Renal fibrosis is one of the largest global health care problems, and microvascular (MV) injury is important in the development of progressive fibrosis. Although conventional cell therapy suppresses kidney injury via the role of vasoprotective cytokines, the effects are limited due to low retention of administered cells. We recently described that transplantation of hepatocyte growth factor (HGF)transgenic mesothelial cell sheets showed a remarkable cell survival and strong therapeutic effects in a rat renal fibrosis model. Due to the translational hurdles of transgenic cells, we here applied this technique for allogeneic transplantation using rat bone marrow mesenchymal stromal cells (MSCs). MSC sheets were transplanted onto the kidney surface of a rat renal ischemia-reperfusion-injury model and the effects were compared between those in untreated rats and those receiving intravenous (IV) administration of the cells. We found that donor-cell survival was superior in the cell sheet group relative to the IV group, and that the cell sheets secreted HGF and vascular endothelial growth factor (VEGF) up to day 14. Transplantation of cell sheets increased the expression of activated HGF/VEGF receptors in the kidney. There was no evidence of migration of transplanted cells into the kidney parenchyma. Additionally, the cell sheets significantly suppressed renal dysfunction, MV injury, and fibrosis as compared with that observed in the untreated and IV groups. Furthermore, we demonstrated that the MSC sheet protected MV density in the whole kidney according to threedimensional microcomputed tomography. In conclusion, MSC sheets strongly prevented renal fibrosis via MV protection, suggesting that this strategy represents a potential novel therapy for various kidney diseases. STEM CELLS TRANSLATIONAL MEDICINE 2019;8:1330-1341 SIGNIFICANCE STATEMENTCell therapy has been applied to various diseases that are resistant to conventional therapy. Renal fibrosis is one of the most difficult issues, and many researchers have tried intravascular administration of stem cells. The present study revealed that transplantation of mesenchymal stromal cell (MSC) sheets onto the kidney showed dramatic effects, including long-term cell survival, amelioration of kidney dysfunction, vasoprotection, and antifibrosis, compared with intravenous administration of MSCs. These results suggest that cell sheet technology improves the effects of cell therapy in various aspects. Therefore, cell sheet therapy could be a potential novel therapeutic approach for various kidney diseases in the future.

Rituximab treatment was effective and safe in patients with steroid-dependent nephrotic syndrome, allowed reduction of the PRED dose, and ameliorated the adverse effects of PRED. It may be preferentially used in patients at a risk of the adverse effect of PRED.

Rituximab has been approved in Japan for the treatment of intractable nephrotic syndrome, but in cases of childhood-onset disease only; its efficacy and safety in adult-onset disease has yet to be established. This study was undertaken to evaluate the efficacy of rituximab and adverse effects in patients with adult-onset minimal change nephrotic syndrome (MCNS).The study involved 32 childhood-onset cases (mean age at onset: 8.6 years) and 19 adult-onset cases (mean age at onset: 30.6 years) of frequently relapsing steroid-dependent MCNS, all of whom received intravenous rituximab drip infusion (375 mg/m2 body surface area per dose) at 4 time points at 6-month intervals. Relapse frequency, oral dose of immunosuppressants, and adverse effects were compared between the 2 groups.Remission was maintained in all cases in the childhood-onset and adult-onset groups; a significant reduction in relapse frequency was noted during the first 24 months of rituximab therapy (0.3 ± 0.7 times and 0.3 ± 0.6 times in the childhood-onset and adult-onset groups, respectively; P < .001). Oral corticosteroid therapy could be discontinued in 81.3% of cases of the childhood-onset group (26/32 cases) and in 70.6% of cases of the adult-onset group (12/17 cases); the oral corticosteroid dose was reduced significantly to 0.9 ± 2.5 mg/day in the childhood-onset group and to 0.8 ± 1.6 mg/day in the adult-onset group (P < .001). Cyclosporin treatment was also discontinued in 87.5% of cases in the childhood-onset group (21/24 cases) and in 80.0% of cases of the adult-onset group (15/21 cases); the oral cyclosporin dose was reduced significantly to 8.6 ± 27.4 mg/day and 9.2 ± 22.0 mg/day, respectively (P < .001). Regarding adverse reactions, infusion reactions developed at a frequency of 21.1% and 19.7% in both groups, respectively, with no significant inter-group difference (P = .72).Rituximab showed significant efficacy in adult-onset MCNS, with a comparable incidence of adverse reactions to that in childhood-onset cases, suggesting that this drug can also be used safely in adult-onset MCNS.

The Oxford classification for IgA nephropathy (IgAN) was updated in 2017. We have validated the revised Oxford classification considering treatment with corticosteroids/immunosuppressors. In this retrospective analysis, 871 IgAN patients were enrolled. Patients were divided into two groups, those treated with or without corticosteroids/immunosuppressors. The 20-year renal prognosis up to end-stage renal disease was assessed using the Oxford classification. In all patients, the renal survival rate was 87.5% at 10 years and 72.6% at 20 years. The T score alone was significantly related to renal prognosis in the Kaplan-Meier analysis and multivariate Cox regression analysis. In the non-treatment group (n = 445), E, S, T, and C scores were significantly related to renal survival rates, however, in the treatment group (n = 426), T score alone was significantly related to renal prognosis on Kaplan-Meier analysis, indicating that corticosteroids/immunosuppressors improved renal prognosis in E1, S1, and C1. In patients with E1, S1, or C1, the treatment group showed significantly better renal prognosis than the non-treatment group in univariate and multivariate analysis. The Oxford classification and T score were used to determine renal prognosis in IgAN patients. Corticosteroids/immunosuppressors improved renal prognosis, especially E1, S1, and C1 scores. IgA nephropathy (IgAN) was first reported 50 years ago by Berger 1. IgAN was initially labelled as a benign disease; however, it was later shown to have a poor long-term prognosis 2-5. Although the prognostic risk factors of IgAN have not been clearly defined, hypertension, deterioration of renal function, and increased levels of proteinuria are known prognostic factors 2-5. Histological findings may also inform prognosis 6-9 , although these factors have not achieved worldwide acceptance. In 2009, the Oxford classification was reported by the International IgAN Network and International Renal Pathology Society 10,11. In the Oxford classification, mesangial hypercellularity (M), segmental glomerulosclerosis (S), tubular atrophy/interstitial fibrosis (T), were selected as prognostic factors and endothelial hypercellularity (E) were selected as reactive factors against corticosteroids/immunosuppressors (MEST score). After this report of the Oxford classification, several validation studies were performed, with different results among those studies 12-25. Using a multivariate analysis, it was determined that the T score was the most valuable marker of progression; however, other factors differed according to the clinical background (race, age), inclusion criteria (estimated glomerular filtration rate [eGFR] > 30 mL/min/1.73 m 2 , proteinuria > 0.5 g/day, minimum followup > 1 year), duration of follow-up, treatment, and endpoint of each study (eGFR slope, 50% reduction of eGFR, or end-stage renal disease [ESRD]). Interestingly, several reports validated not only the MEST score but also the crescent formation (as the C score), and multivariate analysis indicated that the C s...

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