A novel renal perivascular mesenchymal cell subset gives rise to fibroblasts distinct from classic myofibroblasts.

Perivascular mesenchymal cells (PMCs), which include pericytes, give rise to myofibroblasts that contribute to chronic kidney disease progression. Several PMC markers have been identified; however, PMC heterogeneity and functions are not fully understood. Here, we describe a novel subset of renal PMCs that express Meflin, a glycosylphosphatidylinositol-anchored protein that was recently identified as a marker of fibroblasts essential for cardiac tissue repair. Tracing the lineage of Meflin+ PMCs, which are found in perivascular and periglomerular areas and exhibit renin-producing potential, showed that they detach from the vasculature and proliferate under disease conditions. Although the contribution of Meflin+ PMCs to conventional α-SMA+ myofibroblasts is low, they give rise to fibroblasts with heterogeneous α-SMA expression patterns. Genetic ablation of Meflin+ PMCs in a renal fibrosis mouse model revealed their essential role in collagen production. Consistent with this, human biopsy samples showed that progressive renal diseases exhibit high Meflin expression. Furthermore, Meflin overexpression in kidney fibroblasts promoted bone morphogenetic protein 7 signals and suppressed myofibroblastic differentiation, implicating the roles of Meflin in suppressing tissue fibrosis. These findings demonstrate that Meflin marks a PMC subset that is functionally distinct from classic pericytes and myofibroblasts, highlighting the importance of elucidating PMC heterogeneity.

Survival Benefit of Maintained or Increased Body Mass Index in Patients Undergoing Extended-Hours Hemodialysis Without Dietary Restrictions.

OBJECTIVE: Low body mass index (BMI) is a potential risk factor for mortality in patients on maintenance hemodialysis. This suggests the usefulness of BMI as a prognostic factor and implies the importance of nutritional status, inflammation, and oxidative stress, all of which affect BMI. We aimed to evaluate BMI changes over time and the mortality risk in patients undergoing a novel combination therapy consisting of an extended-hours hemodialysis protocol without dietary restrictions, which enabled sufficient nutrition. DESIGN AND METHODS: This is a retrospective cohort study. Patients were divided into 2 groups based on BMI change (ΔBMI < 0, ΔBMI ≥ 0) between the 3rd and 12th month after transfer to the clinic. We studied the associations of BMI changes with all-cause mortality. Further subgroup analyses were performed using Cox models. We finally studied 187 patients who were receiving the combined therapy. The main outcome measure was all-cause mortality of the study group. RESULTS: The median (interquartile range) follow-up time was 4.9 (3.0-8.6) years. Overall, 138 patients were in the ΔBMI ≥ 0 group. As per unadjusted and adjusted Cox models, maintained or increased BMI during this period was associated with hazard ratios of 0.45 (confidence interval 0.23-0.87, P < .05) and 0.35 (confidence interval 0.17-0.75, P < .01) for all-cause mortality, respectively. In the same group, maintained or increased BMI was found to be significantly associated with decreased mortality in female, older, and nondiabetic patients. The data indicated that diabetic status could have a modifying effect on the association between variation in BMI and mortality (P = .006). CONCLUSIONS: Extended-hours hemodialysis without dietary restrictions led to a beneficial effect of maintenance or increase in BMI, especially in females, patients aged ≥65 years, and those without diabetic nephropathy, which could lead to prolonged survival.

Circulating levels of CD34+ cells predict long-term cardiovascular outcomes in patients on maintenance hemodialysis.

CD34+ cells maintain vascular homeostasis and predict cardiovascular outcomes. We previously evaluated the association of CD34+ cells with cardiovascular disease (CVD) events over 23 months, but long-term CVD outcomes in relation to levels of CD34+ cells in patients on maintenance hemodialysis are unclear. Herein, we analyzed the long-term predictive potential levels of CD34+ cells for CVD outcomes and all-cause mortality. Between March 2005 and May 2005, we enrolled 215 patients on maintenance hemodialysis at Nagoya Kyoritsu Hospital and followed them up to 12.8 years. According to the CD34+ cell counts, patients were classified into the lowest, medium, and highest tertiles. Levels of CD34+ cells were analyzed in association with four-point major adverse CV events (MACEs), CVD death, and all-cause mortality. In univariate analysis age, smoking habit, lower geriatric nutrition risk index, lower calcium × phosphate product, and lower intact parathyroid hormone were significantly associated with the lowest tertile. Whereas, in multivariate analysis, age and smoking habit were significantly associated with the lowest tertile. Among 139 (64.7%) patients who died during a mean follow-up period of 8.0 years, 39 (28.1%) patients died from CVD. Patients in the lowest tertile had a significantly lower survival rate than those in the medium and highest tertiles (p ≤ 0.001). Using multivariable analyses, the lowest tertile was significantly associated with four-point MACEs (hazard ratio 1.80, p = 0.023) and CVD death (hazard ratio 2.50, p = 0.011). In conclusion, our long-term observational study revealed that a low level of CD34+ cells in the circulation predicts CVD outcomes among patients on maintenance hemodialysis.

Clinical impact of endocapillary proliferation with modified cutoff points in IgA nephropathy patients.

Predictive values of mesangial proliferation (M), endocapillary proliferation (E), segmental glomerulosclerosis (S), and crescents (C) among 19 validation studies of the Oxford Classification of IgA nephropathy (IgAN) were discrepant, especially in Asian patients. These validation studies indicate that cutoffs of MESC score in the Oxford Classification may not be generalizable. Thus, we aimed to improve the clinical value of MESC scores by modifying the cutoff points. A total of 104 patients with IgAN were diagnosed from 2001 to 2012 vai renal biopsy and retrospectively evaluated at Nagoya University Hospital. The cutoff point for modified (M´E´S´C´) was determined using the receiver operating characteristic curve in association with renal outcome in the training cohort. Clinical values of the Oxford MESTC vs M´E´S´C´ cutoff points were analyzed using Kaplan-Meier and Cox regression in association with poor renal outcome in the validation and the entire cohort. Of 104 patients, 12.5% reached poor renal outcome over a median of 6.25 [4.16-9.61] years of follow-up. The modified cutoffs were defined as ≥40%, ≥10%, ≥20%, and ≥5% in the glomeruli for M´E´S´, and C´ respectively. In univariate analysis, E´, S ´, and T were significantly associated with poor renal outcome, whereas Oxford MESC, M´, and C´ in the training and validation cohort were not associated with poor renal outcome. Using multivariate analysis in the presence of estimated glomerular filtration rate (eGFR), only E´ was a significant predictive factor for poor renal outcome. The E´ with modified cutoff point of 10% significantly improved predictive value for poor renal outcome in IgAN. Therefore, the clinical value of modified cutoff points for M´E´S´C´ scores should be validated with various cohort studies in different regions.

Clinical impact of endocapillary proliferation according to the Oxford classification among adults with Henoch-Schönlein purpura nephritis: a multicenter retrospective cohort study.

BACKGROUND: Henoch-Schönlein purpura nephritis (HSPN) is a form of small vessel vasculitis associated with purpura and IgA deposition in the glomeruli. The International Study of Kidney Disease in Children (ISKDC) classification predicts renal prognosis in children with HSPN, but not in adults. Additionally, it is not well known whether the Oxford classification 2016 and/or the Japanese Histologic classification (JHC) are associated with renal outcome. Herein, we investigated the relationship between pathological characteristics and renal outcome among adult patients with HSPN. METHODS: A multicenter retrospective cohort study was conducted in adult patients with HSPN who underwent renal biopsy between 2004 and 2014. Two nephrologists classified each patient according to the Oxford classification 2016, JHC, and the ISKDC classification. Renal outcome was defined by a 30% decline in the eGFR and/or end-stage kidney disease. RESULTS: We enrolled 74 adult patients with HSPN (mean age, 47.8 ± 17.4 years; mean eGFR, 76.4 ± 25.8 ml/min/1.73 m2; median proteinuria, 1.40 [IQR: 0.70-2.38] g/day). During a mean follow-up period of 68.0 ± 33.0 months, fourteen patients (18.9%) reached the renal outcome, and all 14 had received immunosuppressive therapy. The log-rank test revealed that event-free renal survival was significantly shorter in patients with endocapillary proliferation (E1) according to the Oxford classification than in those with E0 (p = 0.0072). However, the JHC, ISKDC classification and other Oxford lesions could not demonstrate a significant difference in event-free renal survival. In a multivariate Cox model adjusted for clinical and pathological factors, age (HR, 1.57; 95% CI, 1.12-2.21) and E lesion (HR, 6.71; 95% CI, 1.06-42.7) were independent risk factors for renal outcome. CONCLUSIONS: Endocapillary proliferation is significantly associated with renal outcome in adult patients with HSPN, including those receiving immunosuppressive therapy. Other Oxford classification lesions, JHC, and ISKDC classification were not associated with renal outcome.

Seasonal proteinuria changes in IgA nephropathy patients after proteinuria remission.

BACKGROUND: Proteinuria is a powerful prognostic factor for end-stage renal disease in IgA nephropathy (IgAN) patients. However, it is not known whether proteinuria exacerbations are related to seasonal changes. METHODS: We retrospectively enrolled consecutive patients diagnosed with IgAN by kidney biopsy at our hospital between 2002 and 2014. Proteinuria remission was defined as urinary protein <0.3 g/gCr in two consecutive outpatient urinalyses and exacerbation as urinary protein ≥0.75 g/gCr. Four seasons were defined: spring (March-May), summer (June-August), autumn (September-November), and winter (December-February). We performed a multivariate analysis to identify factors associated with the second remission following a proteinuria exacerbation. RESULTS: We analyzed 116 patients. Proteinuria remission and exacerbation occurred in 77, and 43 patients, respectively. The incidence of proteinuria exacerbation was significantly higher in autumn and winter than in spring and summer (p = 0.040). The cumulative second remission rate was significantly higher in patients with autumn and winter proteinuria exacerbation than in patients with spring and summer exacerbations (p = 0.0091). In multivariate analyses, exacerbation onset in autumn and winter (hazard ratio [HR], 3.51; 95% confidence interval [CI], 1.41-8.74) and intensive therapy (HR, 2.26; 95% CI, 1.05-4.88) were significantly associated with a second proteinuria remission. CONCLUSION: In IgAN patients in proteinuria remission, proteinuria exacerbation frequently occurred in autumn and winter. Exacerbations occurring in autumn and winter tended to remit early.

The Japanese Histologic Classification and T-score in the Oxford Classification system could predict renal outcome in Japanese IgA nephropathy patients.

BACKGROUND: The Oxford Classification is utilized globally, but has not been fully validated. In this study, we conducted a comparative analysis between the Oxford Classification and Japanese Histologic Classification (JHC) to predict renal outcome in Japanese patients with IgA nephropathy (IgAN). METHODS: A retrospective cohort study including 86 adult IgAN patients was conducted. The Oxford Classification and the JHC were evaluated by 7 independent specialists. The JHC, MEST score in the Oxford Classification, and crescents were analyzed in association with renal outcome, defined as a 50% increase in serum creatinine. RESULTS: In multivariate analysis without the JHC, only the T score was significantly associated with renal outcome. While, a significant association was revealed only in the JHC on multivariate analysis with JHC. CONCLUSIONS: The JHC and T score in the Oxford Classification were associated with renal outcome among Japanese patients with IgAN. Superiority of the JHC as a predictive index should be validated with larger study population and cohort studies in different ethnicities.