Role of Human Mesangial-Tubular Crosstalk in Secretory IgA-Induced IgA Nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is characterized by the mesangial deposition of pathogenic IgA. We previously detected the deposition of pathogenic secretory IgA (SIgA) in the mesangium of about one-third of IgAN patients. Tubulointerstitial injury has an important role in the development of IgAN. However, the relationship between SIgA and tubulointerstitial damage is currently unclear. In this work, the role of the mesangial-tubular crosstalk was explored in the tubulointerstitial damage in SIgA-induced IgAN. METHODS: SIgA deposition in renal tissues of IgAN patients was detected by immunofluorescence. Flow cytometry was used to assess the binding of SIgA to human renal mesangial cells (HRMC) and human proximal tubule epithelial (HK-2) cells. HK-2 was co-cultured with HRMC added with SIgA isolated from patients or normal volunteers. Protein synthesis and gene expressions of TNF-α, TGF-ß1, and MCP-1 were determined by ELISA and PCR, respectively. The expressions of the above cytokines in renal tissues of patients and normal controls were detected by immunohistochemistry. RESULTS: Twenty-nine of 96 patients had SIgA deposition in the mesangium, but SIgA was rarely detected in the tubulointerstitium. The binding rate of SIgA to HK-2 (2.79%) was significantly lower than that of HRMC (81.6%) (p < 0.001). The expressions of TNF-α, TGF-ß1, and MCP-1 in HRMC were significantly higher than in SIgA-stimulated HK-2 (p < 0.05), and their expressions were significantly higher in the SIgA-stimulated co-culture group compared with SIgA-stimulated HRMC (p < 0.05). The expressions of the above cytokines were mainly detected in tubulointerstitium of IgAN patients with positive and negative SIgA deposition, without significant difference between the 2 groups, but to a significantly higher level than that in normal controls, and their expressions positively correlated with tubulointerstitial injury. CONCLUSION: Inflammatory factors released from the mesangium after SIgA deposition might mediate tubulointerstitial damage via mesangial-tubular crosstalk in IgAN.

Overlapping obesity-related glomerulopathy and immunoglobulin A nephropathy: clinical and pathologic characteristics and prognosis.

BACKGROUND: In this study, we investigated the clinical and pathologic characteristics and prognosis of overlapping obesity-related glomerulopathy (ORG) and immunoglobulin A nephropathy (IgAN) (ORG + IgAN), which is rare in the clinic. METHODS: We included 62 cases of ORG + IgAN, 110 cases of ORG without other glomerulopathy (ORG alone) and 124 cases of IgAN without other glomerulopathy (IgAN alone). The clinical, pathologic and prognostic data were collected and compared. RESULTS: ORG + IgAN patients showed a higher incidence of body mass index (BMI), higher incidence of hyperuricemia, higher incidence of hypertriglyceridemia and higher blood glucose than the IgAN alone(all P < 0.05). ORG + IgAN patients presented with higher incidence of microscopic hematuria, greater mesangial cell proliferation and a higher proportion of crescents than the ORG alone (all P < 0.05). The ORG + IgAN patients who received corticosteroid or immunosuppressive therapy achieved a higher cumulative rate of partial or complete remission (PR or CR, P = 0.009). However, there was no significant difference in the cumulative renal survival rate between the ORG + IgAN patients in the glucocorticoids/immunosuppressors and non-glucocorticoids/immunosuppressors groups (P = 0.356). Obesity-related focal segmental glomerulosclerosis (O-FSGS) and body mass index (BMI) were significantly associated with poor prognosis (all P < 0.05). CONCLUSIONS: ORG + IgAN should be considered in obese patients who present with metabolic abnormalities and microscopic hematuria. Although corticosteroid or immunosuppressive therapy achieves higher cumulative incidence rates of PR or CR, there is no benefit to long-term prognosis but an increased risk of infection. Moreover, O-FSGS and BMI are significantly associated with poor prognosis.

External Validation of the International IgA Nephropathy Prediction Tool.

BACKGROUND AND OBJECTIVES: The International IgA Nephropathy Network recently developed and externally validated two models to predict the risk of progression of IgA nephropathy: full models without and with race. This study sought to externally validate the International IgA Nephropathy Prediction Tool in a large, independent, and contemporary cohort in China. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We included 1373 patients with biopsy-confirmed primary IgA nephropathy from The First Affiliated Hospital of Zhengzhou University from January 2012 to May 2018 and calculated predicted risks for each patient. The outcomes of interest were a 50% decline in eGFR or kidney failure. We assessed the performance of both models using discrimination (concordance statistics and Kaplan-Meier curves between subgroups), calibration (calibration plots), reclassification (net reclassification improvement and integrated discrimination improvement), and clinical utility (decision curve analysis). RESULTS: The median follow-up was 29 months (interquartile range, 21-43 months; range, 1-95 months), and 186 (14%) patients reached the kidney outcomes of interest. Both models showed excellent discrimination (concordance statistics >0.85 and well separated survival curves). Overall, the full model without race generally underestimated the risk of primary outcome, whereas the full model with race was well calibrated for predicting 5-year risk. Compared with the full model without race, the full model with race had significant improvement in reclassification, as assessed by the net reclassification improvement (0.49; 95% confidence interval, 0.41 to 0.59) and integrated discrimination improvement (0.06; 95% confidence interval, 0.04 to 0.08). Decision curve analysis showed that both full models had a higher net benefit than default strategies, and the model with race performed better. CONCLUSIONS: In this study, both full models demonstrated remarkable discrimination, acceptable calibration, and satisfactory clinical utility. The relatively short follow-up time may have limited the validation of these models.

The TLR4-MyD88-NF-κB pathway is involved in sIgA-mediated IgA nephropathy.

Previous studies have shown that secretory IgA (sIgA) was critically involved in IgA nephropathy (IgAN) immune responses. Toll-like receptors (TLRs), especially TLR4 which participates in mucosal immunity, may be involved in the pathogenesis of IgAN. The purpose of this study was to investigate whether sIgA and TLR4 interact to mediate kidney damage in IgAN patients. IgAN patients with positive sIgA deposition in renal tissues were screened by immunofluorescence assay. Patient salivary sIgA (P-sIgA) was collected and purified by jacalin affinity chromatography. Salivary sIgA from healthy volunteers was used as a control (N-sIgA). Expression of TLR4, MyD88, NF-κB, TNF-α, IL-6, and MCP-1 were detected in the mesangial area of IgAN patients by immunohistochemistry, the expression levels in patients with positive sIgA deposition were higher than that with negative sIgA deposition. Human renal mesangial cells (HRMCs) were cultured in vitro, flow cytometry showed that P-sIgA bound HRMCs significantly better than N-sIgA. HRMCs were cultured in the presence of sIgA (400 µg/mL) for 24 h, compared with cells cultured with N-sIgA, HRMCs cultured in vitro with P-sIgA showed enhanced expression of TLR4, increased secretion of TNF-α, IL-6, and MCP-1, and increased expression of MyD88/NF-κB. TLR4 shRNA silencing and NF-κB inhibition both reduced the ability of HRMCs to synthesize TNF-α, IL-6, and MCP-1. Our results indicate that sIgA may induce high expression of TLR4 in HRMCs and further activate downstream signalling pathways, prompting HRMCs to secrete multiple cytokines and thereby mediating kidney damage in IgAN patients.