To date, no specific therapies have been approved for immunoglobulin A nephropathy (IgAN) treatment. Telitacicept is a fusion protein composed of transmembrane activator and calcium-modulating cyclophilin ligand interactor and fragment crystallizable portion of immunoglobulin G (IgG), which neutralizes the B lymphocyte stimulator and a proliferation-inducing ligand. This phase 2 randomized placebo-controlled trial aimed to evaluate the efficacy and safety of telitacicept in patients with IgAN. Participants with an estimated glomerular filtration rate (eGFR) >35 ml/min per 1.73 m² and proteinuria ≥0.75 g/d despite optimal supportive therapy, were randomized 1:1:1 to receive subcutaneous telitacicept 160 mg, telitacicept 240 mg, or placebo weekly for 24 weeks. The primary end point was the change in 24-hour proteinuria at week 24 from baseline. Forty-four participants were randomized into placebo (n = 14), telitacicept 160 mg (n = 16), and telitacicept 240 mg (n = 14) groups. Continuous reductions in serum IgA, IgG, and IgM levels were observed in the telitacicept group. Telitacicept 240 mg therapy reduced mean proteinuria by 49% from baseline (change in proteinuria vs. placebo, 0.88; 95% confidence interval, -1.57 to -0.20; P = 0.013), whereas telitacicept 160 mg reduced it by 25% (-0.29; 95% confidence interval, -0.95 to 0.37; P = 0.389). The eGFR remained stable over time. Adverse events (AEs) were similar in all groups. Treatment-emergent AEs were mild or moderate, and no severe AEs were reported. Telitacicept treatment led to a clinically meaningful reduction in proteinuria in patients with IgAN in the present phase 2 clinical trial. This effect is indicative of a reduced risk for future kidney disease progression.

Objective. IgA ₁ aberrant O -glycosylation is one of the main pathogeneses of IgA nephropathy (IgAN), and the core I β3-Gal-T-specific molecular chaperone (Cosmc) mRNA expression of IgAN patients was significantly decreased. This study tried to clarify whether the down-regulation was a result of genetic disorders or external suppressions. Method. Sixty-five IgAN patients, 23 non-IgAN glomerulonephritis patients and 21 normal controls were recruited. Genomic DNA was extracted and the Cosmc gene was PCR amplified and directly sequenced. Peripheral B lymphocytes of IgAN patients and normal controls were isolated, and cultured with RPMI-1640 alone or with lipopolysaccharide (LPS) for 72 h. The Cosmc mRNA expression levels at baseline, after RPMI culture or RPMI + LPS treatment were measured by real-time RT-PCR. Results. (1) The whole coding frame region of the Cosmc gene was successfully amplified and directly sequenced. Four single nucleotide polymorphisms were detected in two IgAN patients. Two were missense mutations and the others were silent mutations. However, they are different from each other, and unrelated to expression levels; (2) the baseline Cosmc mRNA expression in IgAN patients was significantly lower than normal controls (Ct _COSMC/GAPDH 1.29 ± 0.08 versus 1.20 ± 0.01, 31% of normal controls); (3) the Cosmc mRNA expression level of IgAN patients was remarkably increased after the RPMI culture (1.22 ± 0.12 versus 1.29 ± 0.08, 219% of the baseline level), while not in normal controls and (4) treatment with LPS (culture with RPMI + LPS) could strongly inhibit the expression of Cosmc mRNA (1.25 ± 0.01 versus 1.22 ± 0.12, 61% of the RPMI treatment group). Conclusion. No common Cosmc gene mutation was detected. Significantly increased Cosmc expression was observed in plasma-free culture, while LPS could significantly inhibit it, which suggested that it might not be genetic disorders but external suppression that causes the low Cosmc mRNA expression in IgAN.

Background: Recently, a few studies have indicated a relationship between the gut microbiota and IgA nephropathy (IgAN). Whether the gut microbiota participates in the pathogenesis of IgAN and whether probiotics are effective in treating IgAN are still controversial. Therefore, this study aimed to identify the differences in the structure of the gut microbiota between IgAN and controls and to evaluate the efficacy and mechanism of probiotics in the treatment of IgAN. Methods: To address this question, 35 IgAN patients and 25 healthy volunteers were enrolled, and a mouse IgAN model was also constructed. The stool microbes were analyzed by 16S rRNA high-throughput sequencing to identify the differential strains between IgAN and healthy controls. The impact of probiotics on the structure of the intestinal flora and the efficacy of the probiotics in the treatment of IgAN were evaluated. Results: Although the microflora structure of mice and humans was not the same, both patients and mice with IgAN exhibited gut microbiota dysbiosis, with all subjects presenting an evident decrease in Bifidobacterium levels. The Bifidobacterium proportion was negatively correlated with proteinuria and hematuria levels, indicating that the decreased Bifidobacterium abundance could be related to IgAN severity. Probiotic treatment containing Bifidobacterium in IgAN mice could significantly alleviate gut dysbiosis, specifically by increasing the proportion of beneficial bacteria and reducing the abundance of potentially pathogenic bacteria. Moreover, both probiotics and their metabolites, short-chain fatty acids (SCFAs), could attenuate IgAN clinicopathological manifestations by inhibiting the NLRP3/ASC/Caspase 1 signaling pathway. Conclusions: Supplementation with probiotics mainly containing Bifidobacterium could markedly improve gut dysbiosis in IgAN. Moreover, both probiotics and their SCFA metabolites could attenuate the clinicopathological manifestations of IgAN by inhibiting the NLRP3/ASC/Caspase 1 signaling pathway. Therefore, probiotics have potential as an adjunctive therapy for IgAN.

: Purpose.  Aberrant O‐glycosylation of serum IgA₁ is presumed to be one of the main pathogenesis of immunoglobulin A nephropathy (IgAN). β1,3‐galactosyltransferase (β1,3GT), whose activity requires coexistence of a specific chaperone, is the main enzyme which participate in the glycosylation process. The current study was carried out to elucidate the expression level of β1,3GT (C1GALT1) and its chaperone (Cosmc) in IgAN, and their relationships with clinical features as well as IgA glycosylation level.Design, setting and subjects.  Forty‐one patients with IgAN, 21 patients with non‐IgAN glomerulonephritis and 26 normal controls were included in the present study. Peripheral B lymphocytes were isolated, and then expression level of C1GALT1 and Cosmc were quantitatively measured by real‐time reverse transcriptase polymerase chain reaction (RT‐PCR). Serum IgA level and glycosylation level were determined by enzyme‐linked immunosorbent assay (ELISA) and VV lectin‐binding method. Correlation analysis was performed between C1GALT1/Cosmc expression levels and clinical manifestations (severe proteinuria, renal dysfunction, gross haematuria).Results.  B‐lymphocyte Cosmc gene expression level was significantly lower in IgAN patients than that of normal control and non‐IgAN patients (P < 0.05), whilst no apparent disparity was observed in C1GALT1 expression level. Cosmc expression showed a negative correlation with IgA O‐glycosylation level indicated by VV lectin‐binding assay. Statistical analysis also indicated that the level of Cosmc expression was negatively correlated with severe proteinuria (P < 0.05) instead of gross haematuria (P > 0.05).Conclusion.  These data suggested that the aberrant IgA O‐glycosylation in IgAN was resulted from a downregulation of β1,3GT chaperone (Cosmc) expression in B lymphocyte, which is closely associated with clinical characteristics of the disease. This downregulation might be one of the fundamental pathogenic abnormalities in IgAN.