS: MN patients concurrent with ALECT2 presented massive proteinuria or NS. When nephrotic range proteinuria is present in ALECT2, it is important to consider that it may be due to a concomitant underlying nephropathy especially MN and treated according to MN will get good therapeutic effect.

Quantitative evaluation of retinal and choroidal changes in Fabry disease using optical coherence tomography angiography.

To examine the retinal and choroidal changes in patients with Fabry disease (FD) using optical coherence tomography angiography (OCTA). FD patients and age- and sex-matched healthy subjects were enrolled. A detailed ophthalmological examination was performed for all participants. The retinal thickness, ganglion cell layer with inner plexiform layer (GCIPL) thickness, choroidal thickness (CT), vessel length density (VLD), vessel perfusion density (VPD), and foveal avascular zone (FAZ) were analyzed in a detailed way with OCTA. Moreover, all FD patients underwent several laboratory tests to evaluate systemic conditions. A total of 54 subjects comprising 26 FD patients and 28 normal controls were enrolled. The retinal thickness, GCIPL thickness, and FAZ area showed no significant differences between the two groups (all P > 0.05). Only the superior CT in FD patients was significantly thinner than that in the normal subjects (P = 0.040). The macular VLD and VPD in the FD group were significantly reduced compared with the healthy controls (P = 0.026, P = 0.008). The macular VLD in FD patients had no significant correlations with different laboratory results (all P > 0.05), while the macular VPD were negatively correlated with creatinine (r = - 0.432, P = 0.028) and cystatin C (r = - 0.422, P = 0.032). FD patients may have retinal vascular dropout and choroidal vascular alterations. Analysis of vessel density using OCTA might be useful in the clinical assessment in FD patients.

Coordinative Changes in Metabolites in Grape Cells Exposed to Endophytic Fungi and Their Extracts.

Endophytes and their elicitors can all be utilized in regulating crop biochemical qualities. However, living endophytes and their derived elicitors are always applied separately; little is known about the similarities and differences of their effects. To increase the efficiency of this system when applied in practice, the present work profiled simultaneously the metabolomes in grape cells exposed to endophytic fungi (EF) and their corresponding fungal extracts (CFE). As expected, grape cells exposed separately to different fungi, or to different fungi derived extracts, each exhibited different modifications of metabolite patterns. The metabolic profiles of certain EF- and CFE-exposed grape cells were also differently influenced to certain degrees, owing to the presence of differentially responding metabolites (DRMs). However, the detected majority proportions of coordinately responding metabolites (CRMs) in both the EF- and the CFE-exposed grape cells, as well as the significantly influenced metabolites (SIMs) which are specific to certain fungal strains, clearly indicate coordinative changes in metabolites in grape cells exposed to EF and CFEs. The coordinative changes in metabolites in EF- and CFE-treated grape cells appeared to be fungal strain-dependent. Notably, several of those fungal strain-specific CRMs and DRMs are metabolites and belong to amino acids, lipids, organic acids, phenolic acids, flavonoids, and others, which are major contributors to the biochemistry and sensory qualities of grapes and wines. This research clarifies the detailed responses of metabolites in grape cells exposed to EF and CFEs. It also demonstrates how endophytes can be selectively used in the form of extracts to produce functions as CRMs of the living fungus with increased eco-safety, or separately applied to the living microbes or elicitors to emphasize those effects related to their specifically initiated SIMs and DRMs.

Evaluating renal outcome of ANCA-associated renal vasculitis: comparative study of two histopathological scoring systems.

OBJECTIVES: Renal risk score (RRS) and chronicity score (CS) are both newly proposed tools to predict end stage renal disease (ESRD) which could be applicable in antineutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis patients. Their predictive value has not been fully studied and compared. METHODS: 252 patients with newly biopsy-proven ANCA-associated renal vasculitis were retrospectively studied at the Department of Nephrology, Ruijin Hospital, China. Patients were evaluated with RRS and CS for clinical factors, pathological lesions and outcome. Their predictive value of renal survival was also compared. RESULTS: The median RRS score point at diagnosis was 6 (interquartile range [IQR] 0-9) and CS score point was 4 (IQR 3-7). In accordance with severity of RRS category and CS grade, percentage of hypertensive patients, dialysis dependency, and level of proteinuria increased accordingly. Significant differences were found regarding dialysis dependency within RRS and CS groups (p<0.001 and p<0.01 respectively). The addition of RRS or CS scoring scheme to the base model of dialysis dependency significantly improved discrimination. The C statistic, integrated discrimination improvement and net reclassification improvement were significantly increased by adding either RRS/CS or both. Furthermore, RRS had better ROC. CONCLUSIONS: Among ANCA associated renal vasculitis patients, RRS and CS achieved similar discrimination, but the discrimination of RRS was superior.

A Pilot Study of Rare Renal Amyloidosis Based on FFPE Proteomics.

Renal amyloidosis typically manifests albuminuria, nephrotic-range proteinuria, and ultimately progresses to end-stage renal failure if diagnosed late. Different types of renal amyloidosis have completely different treatments and outcomes. Therefore, amyloidosis typing is essential for disease prognosis, genetic counseling and treatment. Thirty-six distinct proteins currently known to cause amyloidosis that have been described as amyloidogenic precursors, immunohistochemistry (IHC) or immunofluorescence (IF), can be challenging for amyloidosis typing especially in rare or hereditary amyloidosis in clinical practice. We made a pilot study that optimized the proteomics pre-processing procedures for trace renal amyloidosis formalin-fixed paraffin-embedded (FFPE) tissue samples, combined with statistical and bioinformatics analysis to screen out the amyloidosis-related proteins to accurately type or subtype renal amyloidosis in order to achieve individual treatment. A sensitive, specific and reliable FFPE-based proteomics analysis for trace sample manipulation was developed for amyloidosis typing. Our results not only underlined the great promise of traditional proteomics and bioinformatics analysis using FFPE tissues for amyloidosis typing, but also proved that retrospective diagnosis and analysis of previous cases laid a solid foundation for personalized treatment.

A regulatory role for CD72 expression on B cells and increased soluble CD72 in primary Sjogren's syndrome.

BACKGROUND: CD72, a co-receptor of B cell receptor (BCR), has been reported to have both positive and negative effects on B cell functions in several immunological diseases. The B cell plays an important role in the pathogenesis of primary Sjogren's syndrome (pSS). However, whether CD72 is involved in the process remains unknown. This study aimed to observe the possible role of CD72 in the pathogenesis of pSS. RESULTS: A total of 60 cases who fulfilled the American-European Consensus Group (AECG) criteria for the diagnosis of pSS and 61 gender and age-matched healthy controls were recruited in this study. The percentage of CD72+ B cells was 85.31 ± 8.37% in pSS patients and 76.91 ± 8.50% in healthy controls(p < 0.001). The percentage of CD72+ B cells was correlated to serum IgG levels in patients [ß = 0.018(0.001-0.036), p = 0.034]. The level of serum soluble CD72 was significantly higher in pSS patients than the one in healthy controls (0.41 (0.29) vs 0.07 (0.08) ng/mL, p < 0.001). CONCLUSIONS: The percentage of CD72+ B cells was upregulated in pSS patients and was correlated to the serum IgG level, which revealed the hyperactivity of B cells in this disease. The serum soluble CD72 level was also increased in pSS patients. These results indicated a potential role of CD72 in the pathogenesis of pSS.

New risk score for predicting steroid resistance in patients with focal segmental glomerulosclerosis or minimal change disease.

BACKGROUND: Glucocorticosteroid is used for patients with primary nephrotic syndrome. This study aims to identify and validate that biomarkers can be used to predict steroid resistance. METHODS: Our study contained two stages, discovery and validation stage. In discovery stage, we enrolled 51 minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS) patients treated with full dose steroid. Five urinary biomarkers including ß2-microglobulin (ß2-MG) and α1-microglobulin (α1-MG) were tested and candidates' biomarkers were selected based on their associations with steroid response. In validation stage, candidates' biomarkers were validated in two prospectively enrolled cohorts. Validation cohort A included 157 FSGS/MCD patients. Validation cohort B included 59 membranous nephropathy (MN) patients. Patients were classified into response group (RG) or non-response group (NRG) based on their responses to steroid treatment. RESULTS: In discovery stage, higher urinary ß2-MG was independently associated with response to corticosteroid treatment in MCD/FSGS patients [OR = 1.89, 95% CI 1.02-3.53] after adjusted by age and gender. In validation cohort A, patients in NRG had a significant higher urinary ß2-MG [Ln (ß2-MG/uCr): 4.6 ± 1.7 vs 3.2 ± 1.5] compared to patients in RG. We then developed a 3-variable risk score in predicting steroid resistance in FSGS/MCD patients based on the best predictive model including Ln(ß2-MG/uCr) [OR = 1.76, 95% CI 1.30-2.37], age [OR = 1.005, 95% CI 0.98-1.03] and pathology [MCD vs FSGS, OR = 0.20, 95% CI 0.09-0.46]. The area under the ROC curves of the risk score in predicting steroid response was 0.80 (95% CI 0.65-0.85). However, no such association was found in MN patients. CONCLUSIONS: Our study identified a 3-variable risk score in predicting steroid resistance in patients with FSGS or MCD.

Acute Kidney Disease Increases the Risk of Post-Kidney Biopsy Bleeding Complications.

INTRODUCTION: Kidney biopsy, providing the insightful information for most kidney diseases, is an invasive diagnostic tool with certain risks ranging from the least severe macroscopic hematuria to the most severe life-threatening bleeding necessitating renal artery embolization. We aimed to compare the postbiopsy bleeding complications between 2 common methods and to further explore the risk factors of bleeding complications in patients using the negative pressure suction puncture (NPS) method. METHODS: We retrospectively collected the data from percutaneous native kidney biopsies in 2016. The clinical, laboratory tests, pathological findings, and the occurrence of bleeding complications following kidney biopsy were analyzed. The kidney biopsy was performed in our center by experienced nephrologists with 2 different methods, namely, NPS method and real-time ultrasound-guided needle (RTU) method. We compared rates of complications between 2 methods and evaluated univariate and multivariate association of risk factors with bleeding complications in the NPS group. RESULTS: 626 kidney biopsies were performed between January 2016 and December 2016. There were 83.2% (521/626) participants in the NPS group and 16.8% (105/626) in the RTU group. There were more participants in the RTU group needing >1 needle pass during biopsy than those in the NPS group (61.0 vs. 14.7%, p < 0.001). Acute kidney disease (AKD) occurred before the procedure of kidney biopsy accounted for 13.8% (72/521) in the NPS group and 1.9% (2/105) in the RTU group. The renal pathological findings revealed higher number of glomeruli in the NPS group than in the RTU group (26.8 ± 13.0 vs. 17.2 ± 8.6, p < 0.001). The incidence of bleeding complications in the NPS group was lower than that in the RTU group (9.2 vs. 21.9%, p < 0.01). Logistic multivariate regression showed that AKD was independently associated with bleeding complications after kidney biopsy in the NPS group. CONCLUSION: Regarding the bleeding risk, there was noninferiority of NPS over RTU. AKD contributes to higher risks of bleeding complications after kidney biopsy.

Mutations in NUP160 Are Implicated in Steroid-Resistant Nephrotic Syndrome.

BACKGROUND: Studies have identified mutations in >50 genes that can lead to monogenic steroid-resistant nephrotic syndrome (SRNS). The NUP160 gene, which encodes one of the protein components of the nuclear pore complex nucleoporin 160 kD (Nup160), is expressed in both human and mouse kidney cells. Knockdown of NUP160 impairs mouse podocytes in cell culture. Recently, siblings with SRNS and proteinuria in a nonconsanguineous family were found to carry compound-heterozygous mutations in NUP160. METHODS: We identified NUP160 mutations by whole-exome and Sanger sequencing of genomic DNA from a young girl with familial SRNS and FSGS who did not carry mutations in other genes known to be associated with SRNS. We performed in vivo functional validation studies on the NUP160 mutations using a Drosophila model. RESULTS: We identified two compound-heterozygous NUP160 mutations, NUP160R1173× and NUP160E803K . We showed that silencing of Drosophila NUP160 specifically in nephrocytes (fly renal cells) led to functional abnormalities, reduced cell size and nuclear volume, and disorganized nuclear membrane structure. These defects were completely rescued by expression of the wild-type human NUP160 gene in nephrocytes. By contrast, expression of the NUP160 mutant allele NUP160R1173× completely failed to rescue nephrocyte phenotypes, and mutant allele NUP160E803K rescued only nuclear pore complex and nuclear lamin localization defects. CONCLUSIONS: Mutations in NUP160 are implicated in SRNS. Our findings indicate that NUP160 should be included in the SRNS diagnostic gene panel to identify additional patients with SRNS and homozygous or compound-heterozygous NUP160 mutations and further strengthen the evidence that NUP160 mutations can cause SRNS.

A validation study of crescents in predicting ESRD in patients with IgA nephropathy.

BACKGROUND: A working group on the Oxford classification of IgA nephropathy (IgAN) recently reported that crescents detected in kidney tissue predicted a worse renal outcome. However, this finding must be validated in independent cohorts before it can be widely applied to clinical practice. METHODS: Biopsy-proven IgAN patients were continuously recruited from two large renal centers in China from 1989 to 2014. All patients were followed for more than 1 year unless end stage renal disease (ESRD) occurred within 12 months. Crescents were defined as focal cellular or fibrocellular crescent formations. IgAN patients without detectable crescents were recruited to the C0 group. Patients with crescents in less than or more than 1/4 of all glomeruli were recruited to the C1 or C2 group, respectively. Primary outcome was defined as the time to ESRD, and the secondary outcome was defined as the time to an estimated glomerular filtration rate (eGFR) decline equal to or greater than 50% or to ESRD. RESULTS: In total, 1152 IgAN patients were recruited in this study. Among all patients, 53.7% were in the C0 group, 38.8% were in the C1 group, and 7.5% were in the C2 group. Compared to patients in the C0 group, patients in the C1 or C2 group were younger, had more urinary protein excretion and lower eGFR, and presented with more severe mesangial hypercellularity, endocapillary proliferation or tubular atrophy/interstitial fibrosis. After 45 months of follow-up, ESRD had occurred in 80 (12.9%), 46 (10.3%) and 18 (20.9%) of patients in the C0, C1 and C2 groups, respectively. By multivariable Cox regression analysis, inclusion in the C1 (HR = 1.07, 95% CI 0.71-1.63), C2 (HR = 0.84, 95% CI 0.41-1.73), or C1 or C2 group (HR = 1.02, 95% CI 0.68-1.52) was not associated with a higher rate of ESRD than inclusion in the C0 group after adjusting for age, gender, eGFR, mean arterial pressure (MAP), MEST scores, and immunosuppressive treatment. However, in patients with nephrotic-range proteinuria, patients in either the C1 or C2 group had a higher rate of the primary outcome, ESRD (HR = 2.54, 95% CI 1.14-5.66) after adjusting for age, gender, eGFR, MAP, MEST scores, and immunosuppressive treatment. Similar results were found when we evaluated the association between crescents and the secondary outcome. CONCLUSIONS: IgAN patients with crescents had more severe clinical and pathological manifestations than those without crescents. However, we failed to replicate the association between crescents and renal function progression in Chinese IgAN patients followed for more than 1 year.

Glucocorticoids in the treatment of patients with primary focal segmental glomerulosclerosis and moderate proteinuria.

BACKGROUND: To compare the efficacy of glucocorticoids in primary focal segmental glomerulosclerosis (pFSGS) patients with moderate proteinuria. Registered at http://www.chictr.org.cn/ , study No. ChiCTR-OPN-17012789. METHODS: pFSGS patients with urine protein between 1.0 and 3.5 g/24 h were recruited from 2006 to 2016. No decline in urine protein > 50% was observed after 2 months of run-in angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (ACEI/ARB) treatment. Patients were assigned to study group (glucocorticoids with ACEI/ARB) or control group (ACEI/ARB without glucocorticoids). Variables including 24-h urinary protein, serum albumin and serum creatinine during the trial were recorded. Remission was defined as proteinuria < 0.3 g/24 h or declined > 50%, and our composite end point as > 30% decrease of eGFR or eGFR < 30 ml/min. RESULTS: A total of 102 patients were enrolled (study group N = 52, control group N = 50), and the median follow-up time was 36 (12-117) months without significant difference between groups. During the 12-month follow-up, the remission rate was significantly higher in study group [73.1 vs 50.0% (P = 0.01)], and the initial median response time was 3 months in the study group while 6 in the control group. The end point was reached by 22.2% cases in study group, and 42.0% in control. The medium survival times were study group 72 months and control 57 (P = 0.03). Minor adverse reactions were observed in 10 patients (study group N = 8, control group N = 2). CONCLUSIONS: Additional glucocorticoids therapy is more efficacious compared to ACEI/ARB alone in the treatment of patients with pFSGS and moderate proteinuria.

Combination Cyclophosphamide/Glucocorticoids Provide Better Tolerability and Outcomes versus Glucocorticoids Alone in Patients with Sjogren's Associated Chronic Interstitial Nephritis.

BACKGROUND: Steroid therapy has become an effective option for patients with primary Sjogren's syndrome with tubulointerstitial nephritis (TIN), while the use of cytotoxic agents is still debated. Our study aimed to compare the clinical outcomes of patients treated with cyclophosphamide (CTX) combined with glucocorticoids with those of patients treated with glucocorticoids alone. METHODS: All patients with primary Sjogren's syndrome with chronic TIN admitted to the Division of Nephrology, Ruijin Hospital, from January 1, 2002, to April 30, 2016, and treated with steroids alone or combined with CTX were included. The immunological prognosis, improvements of renal function, and acquired tubular defects of the patients were retrospectively compared between the 2 therapeutic groups. RESULTS: A total of 70 cases were included. Of these, 36 were diagnosed by renal biopsy. A total of 56 patients were treated with glucocorticoids alone, while 14 patients received glucocorticoids combined with CTX. There were no significant differences in clinical characteristics and laboratory parameters between the 2 therapeutic groups at baseline. Compared with patients in the steroid group, patients in the CTX group showed better estimated glomerular filtration rate (eGFR) improvement (21.35 ± 19.63 vs. 2.72 ± 19.11 mL/min/1.73 m2, p = 0.006) but a similar decline in immunoglobulin G (IgG; 450 [interquartile range, IQR 910] vs.176 [IQR 1,910] mg/dL, p = 0.93) at 12 months of follow-up. CTX therapy was associated with better eGFR improvement (ß = 12.96 [2.95-22.97]) even after adjusting for dry mouth, anti-Sjögren's-syndrome-related antigen A and anti-Sjögren's-syndrome-related antigen B positivity, hemoglobin, initial steroid dose, and baseline eGFR by linear regression analyses. Subgroup analyses revealed that the beneficial effects of CTX therapy on renal function were only observed in patients with baseline IgG ≥1,560 mg/dL or eGFR <90 mL/min/1.73 m2. The urine α1-microglobulin improvement was better in the CTX group than in the steroid group at 12 months of follow-up (ß = 1.29, 95% CI 0.56-2.02, p = 0.001). CONCLUSIONS: CTX therapy is suggested for primary Sjogren's syndrome patients with chronic TIN, especially those with higher IgG levels and abnormal renal function at baseline.

The importance of sensitive screening for abnormal glucose metabolism in patients with IgA nephropathy.

AIM: To investigate the prevalence of abnormal glucose metabolism, insulin resistance (IR) and the related risk factors in IgA nephropathy (IgAN) patients. METHODS: We analyzed oral glucose tolerance test (OGTT) and clinical data of 107 IgAN patients and 106 healthy controls. Glucose metabolism, homeostasis model assessment of insulin resistance (HOMA-IR) and the insulin sensitivity index (ISI) of both groups were evaluated. RESULTS: The prevalence of abnormal glucose metabolism was significantly higher in the IgAN group than in the control group (41.12% vs. 9.43%, p < 0.001), while the prevalence of IR between the two groups was not significantly different. IgAN patients have significantly higher fasting blood glucose, fasting insulin, OGTT 2-hour blood glucose, OGTT 2-hour insulin, HOMA-IR, and lower ISI than healthy controls. Triglyceride (OR = 2.55), 24-hour urine protein excretion (OR = 1.39), and age (OR = 1.06) were independent risk factors for abnormal glucose metabolism in IgAN patients. BMI, eGFR, 24-hour urine protein excretion, triglyceride, fasting blood glucose, fasting insulin, OGTT 2-hour blood glucose, and OGTT 2-hour insulin were significantly higher in IgAN patients with IR than in IgAN patients without IR, while HDL and ISI were significantly lower. BMI, serum albumin, and 24-hour urine protein excretion were correlated factors of IR in IgAN patients. CONCLUSIONS: Our study highlighted that abnormal glucose metabolism was common in IgAN patients. Triglyceride and 24-hour urine protein excretion were significant risk factors for abnormal glucose metabolism. Therefore, sensitive screening for glucose metabolism status and timely intervention should be carried out in clinical work.

Novel mutations in the inverted formin 2 gene of Chinese families contribute to focal segmental glomerulosclerosis.

Here, we report a genetic study of an extended family of Chinese ancestry with focal segmental glomerulosclerosis (FSGS), with one of the affected members also concurrently diagnosed with IgA nephropathy (IgAN). By genome-wide linkage analysis and subsequent sequencing, we identified an S85W mutation in the inverted formin 2 (INF2) gene that perfectly cosegregated with the kidney disease phenotype. The entire INF2 coding region was sequenced in 200 healthy controls, 55 families with FSGS, and 34 families with IgAN. This analysis identified a novel insertion, S129_Q130insVRQLS, in another FSGS pedigree. In vitro studies found that α-actinin 4 expression was decreased and INF2 showed perinuclear localization in S85W-transfected podocytes. Phosphorylation of serum response factor, and that its nuclear translation was decreased in S85W podocytes, indicated decreased activation in mutants. Abnormal actin organization was also found in S85W podocytes, while no change of microtubule structure was observed. Co-immunoprecipitation and immunofluorescence found decreased interaction between INF2 and Cdc42 in S85W podocytes. However, all these changes were not found in S129_Q130insVRQLS podocytes. The overall frequency of INF2 mutations was ~3.6% among Chinese familial FSGS, which was considerably lower than that from studies of European FSGS families. Thus, S85W but not the S129_Q130insVRQLS variant leads to podocyte cytoskeletal abnormalities, probably by impaired serum response factor phosphorylation.

Effect of Puerarin on Expression of ICAM-1 and TNF-α in Kidneys of Diabetic Rats.

BACKGROUND: As an important factor causing end-stage renal disease, diabetic nephropathy is correlated with low-grade chronic inflammation and immune system activation. This study aimed to investigate the protective function of puerarin on the kidneys of diabetic rats. MATERIAL AND METHODS: A cohort of healthy male SD rats (7 weeks old) were randomly divided into a control group, a model group, and a puerarin treatment group with high (H), moderate (M), and low (L) dosage. After streptozotocin induction, puerarin was applied via intragastric administration for 8 consecutive weeks with dosages of 0.25, 0. 5 and 1.0 mg/(kg·d) for L, M, and H groups, respectively. Fasting blood glucose (BG), creatinine (Scr), urea nitrogen (BUN), and urine albumin excretion rate (UAER) were measured, along with morphological observation of renal cells. The expression of intracellular adhesion molecule 1 (ICAM-1) and tumor necrosis factor α (TNF-α) was determined using immunohistochemical (IHC) staining, while renal cortex cell apoptosis was assayed by in situ end-labeling method. RESULTS: Model rats had significantly elevated levels of BG, Scr, BUN, and UAER compared to controls (p<0.05). All these increases were partially but significantly suppressed by puerarin (p<0.05), which also caused marked improvement of histopathological damages. Puerarin at each dosage significantly eliminated elevations of ICAM-1 and TNF-α levels in model rats (p<0.05), and decreased apoptotic indexes of renal cortex cells (p<0.05). CONCLUSIONS: Early-stage renal damages can be significantly improved by puerarin, possibly via its suppression of ICAM-1 and TNF-α expression in diabetic rat kidneys.

Clinical and pathological study on patients with primary antineutrophil cytoplasmic autoantibody-associated vasculitis with renal immune complex deposition.

BACKGROUND: Traditionally, antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) is histologically characterized by pauci-immune glomerulonephritis. However, more and more literature has reported immune complex (IC) deposits to be found in renal specimen from patients with AAV. The role that these IC deposits play in the development of AAV, as well as their clinical and pathological significance, is worthy of studying. OBJECTIVES: The objective of this study was to analyze the clinical and pathological characteristics of Chinese patients with AAV having renal IC deposition. METHODS: A retrospective study was performed on 34 patients with AAV in Shanghai Ruijin Hospital with renal IC deposition. Clinical and pathological data were collected and studied and compared with other 76 AAV patients having classic pauci-immune glomerulonephritis. RESULTS: Thirty-four patients were enrolled in this study, with a mean age of 56.4 ± 16.4 years and a male-female ratio of 1:1.3 (19/15). Twenty-seven patients (79.4%) had impaired renal function, with an average serum creatinine of 4.4 ± 3.2 mg/dL. C3 (82.4%) and immunoglobulin M (50%) were the most common IC deposits observed in the kidneys. During the follow-up (median, 39 months), 6 patients (17.7%) died, and 11 (32.4%) finally progressed to end-stage renal disease despite immunosuppressive therapy. Compared with patients having classic pauci-immune glomerulonephritis, patients with renal IC deposits had similar clinical and laboratory features except for more proteinuria (2374 ± 2221 vs 1444 ± 1956 mg/24 h, P = 0.002), a higher prevalence of nephrotic syndrome (30.3% vs 9.6%, P = 0.007) and hypocomplementemia (86.8 ± 33.1 vs 110 ± 45.5 mg/dL, P = 0.029), and also a higher risk for progressing to end-stage renal disease (32.4% vs 13.1%, P = 0.018). CONCLUSIONS: Patients with AAV with renal IC deposition might have a worse renal prognosis than those having classic pauci-immune glomerulonephritis.

Vasodilatory effect of 14,15-epoxyeicosatrienoic acid on mesenteric arteries in hypertensive and aged rats.

The objective of this study was to investigate the 14,15-epoxyeicosatrienoic acid (14,15-EET)-induced vasodilatations as well as the underlying signaling pathways in rat mesenteric arteries from young, adult and old normotensive (WKY) and hypertensive rats. Protein expressions for prostaglandin EP(1-4) receptors, large conductance Ca(2+)-activated K(+) (BK(Ca)) channels, and adenylate cyclase (AC) were determined together with 14,15-EET-induced vasodilatations in primary- versus secondary-branches of the mesenteric artery. Responses to 14,15-EET were greater in the smaller secondary- versus primary-branches (and also more sensitive with lower EC50) and were reduced in vessels from old (80 weeks) rats as well as from vessels from the spontaneous hypertensive rats (SHR). Regardless of age or hypertension responses to 14,15-EET were inhibited by the EP2 antagonist AH6809, BK(Ca) channel inhibitor iberiotoxin, or 3',5'-cyclic monophosphate (cAMP)-protein kinase A (PKA) pathway antagonists. These data indicate 14,15-EET-induced vasodilatation is mediated via the activation of EP2 receptors and opening of BK(Ca) channels. The expressions of the EP2 receptor and AC were markedly reduced in vessels from SHR as well as old rats, whereas BK(Ca) expression was reduced in old WKY and SHR, but not adult SHR. Furthermore, expression of the p53 protein, an indicator of cell senescence and apoptosis, was elevated in adult and old SHR as well as in old WKY. In summary, attenuated 14,15-EET-induced vasodilatation in mesenteric arteries from old normotensive WKY as well as adult and old SHR is associated with reduced expression of EP2 receptors and AC.