Glomerular IgG deposition predicts kidney disease progression in IgA nephropathy.

Objective: We aimed to explore the relationship between the presence and intensity of glomerular IgG deposition and the occurrence of kidney progression events in IgA nephropathy (IgAN). Methods: This retrospective study encompassed a total of 1207 patients with IgAN spanning the period from 2010 to 2022, and complete follow-up data were accessible for 736 patients. The IgG intensity was categorized as follows: low-level, defined as IgG (±) and IgG (+), and high-level, defined as IgG (++) and IgG (+++). Results: We found that the IgG-positive deposited group (N = 113, 9.36%) had significantly higher levels of ESR, TC, LDL, uric acid, proteinuria, and blood glucose, and lower serum albumin level compared to the IgG-negative deposited group (N = 1094, 90.64%). In terms of pathology, the IgG-positive deposited group had a significantly higher percentage of T2 score compared to the IgG-negative deposited group (p = 0.002). At the end of the follow-up period, the IgG-positive deposited group had a higher eGFR decline (-5.7 ± 4.37 ml/year) compared to the IgG-negative deposited group (-4 ± 2.52 ml/year), however, there was not a statistically significant difference between the two groups (p = 0.096). We observed that the high-IgG group had significantly higher level of TG compared to the low-IgG group (p = 0.042). Further analysis revealed that the group of patients with high level of IgG deposition in the kidney experienced a higher incidence of composite kidney outcomes compared to the group with low level of IgG deposition (p = 0.009). Logistic regression analyses showed that high level IgG deposition was an independent risk factor for kidney progression of IgAN (HR 13.419; 95% CI 2.690-66.943, P = 0.029). Further analyses for a solid conclusion using Cox regression that we found high level IgG deposition (HR 115.277; 95% CI 2.299-5.779E3, P = 0.017), eGFR (HR 0.932; 95% CI 0.870-0.999, P = 0.047), and urine protein excretion (HR 1.001; 95% CI 1.000-1.002, P = 0.015) were independent risk factor for kidney progression of IgAN. Conclusions: The intensity of IgG deposition has been found to be associated with the progression of IgAN. Future prospective studies should provide more robust evidence on the impact of IgG deposition on kidney outcomes in patients with IgAN.

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.

Clinical and pathological findings of IgA nephropathy following SARS-CoV-2 infection.

The features of IgA nephropathy (IgAN) after SARS-CoV-2 infection have not been well characterized. In this study, we compared the clinical and pathological characteristics of patients with IgAN who had experienced SARS-CoV-2 infection to those who had not. We conducted a retrospective study that enrolled 38 patients with biopsy-proven IgAN following SARS-CoV-2 infection with 4 months (post-SARS-CoV-2 infection group) and 1154 patients with IgAN prior to the pandemic (pre-SARS-CoV-2 infection group). Among the SARS-CoV-2 group cases, 61% were females. The average duration from SARS-CoV-2 infection to renal biopsy was 78.6 days. Prior to SARS-CoV-2 infection, the patients had different presentations of nephropathy. One patient had isolated hematuria, two had isolated proteinuria, twenty presented with both hematuria and proteinuria, and one patient had elevated serum creatinine. Additionally, there were eight cases with uncertain nephropathy history, and six cases did not have a history of nephropathy. Following SARS-CoV-2 infection, five patients experienced gross hematuria, one case exhibited creatinine elevation, and five cases showed an increase in proteinuria. The group of patients infected with SARS-CoV-2 after the COVID-19 pandemic exhibited older age, higher hypertension ratio and lower eGFR values compared to the pre-SARS-CoV-2 infection group. As for pathological parameters, a higher proportion of patients in the post-SARS-CoV-2 infection group exhibited a higher percentage of sclerotic glomeruli and glomerular ischemic sclerosis. There were no significant differences observed between the two groups in terms of therapy involving steroids, immunosuppressants, or RAS inhibitors. IgA nephropathy patients who were infected with SARS-CoV-2 were generally older and experienced more severe kidney damage compared to those without SARS-CoV-2 infection.

The optimal cut-off values of Klotho for predicting all-cause and cardiovascular mortality among chronic kidney disease: results from NHANES.

To explore the optimal cut-off values of Klotho for predicting all-cause and cardiovascular mortality among chronic kidney disease (CKD) patients. Klotho was measured in 40-79-year-old individuals in the NHANES 2007-2016. A total of 2418 patients with stage 1-4 CKD were included. The optimal cut-off values of Klotho were utilized using receiver operator characteristic (ROC) curves and be verified on the effects of all-cause and cardiovascular mortality. Restricted cubic splines were used to examine the relationship between Klotho and all-cause and cardiovascular mortality with the optimal cutpoints as the reference. After a mean follow-up period of 87.9 months, 535 deaths occurred and 188 died of cardiovascular disease. Cubic splines showed that the risk of all-cause and cardiovascular mortality increased gradually for Klotho < 700 pg/ml. ROC curves revealed that the optimal cut-off values of Klotho for all-cause and cardiovascular mortality are 548.8 pg/ml and 660.9 pg/ml, respectively. Compared to patients with higher levels of Klotho, HRs (95% CIs) for all-cause and cardiovascular mortality were 1.52 (1.23, 1.87) and 1.58 (1.13, 2.22) among patients with lower levels of Klotho, respectively, in the multivariate model (P < .0001 and P = 0.008). Our findings revealed the optimal cut-off values of Klotho for all-cause and cardiovascular mortality in CKD.

The protease inhibitor E64d might attenuate the development of experimental anti-glomerular basement membrane disease through regulating the activation of Th1 cells.

BACKGROUND: Cathepsins have been recently identified as a regulator in the activation of Th1 and Th17 cells, which play an important role in the pathogenesis of anti-glomerular basement membrane (GBM) disease. Whether cathepsins contribute to the development of anti-GBM disease through regulating the activation of CD4+ T cell is still unclear. METHODS: Rats with experimental anti-GBM disease was established by immunization with the nephritogenic T cell epitope α3127-148. E64d, a cysteine cathepsin inhibitor, was administered in vitro and vivo to evaluate the effect of cathepsins on regulating the activation of antigen specific T cells and the development of anti-GBM disease. RESULTS: In rats with experimental anti-GBM diseases, E64d treatment not only reduced the levels of proteinuria, serum creatinine and anti-GBM antibody, but also ameliorated the kidney injury with less glomerular IgG deposition, a lower percentage of crescents and less infiltration of CD4+ T cells, CD8+ T cells and macrophages, as well as a lower percentage of splenic Th1 cells. In vitro, E64d treatment could significantly reduce the production of IFN-γ in the supernatant which might be produced by the activation of Th1 cells after being recalled with the autoantigen α3127-148. We also found the CD4+ T cells of rats with anti-GBM disease had an increased expression of cathepsin L (Cts-L), and the percentage of CD4+ T cells with extracellular expression of Cts-L was obviously higher, indicating it as a potential key regulator. CONCLUSIONS: E64d might attenuate the development of anti-GBM disease by participating in the activation of Th1 cells, indicating it as a potential drug for anti-GBM disease in the future.

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.

Effect of hematuria on the kidney disease progression in IgA nephropathy patients with mild proteinuria and well-preserved renal function.

OBJECTIVE: To investigate whether hematuria is a risk factor in IgA nephropathy (IgAN) patients with mild proteinuria and well-preserved renal function. METHODS: This retrospective study included a total of 63 IgAN patients, with complete clinical data available for 50 patients. Hematuria assessment was conducted using two methods: 1) an automated method using a urine particle analyzer, and 2) a manual method performed by a skilled examiner to examine microscopic urine sediment. RESULTS: The results of hematuria measurement using both automated and manual methods showed a strong linear correlation (r = 0.78, P < 0.001). In IgAN patients, those with high urinary red blood cell count (U-RBCs) exhibited higher serum IgA levels compared to patients with low U-RBCs. Additionally, patients with crescent formation had higher levels of proteinuria compared to those without crescents. Patients who received immunosuppressive treatment displayed higher levels of systolic blood pressure (SBP) and mean arterial pressure (MAP), as well as lower levels of serum hemoglobin and albumin. They also had a higher prevalence of T1 lesions compared to patients who did not undergo immunosuppression. Furthermore, among patients with crescent formation, those who received immunosuppressive agents exhibited higher levels of SBP, diastolic blood pressure (DBP), MAP, and U-RBCs, as well as lower levels of albumin and proteinuria at the time of renal biopsy. No composite kidney endpoint events were observed in these groups of patients. The U-RBCs level was not identified as a risk factor influencing the decline of estimated glomerular filtration rate (eGFR) in IgAN. CONCLUSIONS: The presence of hematuria at the time of biopsy was not found to be associated with kidney disease progression in IgAN patients who had mild proteinuria and well-preserved renal function. This suggests that it is possible that these patients may not derive significant benefits from immunosuppressive therapy.

Deciphering prognostic value of CD22 and its contribution to suppression of proinflammatory cytokines production in patients with IgA nephropathy.

BACKGROUND: CD22, mainly expressed in mature B cells, could negatively regulate the function of B cells by binding to sialic acid-positive IgG (SA-IgG). Soluble CD22 (sCD22) is generated by the cleavage of the extracellular domain of CD22 on the membrane surface. However, the role of CD22 in IgA nephropathy (IgAN) remains unknown. METHODS: A total of 170 IgAN patients with a mean follow-up of 18 months were included in this study. The sCD22, TGF-ß, IL-6 and TNF-α were detected using commercial ELISA kits. SA-IgG were purified to stimulate peripheral blood mononuclear cells (PBMCs) from IgAN patients. RESULTS: The plasma levels of sCD22 were lower in IgAN patients in comparison with healthy control. Furthermore, CD22 mRNA levels in PBMCs from patients with IgAN were significantly lower than those of healthy controls. The plasma levels of sCD22 were positively correlated to the mRNA levels of CD22. We found that patients with higher sCD22 levels had a lower level of serum creatinine and a higher level of eGFR on the time of renal biopsy and a higher remission rate of proteinuria and a lower risk of kidney events at the end of follow-up. The logistic regression analysis showed sCD22 was associated with an increased odd of proteinuria remission after being adjusted for eGFR, proteinuria, and SBP. After adjusting for confounding variables, sCD22 was a borderline significant predictor of less kidney composite endpoint. In addition, the sCD22 levels were positively associated with SA-IgG in plasma. The experimental results in vitro showed that addition of SA-IgG enhanced the release of sCD22 in cell supernatant and the phosphorylation of CD22 in PBMCs, further inhibiting the production of IL-6, TNF-α, and TGF-ß in cell supernatant in a dose-dependent manner. Pretreatment with CD22-antibody significantly increased the expression of cytokines in PBMCs. CONCLUSIONS: This is the first study to demonstrate that lower plasma soluble CD22 in IgAN patients and high soluble CD22 levels are associated with an increased odd of proteinuria remission and a decreased odd of kidney endpoint. The interaction between CD22 and SA-IgG can inhibit proliferation and inflammation release in PBMCs from IgAN patients.

Effects of sodium-glucose co-transporter-2 inhibitors on kidney, cardiovascular, and safety outcomes in patients with advanced chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials.

AIMS: The overall effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors in patients with advanced chronic kidney disease (CKD) (estimated glomerular filtration rate (eGFR), 15-30 ml/min per 1.73 m2) remain unclear, and we thus conducted a systematic review and meta-analysis to evaluate the effects of SGLT2 inhibitors on kidney, cardiovascular (CV), and safety outcomes in patients with advanced CKD. METHODS: The Medline, Embase, and Cochrane Library databases were systematically searched for randomized controlled trials (RCTs) published up to March 3, 2022, and reporting effects of SGLT2 inhibitors on kidney, CV, or safety outcomes in patients with advanced CKD. RESULTS: From 2675 records, six RCTs with 2167 participants were included in the quantitative analyses. In patients with advanced CKD, SGLT2 inhibitors reduced the risk of the primary kidney outcome (a composite of worsening kidney function, end-stage kidney disease (ESKD), or kidney death) by 23% (RR 0.77, 95% CI 0.61-0.98, p = 0.04, I2 = 0 for the heterogeneity) and slowed the annual decline in eGFR slope, with the difference between SGLT2 inhibitor group and placebo group being 1.24 mL/min/1.73m2 per year (95% CI 0.06-2.42, p = 0.04). SGLT2 inhibitors were also associated with a decreased risk of primary CV outcome (a composite of CV death or hospitalization for heart failure) (HR 0.71, 95% CI 0.53-0.96, p = 0.03, I2 = 0 for the heterogeneity) and with similar risks of adverse events (such as acute kidney injury, fracture, amputation, and urinary tract infection). CONCLUSIONS: Among patients with advanced CKD, SGLT2 inhibitors reduced the risks of primary kidney and CV outcomes and attenuated the progressive decrease in eGFR compared with placebo, with no evidence of additional safety concerns. These observed benefits may support continuing the use of SGLT2 inhibitors in patients with advanced CKD before initiating maintenance dialysis or kidney transplantation. Future large-scale RCTs are needed to confirm the robustness of these results.

Circulating platelets supply ST6Gal-1 in patients with IgA nephropathy.

BACKGROUND: Our previous study showed ST6 ß-galactoside α2,6-sialyltransferase 1 (ST6Gal-1) levels in plasma were associated with a slower progression of IgA nephropathy (IgAN). Platelets are the crucial regulator of cell surface glycosylation events in circulation by supplying glycosyltransferases. METHODS: A total of 180 patients with IgAN were included in this study. ST6Gal-1 levels were analyzed before and after activation of platelets by flow cytometry. RESULTS: We found that IgAN patients in the higher platelet counts group exhibited higher levels of ST6Gal-1 compared with the lower platelet counts group. There was a positive correlation between platelet counts and ST6Gal-1 levels in plasma. Patients with higher platelet counts had higher levels of IgA, serum C3, serum C4 and proteinuria, higher percentages of platelet crits, S1 and T1/2, lower levels of platelet distribution width and the mean platelet volume, as well as a lower percentage of platelet large cell ratio compared with those patients with lower platelet counts. No differences were found in terms of the eGFR decline and composite kidney endpoints between two groups. Furthermore, we investigated whether platelets were activated and released ST6Gal-1 in patients with IgAN. The expression of CD62P in platelets in patients with IgAN was higher than those of healthy controls. There were no obvious changes in ST6Gal-1 levels between the rest and the activated platelets within 1 to 2-hour, however, the difference in ST6Gal-1 levels became more pronounced after 4-hour of incubation. CONCLUSIONS: In conclusion, human circulating platelets contain ST6Gal-1, which may be released by the activation of platelets in IgAN.

What is the context? Our previous study showed ST6 ß-galactoside α2,6-sialyltransferase 1 (ST6Gal-1) levels in plasma were associated with a slower progression of IgA nephropathy (IgAN).Platelets are the crucial regulator of cell surface glycosylation events in circulation by supplying glycosyltransferases.Whether elevated ST6Gal-1 in plasma is partly from platelets in IgAN has not been fully elucidated.What is new? A total of 180 patients with IgAN were included in this study.We found that IgAN patients in the higher platelet counts group exhibited higher levels of ST6Gal-1 compared with the lower platelet counts group.Patients with higher platelet counts had higher levels of IgA, serum C3, serum C4 and proteinuria, higher percentages of platelet crits, S1 and T1/2, lower levels of platelet distribution width and the mean platelet volume, as well as a lower percentage of platelet large cell ratio.There were no differences in terms of the eGFR decline and composite kidney endpoints between two groups.Furthermore, we explored whether platelets were activated and released ST6Gal-1 in patients with IgAN. The expression of CD62P in platelets in patients with IgAN was higher than that of healthy controls.There were no obvious changes in ST6Gal-1 levels between the rest and the activated platelets within 1 to 2-hour, however, the difference in ST6Gal-1 levels became more pronounced after 4-hour of incubation.What is the impact?Human circulating platelets contain ST6Gal-1, which can be released upon platelets activation. These findings suggest ST6Gal-1 is dynamically controlled by platelet activation to remodel cell surface glycans and alter cell behavior.

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.

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.

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.

Exploring the pathogenesis of diabetic kidney disease by microarray data analysis.

Diabetic kidney disease (DKD) is a major complication of diabetes mellitus, and the leading contributor of end-stage renal disease. Hence, insights into the molecular pathogenesis of DKD are urgently needed. The purpose of this article is to reveal the molecular mechanisms underlying the pathogenesis of DKD. The microarray datasets of GSE30528 and GSE30529 were downloaded from the NCBI Gene Expression Omnibus (GEO) database to identify the common differentially expressed genes (DEGs) between the glomerular DKD (GDKD) and tubular DKD (TDKD), respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to analyze the function and pathways of the common DEGs. After constructing the protein-protein interaction (PPI) network and subnetwork analysis, three types of analyses were performed, namely, identification of hub genes, analysis of the coexpressed network, and exploration of transcription factors (TFs). Totally, 348 and 463 DEGs were identified in GDKD and TDKD, respectively. Then, 66 common DEGs (63 upregulated DEGs and three downregulated DEGs) were obtained in DKD patients. GO and KEGG pathway analyses revealed the importance of inflammation response, immune-related pathways, and extracellular matrix-related pathways, especially chemokines and cytokines, in DKD. Fifteen hub genes from the 66 common DEGs, namely, IL10RA, IRF8, LY86, C1QA, C1QB, CD53, CD1C, CTSS, CCR2, CD163, CCL5, CD48, RNASE6, CD52, and CD2 were identified. In summary, through the microarray data analysis, the common functions and hub genes greatly contribute to the elucidation of the molecular pathogenesis associated with DKD.

Elevated activating Fc gamma receptors levels correlated with susceptibility and severity of IgA nephropathy.

Background: It is still uncertain if a dysregulated expression of activating Fc gamma receptors (FcγRs) is associated with the development of immunoglobulin A nephropathy (IgAN). Methods: RNA sequencing was used to determine the mRNA levels of type I FcγRs, which were then verified by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Commercial ELISA kits were used to detect plasma soluble FcγRIIIb (sFcγRIIIb). Results: We first examined the expression of FcγRs genes in 17 patients with IgAN and six healthy controls. The expression of FcγRIa, FcγRIb, FcγRIIa, FcγRIIc, FcγRIIIa, and FcγRIIIb was shown to be higher in IgAN patients. Even without statistical significance, there was a downward trend in FcγRIIb mRNA levels in IgAN. We observed that the expression levels of activating FcγR mRNAs were consistently higher in an independent set of 20 IgAN patients and 20 healthy controls, confirming the RNA-seq results. FcγRIIIb was the IgG receptor with the greatest difference in expression between the two groups (log2 fold-change = 1.82). We observed a much higher percent of FcγRIIIb positive cells in IgAN by flow cytometry. Next, we measured plasma sFcRIIIb levels in 50 patients with IgAN and 50 healthy controls. The findings revealed that the mean sFcγRIIIb level in plasma in participants with IgAN was much higher than that of healthy controls. Increased sFcγRIIIb levels were associated with a substantial increase in body mass index (BMI), lipid levels, serum creatinine level, and a larger percentage of sclerosis compared with lower sFcRIIIb levels. Patients in the group with higher sFcγRIIIb levels were more likely to get glucocorticoid treatment. Conclusion: The results demonstrated that the mRNA levels of the activating Fc receptor of IgG were significantly increased in IgAN. Patients with higher plasma sFcγRIIIb levels may have had more severe illness than those with lower levels.

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.

Plasma ST6GAL1 regulates IgG sialylation to control IgA nephropathy progression.

BACKGROUND: Our previous study revealed that plasma levels of a-2,6-sialyltransferase 1 (ST6GAL1) were increased in patients with IgA nephropathy (IgAN). ST6GAL1 catalyzes terminal sialylation of IgG to shift the antibody effector function to the anti-inflammatory pattern. However, the role of plasma ST6GAL1 in the progression of IgAN and underlying mechanisms are still unknown. METHODS: A total of 180 IgAN patients were included. The kidney outcomes were defined as the eGFR decline or proteinuria remission. Peripheral blood mononuclear cells (PBMCs) were either stimulated with purified sialylated IgG (SA-IgG) or with non-sialylated IgG (NSA-IgG) from IgAN patients to detect the levels of interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) in supernatant. RESULTS: Compared with the lower ST6GAL1 (reference), the risk of eGFR decline decreased for the higher ST6GAL1 group after adjustment for baseline eGFR, systolic blood pressure (SBP), and proteinuria. The results showed that patients with higher ST6GAL1 levels had a higher rate of proteinuria remission. ST6GAL1, expressed as a continuous variable, was a protective factor for eGFR decline and proteinuria remission. An in vitro study showed that the administration of recombinant ST6GAL1 (rST6GAL1) decreased the levels of IL-6 and TNF-α in PBMCs. Furthermore, the administration of rST6GAL1 resulted in the enrichment of SA-IgG in a concentration-dependent manner. In addition, as compared to control, purified SA-IgG-treated PBMCs showed a significant decrease in the expression of IL-6 and TNF-α. CONCLUSION: Our study indicated that elevated ST6GAL1 was associated with a slower progression of IgAN, which may play a protective effect by increasing IgG sialylation to inhibit the production of proinflammatory cytokines in PBMCs.

Sodium-glucose cotransporter 2 inhibitors benefit to kidney and cardiovascular outcomes for patients with type 2 diabetes mellitus and chronic kidney disease 3b-4: A systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: A systematic review and meta-analysis was performed to assess the kidney and cardiovascular (CV) outcomes of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) stage 3b-4. METHOD: We conducted a systematic review and meta-analysis of randomized, placebo-controlled trials (RCTs). Medline, Embase, and the Cochrane Central were searched for available trials up to Jan 18, 2021. RESULTS: From identifying 1892 citations, we included nine studies into quantitative analyses with a total of 6521 participants. In the patients with T2DM and CKD stage 3b-4, SGLT2 inhibitors significantly decreased the risk of the primary kidney outcome (HR 0.65, 95% CI 0.55-0.76) and slowed the decline in eGFR slope with a difference between treatment and control of 0.46 ml/min/1.73 m2 per year (95% CI 0.37-0.55). SGLT2 inhibitors also reduced the risk of the major adverse cardiovascular events (MACE) (HR 0.75, 95% CI 0.60-0.93). CONCLUSIONS: SGLT2 inhibitors can reduce the risk of kidney disease and MACE outcomes for patients with T2DM and CKD stage 3b-4, which may be the most beneficial effects observed in the included trials.

Effects and Safety of a Novel Oral Potassium-Lowering Drug-Sodium Zirconium Cyclosilicate for the Treatment of Hyperkalemia: a Systematic Review and Meta-Analysis.

BACKGROUND: Oral sodium zirconium cyclosilicate (SZC) is a novel potassium binder capable of achieving a rapid reduction of serum potassium (sK+) and maintaining a long-term normokalemia. We undertook a meta-analysis to summarize and evaluate the effects surrounding SZC in patients with hyperkalemia. METHOD: We searched data sources from MEDLINE (from 1950 to Sep 2020), EMBASE (from 1970 to Sep 2020), and the Cochrane Library database (from 1950 to Sep 2020) for eligible studies. All randomized controlled trials (RCTs) regarding comparison of therapeutic effects of SZC in hyperkalemia participants were included. RESULTS: Seven studies, including 1697 patients with hyperkalemia, were analyzed. SZC significantly reduced mean sK+ (-0.42 mmol/L; 95% CI: -0.63 to -0.20 mmol/L, p = 0.0001) compared with placebo, with a significantly greater proportion of patients with normokalemia (RR 3.48, 95% CI 1.49 to 8.11, p = 0.004). Subgroup analyses showed that the longer durations of SZC treatment, the greater magnitudes of potassium reduction when compared with those of placebo (p between subgroups = 0.01) at correction phase. Besides, it also demonstrated sK+ tended to decrease more in patients who got longer treatment or larger dosage of SZC at maintenance phase; however, the difference did not reach statistical significance. Additionally, the drug was equally effective in studies with larger than 50% of patients with chronic kidney disease (CKD) or diabetes or patients using renin-angiotensin aldosterone system inhibitor (RAAS) inhibitors (all p < 0.05). The risk of edema (4.30, 1.17 to 15.84; p = 0.03) in SZC group was higher than those of placebo group. No statistically significant differences in the risks of other adverse events were observed between the two groups. CONCLUSIONS: SZC effectively decreased the sK+ level in patients with hyperkalemia within 48 h and had benefits in the long-term control of serum potassium in patients who continued to receive SZC with a favorable safety profile from available data.