Tomomi Aizawa

Aim: We have previously reported the mid‐term efficacy and safety of tacrolimus (Tac)‐based immunosuppressive therapy in such patients, and herein, we aimed to determine their long‐term outcomes (over 10 years).Methods: We retrospectively evaluate the data of 13 consecutive patients with biopsy‐proven long‐standing LN who underwent a long‐term Tac‐based treatment regimen. Tac was administered once daily at a dose of 3 mg as reinduction or maintenance treatment. Treatment outcomes were defined using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), urinary protein/creatinine ratio (Up/cr), serum creatinine, estimated glomerular filtration rate (eGFR) and serological lupus markers (complement C3, complement hemolytic activity [CH 50], and anti‐dsDNA antibody titre), and the concomitantly administered prednisolone (PDN) dose. Data on clinical parameters and serological lupus activity were collected annually from each patient throughout the study period.Results: The patients' baseline characteristics at the treatment initiation were as follows: mean age, 18 years; Up/cr, 0.63 ± 0.69; serum C3 level, 57.2 ± 22.4 mg/dL (normal range, 79–152 mg/dL); CH50, 27.9 ± 15.7 U/mL (normal range, 23.0–46.0 U/mL); serum anti‐dsDNA antibody titre, 111.7 ± 123.4 IU/mL (normal range, p = .002), a marked improvement in the outcomes, compared with the baseline values, was observed within a year. Additionally, these favourable changes persisted throughout study period in most patients. Compared with the baseline values, the following measures confirmed sustained outcome improvements after a 10‐year treatment: SLEDAI, 1.7 ± 2.0; serum C3 level, 83.8 ± 16.1 mg/dL; CH50, 45.6 ± 10.9 U/mL (all p < .01) and Up/cr, 0.16 ± 0.18 and serum anti‐dsDNA antibody titre, 25.8 ± 28.8 IU/mL (both p < .05). Serum creatinine level and eGFR remained within the normal range in all study participants except for one patient who experienced several flare‐ups. No serious adverse effects were observed.Conclusion: Our results suggest that long‐term Tac‐based immunosuppressive treatment as maintenance therapy is beneficial and has low cytotoxicity. Therefore, it represents an attractive option for the treatment of selected patients with paediatric‐onset LN in a real‐world setting. image

Background: Dysregulation of the coagulation fibrinolysis system in resident glomerular cells is associated with the pathogenesis of lupus nephritis. However, the role of plasminogen activator inhibitor‐1 (PAI‐1) and tissue plasminogen activator (tPA) in resident glomerular cells remains undetermined. Methods: We examined the expression of PAI‐1 and tPA mRNA in cultured normal human glomerular endothelial cells (GECs) treated with serum from patients with systemic lupus erythematosus (SLE) using quantitative reverse transcription polymerase chain reactions. We determined the relationship between PAI‐1/tPA mRNA expression and several clinical/laboratory parameters. Serum from 16 patients (nine patients with new‐onset SLE and seven patients with stable SLE) was used in the study. Results: Plasminogen activator inhibitor‐1 and tPA mRNA expression was significantly higher in GECs treated with serum of patients with new‐onset SLE than other groups. The PAI‐1 and tPA mRNA levels were also significantly correlated in GECs treated with serum from patients with SLE. Interestingly, both PAI‐1 and tPA mRNA levels in GECs were inversely correlated with serum C4 level and positively correlated with SLE disease activity. Conclusions: These results suggest that serum from patients with SLE may activate the fibrinolysis system in glomerulus, which may be involved in the pathogenesis of lupus nephritis.

Background Glomerular endothelial cells (GECs) are directly exposed to circulating viral particles in the glomerulus. Although viral infections may trigger the development of acute kidney injury (AKI) or the worsening of pre‐existing chronic kidney disease (CKD), the specific molecular mechanisms underlying antiviral reactions via the activation of endothelial Toll‐like receptor 3 (TLR3) signaling in the kidney remain to be determined. Interferon (IFN)‐induced transmembrane protein 1 (IFITM1), a member of interferon‐stimulated gene (ISG) protein family, is involved in the prevention of viral entry into cerebral vascular endothelial cells, respiratory epithelial cells, and endometrium. However, to our knowledge, the implication of IFITM1 associated with viral infections in GECs has not been investigated to date. Methods Cultured normal human GECs were treated with polyinosinic‐polycytidylic acid (poly IC), a synthesized viral double‐stranded RNA, then the expression of IFITM1 was examined by quantitative real‐time reverse transcription‐polymerase chain reaction and western blotting. To further elucidate the poly IC‐induced signaling pathway, the cells were applied to RNA interference against IFN‐β, nuclear factor (NF)‐κB p65, and IFN regulatory factor (IRF) 3. We also conducted an immunofluorescence study to examine endothelial IFITM1 expression in biopsy specimens from patients with CKD. Results We found that the activation of TLR3 induced endothelial expression of IFITM1, and that this involved IRF3 and IFN‐β, but not NF‐κB. Intense endothelial IFITM1 immunoreactivity was observed in biopsy specimens from patients with lupus nephritis (LN). Conclusion Antiviral reaction‐related endothelial expression of IFITM1 may be involved, at least in part, in the development of particularly in LN. Further detailed studies of the implication of ISGs, including IFITM1 in GECs are needed.

Background: Endothelial expression of membrane-bound fractalkine/CX3CL1 (Fkn) reportedly acts as a strong mediator of inflammation. Toll-like receptor 3 (TLR3) axes are thought to play some roles in the development of chronic glomerulonephritis (CGN) including lupus nephritis (LN). However, detailed mechanism of TLR3-mediated Fkn expression in glomerular endothelial cells (GECs) remains to be elucidated. Methods: We examined the effect of polyinosinic-polycytidylic acid (poly IC) on Fkn expression in cultured human GECs. Fkn mRNA and protein levels were quantified by real-time PCR and enzyme-linked immunosorbent assay, respectively. To further elucidate the effects of poly IC on this signaling pathway, we used small interfering RNA (siRNA) to knockdown expression of TLR3, nuclear factor (NF)-κB p65, interferon (IFN)-β, and IFN regulatory factor 3 (IRF3). We then analyzed whether pretreatment of chloroquine or dexamethasone inhibits poly IC-induced Fkn expression. Results: We found that poly IC-induced Fkn expression in GECs, and that this involved NF-κB, IFN-β, and IRF3. Pretreating cells with chloroquine, but not dexamethasone attenuated poly IC-induced Fkn expression in GECs. Conclusion: Since the activation of TLR3/NF-κB/IFN-β/Fkn and TLR3/IRF3/Fkn axes is involved in inflammatory reactions in GECs, intervention of glomerular TLR3 signaling may be a suitable therapeutic strategy for treating CGN especially LN.