Prognosis of IgA Nephropathy with Stage 3b-5 CKD.

Objective To investigate whether immunosuppressive therapy is beneficial in IgA nephropathy (IgAN) patients with eGFR < 45ml/min/1.73m2. Methods This retrospective study involved 110 IgAN patients for whom clinical data was available; of these, 90 had complete follow-up data. Patients were grouped based on whether they received immunotherapy during follow-up, their renal function, proteinuria levels, and the percentage of crescentic glomeruli observed at the time of renal biopsy. Results The mean eGFR for the participants was 32.0 ± 10.2 ml/min/1.73 m². The average follow-up duration was 46.1 ± 37.9 months. The mean rate of decline in eGFR was 3.6 ml/min/1.73 m² per year. There were 43 (47.8%) composite kidney endpoint occurred in these patients. In the group that received immunotherapy, the incidence of kidney endpoint events was lower than in the untreated group (45.1% vs. 57.9%), but the difference was not statistically significant (P = 0.320). Among patients with stage CKD 3b, the incidence of endpoint events was lower than in those with stages CKD 4 and 5 (36.8% vs. 66.7%, P = 0.006). Conversely, the high proteinuria group saw a higher incidence of endpoint events compared to the low proteinuria group (51.9% vs. 23.1%), although this difference was not statistically significant (P = 0.054). Meanwhile, there was no significant difference in the incidence of endpoint events between the two crescent glomerular ratio groups (48.7% vs. 41.7%, P = 0.649). Kaplan-Meier survival analysis indicated that renal function level (P＜0.001) and proteinuria (P = 0.023) were associated with renal survival in IgAN patients. In contrast, the administration of immunosuppressive therapy (P = 0.288) and the prevalence of C lesions (P = 0.982) did not show a significant association with renal survival. Further, Cox regression analysis identified systolic blood pressure, fibrinogen, and CKD stage as risk factors for eGFR decline in IgAN patients (all P < 0.05). Conclusions IgAN patients with stage 3b-5 CKD exhibited a poor prognosis. It appears that in this specific cohort of IgAN patients, immunosuppressive therapy may not provide significant advantages over supportive care therapeutic regimens in terms of disease management.

Decreased IgA binding levels were accompanied by increased IgG sialylation in IgA nephropathy.

INTRODUCTION: IgA nephropathy (IgAN) is a kidney disorder characterized by the deposition of circulating immune complexes of IgG bound to galactose-deficient IgA1 (Gd-IgA1) in the mesangial glomeruli. However, limited research has been conducted on the levels of IgA binding in relation to the various sialylation profiles of IgG in IgAN. MATERIALS AND METHODS: Sialylated IgG (SA-IgG) and desialylated IgG (DSA-IgG) were isolated from IgAN patients. The IgG-IgA immune complex (IgG-IgA-IC) was detected using two customized commercial ELISA kits. Additionally, IgG was enzymatically digested with neuraminidase to produce DSA-IgG. Subsequently, the binding capacities of both intact IgG and the neuraminidase-digested DSA-IgG with Gd-IgA1 were determined using ELISA kits. RESULTS: Our research revealed that SA-IgG levels were negatively correlated with Gd-IgA1 (R = -0.16, p = 0.03) in IgAN patients. The optical density (OD) levels of IgG-IgA complexes in SA-IgG samples were significantly lower (0.58 ± 0.09) compared to those in DSA-IgG samples (0.78 ± 0.12) when using the Gd-IgA1 assay kit. These results were confirmed using an IgG assay kit, which showed that the SA-IgG groups had significantly lower IgA indices (0.31 ± 0.12) compared to the DSA-IgG groups (0.57 ± 0.19). Furthermore, we investigated the binding capacity of IgG with different sialic acid levels to Gd-IgA1. The results revealed that neuraminidase digestion of IgG increased its propensity to bind to Gd-IgA1. Additionally, we examined the binding capacity of both intact IgG and DSA-IgG to Gd-IgA1 at different mix ratios (IgG 1.5 µg and Gd-IgA1 1.5 µg, IgG 1.5 µg and Gd-IgA1 3 µg, IgG 3 µg and Gd-IgA1 1.5 µg). Interestingly, DSA-IgG demonstrated significantly higher binding capacity to Gd-IgA1 compared to intact IgG at all mix ratios tested. CONCLUSION: The preliminary findings from our present study indicate that the binding level of IgA in purified sialylated IgG is lower than that in desialylated IgG.

The effect of fibrinoid necrosis on the clinical features and outcomes of primary IgA nephropathy.

BACKGROUND: To explore the clinicopathologic features and outcomes of IgAN patients who presented with fibrinoid necrosis (FN) lesions or not and the effect of immunosuppressive (IS) treatment in IgAN patients with FN lesions as well. METHODS: This was a retrospective cohort study with 665 patients diagnosed with primary IgAN from January 2010 to December 2020 in Tianjin Medical University General Hospital and having detailed baseline and follow-up characteristics. Patients were divided into two groups depending on the appearance of FN lesions. Patients with FN lesions were recruited into Group FN1, while patients who were not found FN lesions in their renal biopsy specimens were recruited into Group FN0. Compare the differences between Group FN0 and Group FN1 in baseline clinicopathologic features, treatment solutions and follow-up data as well. To evaluate the impact of different fractions of FN lesions on baseline characteristics and prognosis of IgAN, we subdivided patients in Group FN1 into 3 groups depending on the FN lesions distribution, Mild Group: 0 < FN% < 1/16; Moderate Group: 1/16 < FN% < 1/10; Severe Group: FN% > 1/10. Furthermore, we compared the differences in baseline clinicopathologic features, treatment solutions and follow-up data among these three groups. Kidney endpoint event was defined as patients went into end-stage kidney disease (ESKD), which estimated glomerular filtration rate (eGFR) < 15 ml/min/1.73 m^2, regularly chronic dialysis over 6 months or received renal transplantation surgery. The kidney composite endpoint was defined by a ≥ 30% reduction in eGFR, double Scr increase than on-set, ESKD, chronic dialysis over 6 months or renal transplantation. Compare the survival from a composite endpoint rate in different groups by Kaplan-Meier survival curve. The univariate and multivariate Cox models were used to establish the basic model for renal outcomes in patients with FN lesions. RESULTS: (1) A total of 230 patients (34.59%) were found FN lesions in all participants. Patients with FN lesions suffered more severe hematuria than those without. On the hand of pathological characteristic, patients with FN lesions showed higher proportions of M1, E1, C1/C2 and T1/T2 lesions compared with those without FN lesions. (2) The 1-year, 3-year, and 5-year survival of the composite endpoint were lower in the FN1 group than FN0 group. (3) After adjusting for clinicopathological variables, the presence of FN lesions was a significantly independent risk factor for composite endpoint. By using multivariate Cox regression analyses, we also found when the fraction of FN lesions exceeded 10%, the risk of progression into composite endpoint increased 3.927 times. CONCLUSION: Fibrinoid necrosis of capillary loops is an independent risk factor of poor renal outcomes. More effective treatment should be considered for those who had FN lesions.

The potential pathogenic roles of S100A8/A9 and S100A12 in patients with MPO-ANCA-positive vasculitis.

BACKGROUND: The significance of S100A8/A9 and S100A12 in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) has not been clarified. This study was dedicated to exploring the potential pathogenic roles of S100A8/A9 and S100A12 in patients with myeloperoxidase (MPO)-ANCA-positive vasculitis. METHODS: Serum and urine concentrations of S100A8/A9 and S100A12 of forty-two AAV patients were evaluated. The influence of S100A8/A9 and S100A12 on the chemotaxis, the apoptosis, the release of IL-1ß, the complement activation, the respiratory burst, as well as the neutrophil extracellular traps (NETs) formation of MPO-ANCA-activated neutrophils was investigated. RESULTS: The serum and urine S100A8/A9 and S100A12 of active MPO-AAV significantly increased (compared with inactive AAV and healthy controls, p < 0.001) and were correlated with the severity of the disease. In vitro study showed that S100A8/A9 and S100A12 activated the p38 MAPK/NF-κB p65 pathway, increased the chemotaxis index (CI) and the release of IL-1ß, extended the life span, and enhanced the complement activation ability of MPO-ANCA-activated neutrophils. The Blockade of TLR4 and RAGE inhibited the effects of S100A8/A9 and S100A12. All above-mentioned effects of S100A8/A9 and S100A12 were ROS-independent because neither S100A8/A9 nor S100A12 enhanced the ROS formation and NETs formation of MPO-ANCA-activated neutrophils. CONCLUSION: S100A8/A9 and S100A12 serve as markers for assessing the disease severity, and they may also play a role in MPO-AAV pathogenesis.

The difference between patients with nephrotic syndrome and nephrotic-range proteinuria in IgA nephropathy: a propensity score matched cohort study.

OBJECTIVE: To date, nephrotic syndrome (NS) has not been well characterized in patients with IgA nephropathy (IgAN). Whether decline in serum albumin is an ominous sign in IgAN patients with massive proteinuria remains unknown. In this study, we evaluated clinical and pathological features of IgAN with NS and compared the differences for these features and long-term outcomes between patients with nephrotic syndrome and nephrotic-range proteinuria. METHODS: A retrospective study was conducted, enrolling 1013 patients with biopsy-proven IgAN. The primary endpoint was the composite of a doubling of the base-line serum creatinine, 50% reduction in eGFR, ESKD (eGFR < 15 ml/min per 1.73 m2) or death. RESULTS: A total of 59 patients were presented with NS (5.8%). The patients with NS showed lower levels of hemoglobin, albumin and higher levels of serum creatinine, serum uric acid and urinary protein than patients without NS. As for pathological parameters, more patients with NS showed a higher prevalence of E1 lesions, T1/2 and C1/2 lesions. Furthermore, we used the propensity score matching method to select 57 patients with nephrotic-range proteinuria and normal serum albumin (NR group) who were comparable to 59 patients with NS. Patients with NS had lower levels of hemoglobin, albumin and IgG and higher levels of TC, LDL, FIB and D-dimer as well as more severe E1 and C1/2 lesions than those in NR group. The S1 lesion was more severe in the NR group than that in the NS group. There was no significant difference in long-term outcome between the two groups. In addition, we found that serum albumin level or the presence of hypoalbuminemia was not a risk factor affecting long-term outcome in patients with massive proteinuria. CONCLUSIONS: A prevalence of 5.8% of NS was presented in IgAN adult patients in our study. IgAN with NS patients had low levels of hemoglobin, albumin, high levels of serum creatinine, serum uric acid, urinary protein and more acute lesions. The prognosis of NS in patients with IgAN was not inferior to that of patients with nephrotic range proteinuria and normal serum albumin.

Sialylation of IgG inhibits the formation of galactose-deficient IgA1-containing immune complexes and protects mesangial cells from injury in IgA nephropathy.

BACKGROUND: The addition of sialic acid alters IgG from a pro-inflammatory state to an anti-inflammatory state. However, there is a lack of research on the changes of IgG sialylation in IgA nephropathy (IgAN). METHODS: This study included a total of 184 IgAN patients. The sialylated IgG (SA-IgG), IgG-galactose-deficient IgA1 complex (IgG-Gd-IgA1-IC), IL-6, TNF-α, and TGF-ß were detected using commercial ELISA kits. SA-IgG, non-sialylated IgG (NSA-IgG), sialylated IgG-IgA1 complex (SA-IgG-IgA1), and non-sialylated IgG-IgA1 complex (NSA-IgG-IgA1) were purified from IgAN patients and healthy controls (HCs). RESULTS: The mean SA-IgG levels in plasma and B lymphocytes in IgAN patients were significantly higher than those of healthy controls. A positive correlation was found between SA-IgG levels in plasma and B lymphocytes. In vitro, the results showed that the release of IgG-Gd-IgA1-IC was significantly decreased in peripheral blood mononuclear cells (PBMCs) cultured with SA-IgG from both IgAN patients and healthy controls. The proliferation ability and the release of IL-6, TNF-α, and TGF-ß in human mesangial cells (HMCs) were measured after stimulating with SA-IgG-IgA1-IC and NSA-IgG-IgA1-IC. The mesangial cell proliferation levels induced by NSA-IgG-IgA1-IC derived from IgAN patients were significantly higher than those caused by SA-IgG-IgA1-IC derived from IgAN patients and healthy controls. Compared with NSA-IgG-IgA1 from healthy controls, IgAN-NSA-IgG-IgA1 could significantly upregulate the expression of IL-6 and TNF-α in mesangial cells. The data showed that there weren't any significant differences in the levels of IL-6, TNF-α, and TGF-ß when treated with IgAN-SA-IgG-IgA1 and HC-NSA-IgG-IgA1. CONCLUSIONS: The present study demonstrated that the sialylation of IgG increased in patients with IgA nephropathy. It exerted an inhibitory effect on the formation of Gd-IgA1-containing immune complexes in PBMCs and the proliferation and inflammation activation in mesangial cells.

Significance of thyroid dysfunction in the patients with primary membranous nephropathy.

BACKGROUND: Thyroid dysfunction is common in patients with nephrotic syndrome, especially patients with primary membranous nephropathy (pMN). In view of both MN and thyroid dysfunction are associated with autoimmunity, the current study aimed to elucidate the significance of thyroid dysfunction in patients with pMN. METHODS: Four hundred and twenty patients with biopsy-proven pMN from 2018-2021 were retrospectively enrolled. Clinical and pathological parameters, and treatment response of patients with and without thyroid dysfunction were analyzed. RESULTS: Ninety-one (21.7%) patients with pMN suffered from thyroid dysfunction, among which subclinical hypothyroidism (52.7%) was the main disorder. Compared to patients with normal thyroid function, patients with thyroid dysfunction presented with a higher level of proteinuria, a lower level of serum albumin, a higher level of serum creatinine and more severe tubulointerstitial injury at the time of biopsy. But the positive rate and level of circulating anti-phospholipase A2 receptor (PLA2R) antibody were comparable between these two groups. Though following the similar treatment, the percentage of no response to treatment were significantly higher in the patients with thyroid dysfunction (38.6 vs. 20.0%, P = 0.003). Similar to the urinary protein and the positivity of anti-PLA2R antibody, multivariate COX analysis showed thyroid dysfunction was also identified as an independent risk factor for the failure to remission (HR = 1.91, 95%CI, 1.07-3.40, P = 0.029). CONCLUSION: In conclusion, thyroid dysfunction is common in the patients with pMN and might predict a severe clinical manifestation and a poor clinical outcome, which indicated that the thyroid dysfunction might be involved in the disease progression of pMN.

Identification of tubulointerstitial genes and ceRNA networks involved in diabetic nephropathy via integrated bioinformatics approaches.

BACKGROUND: Diabetic nephropathy (DN) is the major cause of end-stage renal disease worldwide. The mechanism of tubulointerstitial lesions in DN is not fully elucidated. This article aims to identify novel genes and clarify the molecular mechanisms for the progression of DN through integrated bioinformatics approaches. METHOD: We downloaded microarray datasets from Gene Expression Omnibus (GEO) database and identified the differentially expressed genes (DEGs). Enrichment analyses, construction of Protein-protein interaction (PPI) network, and visualization of the co-expressed network between mRNAs and microRNAs (miRNAs) were performed. Additionally, we validated the expression of hub genes and analyzed the Receiver Operating Characteristic (ROC) curve in another GEO dataset. Clinical analysis and ceRNA networks were further analyzed. RESULTS: Totally 463 DEGs were identified, and enrichment analyses demonstrated that extracellular matrix structural constituents, regulation of immune effector process, positive regulation of cytokine production, phagosome, and complement and coagulation cascades were the major enriched pathways in DN. Three hub genes (CD53, CSF2RB, and LAPTM5) were obtained, and their expression levels were validated by GEO datasets. Pearson analysis showed that these genes were negatively correlated with the glomerular filtration rate (GFR). After literature searching, the ceRNA networks among circRNAs/IncRNAs, miRNAs, and mRNAs were constructed. The predicted RNA pathway of NEAT1/XIST-hsa-miR-155-5p/hsa-miR-486-5p-CSF2RB provides an important perspective and insights into the molecular mechanism of DN. CONCLUSION: In conclusion, we identified three genes, namely CD53, CSF2RB, and LAPTM5, as hub genes of tubulointerstitial lesions in DN. They may be closely related to the pathogenesis of DN and the predicted RNA regulatory pathway of NEAT1/XIST-hsa-miR-155-5p/hsa-miR-486-5p-CSF2RB presents a biomarker axis to the occurrence and development of DN.

ST6Gal1 is up-regulated and associated with aberrant IgA1 glycosylation in IgA nephropathy: An integrated analysis of the transcriptome.

Galactose-deficient IgA1 (Gd-IgA1) plays a crucial role in the development of Immunoglobulin A nephropathy (IgAN), however, the underlying pathogenic mechanisms driving Gd-IgA1 production in B cells are not well understood. In this study, RNA-seq analysis identified 337 down-regulated and 405 up-regulated genes in B cells from 17 patients with IgAN and 6 healthy controls. Among them, ST6Gal1, which was associated with IgAN in a previous genome-wide association study (GWAS), was up-regulated in IgAN and significantly positive correlated with elevated Gd-IgA1. In addition, we identified increased plasma ST6Gal1 levels in 100 patients with IgAN, which were associated with higher levels of proteinuria, plasma IgA, Gd-IgA1 levels, greater degrees of systemic complement activation including C3a, Bb, C4d, MAC and a lower proportion classified as C2 grade (crescent proportion ≥25%). Interesting, in vitro, recombinant ST6Gal1 (rST6Gal1) exposure reduced the production of Gd-IgA1 in cultured peripheral blood mononuclear cells from IgAN patients. rST6Gal1 stimuli also increased expression of C1GALT1, which were well-known proportional to the decrease in galactose deficiency of IgA1. In conclusions, we identified increased plasma ST6Gal1 levels and the association of ST6Gal1 with disease severity of IgAN. Additionally, rST6Gal1 administration in vitro increased expression of C1GALT1 and reduced the production of Gd-IgA1.

Effects of ACE Inhibitors and Angiotensin Receptor Blockers in Normotensive Patients with Diabetic Kidney Disease.

The role of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in reducing the progression of albuminuria and risk of cardiovascular events in hypertensive patients with diabetic kidney disease (DKD) is well-documented. However, the efficacy and safety of these agents in normotensive patients with DKD are still controversial. MEDLINE, Embase, and Cochrane Library were searched for relevant random controlled trials. The odd risk (OR) reductions were calculated with a random-effects model. Decrease in albuminuria, changes in eGFR, major cardiovascular events, and drug-related adverse events were analyzed. Thirteen RCTs including 1282 patients were retrieved. Compared with placebo or other active agent groups, ACEIs or ARBs significantly decreased albuminuria (MD -80.28 mg/d, 95% CI -104.79 mg/d to -55.77 mg/d), and the efficacy is independent of changes in blood pressure and systolic blood pressure at baseline. The result of subanalysis showed the declining of albuminuria was more significantly in normotensive DKD patients with 2DM (p=0.005). No significant differences were found with regard to the declining of evaluated glomerular filtration rate (eGFR) (MD -0.29 ml/min/1.73 m2, 95% CI -2.99 to 2.41 ml/min/1.73 m2). There were no significant differences in the side effect of the drugs such as hypotension and hyperkalemia. This meta-analysis demonstrated that ACEIs or ARBs can decrease albuminuria to varying degree in normotensive patients with DKD, and better response occurred in patients with 2DM.

Detection of water-molecular-motion configuration in patients with lupus nephritis: a primary study using diffusion-weighted imaging.

BACKGROUND: Lupus nephritis (LN) is one of most common types of secondary glomerulonephritis, which is characterized by longitudinal pathological changes. Microstructural lesions of LN will impact the motion of water molecules, which can be detected by diffusion-weighted imaging (DWI). There are few reported measurements of water diffusion in patients with LN, and the nature of water diffusion across the entire depth of the renal parenchyma remains largely unknown. METHODS: Twenty adult patients with LN and 11 healthy volunteers underwent DWI inspection. Renal biopsy samples were characterized based on the revised ISN/RPS 2003 classification. The apparent-diffusion coefficient (ADC) was calculated via fitting into a mono-exponential model. To compare the ADC level across the entire renal parenchyma between the two groups, repeated-measures analysis of variance (RM-ANOVA) was performed. ADC data derived from DWI pictures were transformed into tridimensional maps by MATLAB software. RESULTS: Compared with data from healthy volunteers, lower average ADC values with major undulatory magnitudes were found in patients with LN, especially in the cortical zone. Tridimensional maps of patients with LN displayed geographic terrain-like canyons and/or valleys that were different from the corresponding terrain-like flatlands and/or plateaus in healthy volunteers. A heterogeneity of ADC values was found in bilateral kidneys. Left kidneys predominated higher ADC values in patients with LN. The ADC values across the entire renal parenchyma exhibited statistically significant differences among the three identified pathological subclasses (P < 0.001). CONCLUSIONS: Analysis of the motion of water molecules across the entire renal parenchyma may be helpful for better understanding the pathological conditions of LN, for which microstructural and functional heterogeneity may be detected and visualized via DWI.

C1GALT1 expression is associated with galactosylation of IgA1 in peripheral B lymphocyte in immunoglobulin a nephropathy.

BACKGROUND: More and more studies demonstrated that genetic variation at C1GALT1 influences Gd-IgA1 level in IgAN. However, whether the expression of ß1, 3-galactosyltransferase (ß1, 3Gal-T) was influenced may provide insights into how Gd-IgA1 levels are controlled in IgAN. METHODS: Thirty IgAN patients diagnosed in Tianjin Medical University General Hospital from April to September 2018 and 30 healthy volunteers whose age and gender matched with patients were enrolled in this study. Total Gd-IgA1 levels in plasma were determined by ELISA and C1GALT1 levels were determined by RT-PCR. Four databases (PubMed, EMBASE, CNKI, WanFang Medical Network) were searched to identify eligible studies that evaluated a difference in the expression of C1GALT1 in IgAN patients compared with total controls (non-IgAN and health controls). The C1GALT1C1 expression levels, which was indispensable to ß1, 3Gal-T of IgA1, was also been compared. RESULTS: Gd-IgA1 levels were remarkable higher in IgAN patients compared with healthy control. The expression levels of C1GALT1 gene were remarkably down-regulated in IgAN patients compared with healthy control. And the mRNA level of C1GALT1 was inversely correlated to Gd-IgA1 levels. In meta-analysis, six articles including 316 participants that analyzed the expression of ß1, 3Gal-T were met inclusion criteria. There was no significant difference in the expression of C1GALT1 between IgAN patients compared with controls. And we found patients with IgAN had lower levels of C1GALT1 gene expression in the B cells compared to controls. The C1GALT1C1 levels in the IgAN patients were not different from the levels in the control group, which were unchanged no matter according to different ethnic population, different control group and different cell source. Two studies including 46 persons compared enzymatic activity of ß1, 3Gal-T in B cells, and the result showed the ß1, 3Gal-T activity was decreased in B cells. CONCLUSIONS: We found expression levels of C1GALT1 were remarkably downregulated in IgAN patients and negatively correlated with higher levels of Gd-IgA1. Subsequent meta-analysis validated the low expression and activity of ß1, 3Gal-T in B cells in patients with IgAN. However, there was no apparent disparity in the aspect of C1GALT1C1 expression between IgAN and control groups.

Comprehensive analysis of aberrantly expressed profiles of mRNA and its relationship with serum galactose-deficient IgA1 level in IgA nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the leading cause of end-stage kidney disease. Previous mRNA microarray profiling studies of IgAN revealed inconsistent data. We sought to identify the aberrantly expressed genes and biological pathways by integrating IgAN gene expression datasets in blood cells and performing systematically experimental validation. We also explored the relationship between target genes and galactose-deficient IgA1 (Gd-IgA1) in IgAN. METHODS: We retrieved Gene Expression Omnibus (GEO) datasets of IgAN. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used for functional analysis. Deep sequencing on RNA isolated from B cells was used for microarray validation. The relationship between target mRNA expressions and Gd-IgA1 levels in serum were also studied. RESULTS: Three studies with microarray expression profiling datasets met our inclusion criteria. We identified 655 dyregulated genes, including 319 up-regulated and 336 down-regulated genes in three GEO datasets with a total of 35 patients of IgAN and 19 healthy controls. Based on biological process in GO term, these dyregulated genes are mainly related to pentose-phosphate shunt, non-oxidative branch, post-embryonic camera-type eye development and leukocyte activation. KEGG pathway analysis of microarray data revealed that these aberrantly expressed genes were enriched in human T-cell leukemia virus 1 infection, proteoglycans in cancer, intestinal immune network for IgA production and autophagy. We further performed deep sequencing on mRNAs isolated from B cells of an independent set of five patients with IgAN and three healthy persons with the same clinical and demographic characteristics. Seventy-seven genes overlapped with 655 differentially regulated genes mentioned above, including 43 up-regulated and thirty-four down-regulated genes. We next investigated whether these genes expression correlated with Gd-IgA1 levels in IgAN patients. Pearson correlation analyses showed PTEN (phosphatase and tensin homolog) was the most powerful gene negatively correlated with Gd-IgA1 levels. CONCLUSIONS: These results demonstrated that dyregulated genes in patients with IgAN were enriched in intestinal immune network for IgA production and autophagy process, and PTEN in B cells might be involved in the mechanism of Gd-IgA1 production.

Clinical Significance of Galactose-Deficient IgA1 by KM55 in Patients with IgA Nephropathy.

BACKGROUND: Aberrant galactose-deficient IgA1 molecules (Gd-IgA1) are important causal factors in IgA nephropathy (IgAN); however, the detection of Gd-IgA1 in IgAN is complicated and instable. A monoclonal antibody, KM55, which specifically recognizes Gd-IgA1 has been developed. In the present study, we further explored the clinical significance of Gd-IgA1 using KM55. METHODS: In this study, we enrolled 75 patients with IgAN and 80 healthy controls and detected the plasma Gd-IgA1 levels using the KM55 ELISA method. We also stained -mesangial Gd-IgA1 deposition using KM55. RESULTS: We observed that the levels of plasma Gd-IgA1 in IgAN patients were elevated compared to the corresponding levels of healthy controls. Patients were divided into 2 groups based on the median of Gd-IgA1. Patients with high Gd-IgA1 levels had significantly higher levels of uric acid (UA) and IgA. The other clinical manifestations demonstrated that there were no differences in age, sex, blood pressure, initial proteinuria, hematuria, estimated glomerular filtration rate and Oxford pathological classification between the 2 groups of patients. In addition, positive correlations were observed between Gd-IgA1 and Bb, C3a, C4d and MAC. Mesangial Gd-IgA1 was positive in IgAN but negative in the normal renal tissue adjacent to neoplasm. We next analyzed the correlation between plasma Gd-IgA1 and mesangial Gd-IgA1 deposition. The results showed that a high level of plasma Gd-IgA1 was related to the deposition of mesangial Gd-IgA1, although the difference was not significant. CONCLUSION: We verified the elevated level of plasma and -mesangial Gd-IgA1 in patients with IgAN by KM55, which provided an alternative, easy, and reliable tool for diagnosis and activity assessment of IgAN. The level of plasma Gd-IgA1 positively correlated with levels of UA, total IgA levels, and complement activation products.

High serum hepcidin is associated with the occurrence of anemia in anti-myeloperoxidase antibody-associated vasculitis with normal kidney function: a cross-sectional study.

The etiology of anemia in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) has not been elucidated. In this cross-sectional study, we tried to investigate the relationship between serum hepcidin and anemia in myeloperoxidase (MPO)-ANCA-AAV. Data of 64 newly diagnosed AAV patients who did not have kidney dysfunction or hemorrhage were analyzed. Serum hepcidin was measured with enzyme linked immunosorbent assay. Twenty-three of 64 patients had anemia. Compared with patients without anemia, patients with anemia had higher Birmingham vasculitis activity score [10 (3, 23) vs. 5 (3, 17), p = 0.020], lower levels of serum iron (5.83 ± 1.63 vs. 9.76 ± 1.54, p < 0.001) and higher levels of ferrtin [358.00 (59.85, 1314.10) vs. 151.05 (43.00, 645.30), p = 0.006]. All 64 patients had increased levels of serum hepcidin compared with normal controls, while patients with anemia had higher serum hepcidin than patients without anemia (85.30 ± 16.92 ng/mL vs. 53.48 ± 13.32 ng/mL, p < 0.001). In the multivariable analysis, the level of hemoglobin correlated with the levels of serum iron (r = 0.344, p = 0.026) and hepcidin (r = - 0.353, p = 0.022). Low level of serum iron was related to high level of serum hepcidin (r = - 0.472, p = 0.001). Immunosuppressive treatment induced rapid decrease of hepcidin and increase of serum iron on the 1st month, while the recovery of hemoglobin was relatively slow. This study indicated that in MPO-AAV without kidney dysfunction or hemorrhage, the existence of anemia is associated with high level of hepcidin which induces low serum iron and the abnormality of iron utilization.

Pathological severity determines the renal recovery for anti-myeloperoxidase antibody-associated vasculitis requiring dialysis at disease onset: a retrospective study.

BACKGROUND: Many patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) need dialysis at disease onset due to severe kidney injury. Determining whether they can become dialysis independent is an important clinical assessment. METHODS: Forty kidney biopsy-proved myeloperoxidase (MPO)-ANCA associated AAV patients who required dialysis at disease onset were enrolled. Relationships between laboratory and pathological characteristics and prognoses were analyzed. RESULTS: Twenty-five patients obtained dialysis independence within 3 months, while the other 15 patients remained dialysis dependent. No sclerotic class was identified among the 40 patients. Only two biopsies exhibited focal class diagnoses and both these patients recovered their renal function. The renal recovery rate of the 20 patients with mixed class was significantly lower than that of the 18 patients with crescentic class (40.0% vs. 83.3%, p = 0.006). Receiver operating characteristics (ROC) curves showed fibrous crescent+global glomerulosclerosis greater than 32.6% was a strong predictor of dialysis dependence with a sensitivity of 93.3% and specificity of 88.0%. When the percentage of fibrous crescent+global glomerulosclerosis exceeded 47.9%, dialysis independence was not possible. Correlation analysis indicated that platelet counts were negatively correlated with the percentage of fibrous crescent+global glomerulosclerosis (R = -0.448, p = 0.004). Most patients with increased platelets (84.62%) obtained renal recovery. Compared with methylprednisolone pulse therapy, plasma exchange accelerated renal recovery (29.4 ± 15.6 vs. 41.4 ± 11.7 days, p = 0.039). CONCLUSIONS: For MPO-ANCA AAV who required dialysis at disease onset, crescentic and mixed classes accounted for the majority of patients in our cohort. The renal outcome of mixed class patients was worse than that of crescentic class. A high proportion of fibrous crescent+global glomerulosclerosis is a predictor of dialysis dependence. Increased platelet count is associated with active and reversible renal lesions.

Changes E3 ubiquitin protein ligase 1 gene mRNA expression correlated with IgA1 glycosylation in patients with IgA nephropathy.

BACKGROUND: Recent genomewide association study suggested that the top single-nucleotide polymorphism, rs978056, in HECW1 gene (which encodes HECT, C2 and WW domain containing E3 ubiquitin protein ligase 1) associated with the levels of galactose-deficient IgA1 (Gd-IgA1) in IgA nephropathy (IgAN). However, HECW1 expression in IgAN has not yet been examined. METHODS: In the following study, we have enrolled 40 patients with IgAN and 40 healthy controls. The expression level of HECW1, as well as plasma levels of Gd-IgA1 and IgA1, were determined detected. RESULTS: IgAN patients presented with significantly elevated Gd-IgA1 and IgA1 levels compared with those of the healthy controls (p < .001 and p = .03, respectively). We further divided the patients into two groups according to the median level of HECW1 (0.58). We found the levels of Gd-IgA1 and IgA1 were significantly higher in low HECW1 level group compared with those in high HECW1 level group (p = .02 and p = .04, respectively). And HECW1 mRNA expression had a significant inverse correlation with Gd-IgA1 levels in IgAN patients (r= -0.34, p = .03). It seemed that the risk genotype (rs978056 GG) was associated with reduced HECW1 expression in 80 Han Chinese from Beijing, although the difference was not significant (p = .09). No significant association with clinical and pathological manifestations was observed between patients with high and low levels of HECW1. CONCLUSION: We reported for the first time that HECW1 mRNA levels were negatively correlated with Gd-IgA1 levels. Our study points to a new regulatory mechanism of IgAN that can explain the aberrant glycosylation of IgA1.

Human umbilical cord mesenchymal stem cells facilitate the up-regulation of miR-153-3p, whereby attenuating MGO-induced peritoneal fibrosis in rats.

MiRNAs contribute greatly to epithelial to mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs), which is a crucial step in peritoneal fibrosis (PF). In this study, we tried to profile whether miRNA expression differences exist after human umbilical cord mesenchymal stem cells (hUCMSCs) treatment in PF rats and investigate the possible role of miR-153-3p involved in anti-EMT process. We randomly assigned 34 rats into three groups: control group (Group Control), MGO-induced PF rats (Group MGO) and hUCMSCs-treated rats (Group MGO + hUCMSCs). MiRNA microarrays and real-time PCR analyses were conducted in three groups. α-SMA, Snail1 and E-cadherin expression were detected by Western blot. Luciferase reporter assays were used to detect the effects of miR-153-3p overexpression on Snai1 in rat peritoneal mesothelial cells (RPMCs). We identified differentially expressed miRNAs related to EMT, in which miR-153-3p demonstrated the greatest increase in Group MGO + hUCMSCs. Transient cotransfection of miR-153-3p mimics with luciferase expression plasmids resulted in a significant repression of Snai1 3'-untranslated region luciferase activity in RPMCs. These studies suggest that miR-153-3p is a critical molecule in anti-EMT effects of hUCMSCs in MGO-induced PF rats. MiR-153-3p might exert its beneficial effect through directly targeting Snai1.

Corticosteroid for IgA Nephropathy: Are They Really Therapeutic?

BACKGROUND: IgA nephropathy (IgAN) is a common chronic glomerular disease that, in most patients, slowly progresses to end-stage kidney disease. The therapy with corticosteroid in IgAN is still a worldwide problem that is confusing the clinicians. METHODS: MEDLINE, EMBASE, the Cochrane Library, and article reference lists were searched for randomized controlled trials (RCTs) that compared corticosteroids with placebo and any other non-immunosuppressive agents in treating IgAN. Twelve RCTs involving 1,057 patients were included. RESULTS: Overall, we found that steroids had statistically significant effects in preventing the decline in renal function (relative risk 0.42, 95% CI 0.25-0.71, p < 0.001) and reducing proteinuria (SMD: -0.58 g/day, 95% CI -0.80 to -0.36 g/day) in patients with IgAN. The association between glucocorticoid and risk of kidney outcome was not modified by steroids' type (prednisone or methylprednisone), dose (≤30 or > 30 mg/day), duration (≤8 or > 8 months), or serum creatinine (< 1.10 or ≥1.10 mg/dL). But steroids increased the risk of side effects such as gastrointestinal and endocrinium symptoms. CONCLUSION: This study provides the clear beneficial effects of the steroids therapy on the kidney function and proteinuria, although it should be used with caution.

Hypoalbuminaemia in antineutrophil cytoplasmic antibody-associated vasculitis: incidence and significance.

OBJECTIVES: Hypoalbuminaemia has been proved to be a biomarker of poor prognosis in many diseases. The objective of this study was to investigate the significance of hypoalbuminaemia in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Data of 117 AAV patients were analysed retrospectively. The relationship between hypoalbuminaemia and disease severity were studied. The influence of albumin on the pathogenetic role of ANCA was investigated in vitro. RESULTS: Among all patients, 52 had light hypoalbuminaemia (30g/L<=albumin<35g/L) and 40 had nephrotic hypoalbuminaemia (albumin <30g/L). Patients with hypoalbuminaemia had higher inflammation levels and more severe kidney injury than patients without hypoalbuminaemia, but no significant difference of the urinary protein levels were found between patients with nephrotic and light hypoalbuminaemia. Multivariate analysis showed serum albumin correlated with age (r=-0.566, p=0.018), C-reactive protein (r=-0.521, p=0.032) and haemoglobin (r=0.512, p=0.036). Patients with nephrotic hypoalbuminaemia had higher incidence of infection, end stage renal disease and all cause mortality during treatment than patients with light hypoalbuminaemia or normal serum albumin. In vitro study indicated albumin could inhibit the binding between ANCA and neutrophils in a concentration dependent manner. Albumin also inhibited the ANCA-induced respiratory burst and neutrophil extracellular traps formation. CONCLUSIONS: Serum albumin have an inhibitory effect on the binding between ANCA and its antigen. The incidence of hypoalbuminaemia in AAV with kidney involvement is high but is not caused by heavy proteinuria. Hypoalbuminaemia is correlated with the high inflammation level and poor prognosis of AAV. Therapy targeting hypoalbuminaemia might benefit patients with AAV.