ICAM-1 related long noncoding RNA is associated with progression of IgA nephropathy and fibrotic changes in proximal tubular cells.

Intercellular adhesion molecule 1 (ICAM-1) related long noncoding RNA (ICR) is on the antisense strand of ICAM-1 and regulates ICAM-1 expression. ICAM-1 is involved in renal tubulointerstitial injury; however, the expression and clinical implication of ICR are not determined in IgA nephropathy (IgAN). We compared renal ICR levels in 337 IgAN patients with those of 89 biopsy controls, and a markedly increased ICR level was observed in IgAN patients. By Cox proportional hazards models, higher levels of renal ICR were independently associated with disease progression event defined as end-stage renal disease or ≥ 40% decline in estimated glomerular filtration rate. Patients in the highest tertile of renal ICR had a 3.5-fold higher risk for disease progression compared with those in the lowest tertile. The addition of renal ICR to a model with traditional risk factors improved risk prediction of disease progression (net reclassification index: 0.31 [95% CI 0.01-0.50]; integrated discrimination index: 0.10 [95% CI 0.04-0.16]). Inhibition of ICR by transfection with plasmids containing ICR shRNA significantly reduced expression of collagen I and α-SMA, and phosphorylation of Akt and mTOR in TGF-ß1- treated HK-2 cells. Our findings suggest that renal ICR might be an independent predictor of IgAN progression and contribute to renal fibrosis.

Renal Megalin mRNA Downregulation Is Associated with CKD Progression in IgA Nephropathy.

INTRODUCTION: Megalin plays an important role in proximal tubule uptake of filtered proteins. Downregulation and dysfunction of megalin were previously demonstrated in IgA nephropathy (IgAN); however, its relationship to IgAN progression remains unclear. METHODS: We measured renal megalin mRNA and miR-148b, previously identified as a regulator of megalin, in a retrospective cohort of 417 IgAN patients at the time of biopsy, and evaluated their associations with chronic kidney disease (CKD) progression event, defined as end-stage renal disease or ≥40% decline in estimated glomerular filtration rate, using Cox proportional hazard models. Risk classification statistics were calculated for CKD progression. RESULTS: During a median follow-up of 43 months, 121 (29.0%) patients reached the CKD progression event. Patients in the highest tertile of renal megalin mRNA had a lower risk for CKD progression than in the lowest tertile (hazard ratio (HR): 0.407, 95% confidence interval (CI) 0.231-0.719; p = 0.002). Log megalin mRNA was independent and negatively associated with CKD progression in IgAN (HR: 0.529, 95% CI 0.377-0.742; p < 0.001). The addition of renal megalin mRNA to a model with traditional risk factors improved risk prediction of disease progression (C statistic from 0.76 to 0.80; integrated discrimination index: 0.04 [95% CI: 0.02-0.07]). Moreover, patients in the highest tertile of renal miR-148b had a 2.3-fold higher risk for CKD progression compared with those in the lowest tertile. CONCLUSIONS: Lower renal megalin mRNA levels were associated with a greater risk of CKD progression in IgAN independent of clinical and pathological characteristics, suggesting that renal megalin could be an important prognostic factor for IgAN.

Delayed elimination communication is a crucial factor in disposable diaper dependence in Chinese preschool-aged children.

Purpose: Elimination communication (EC) is considered to be a milestone in a child's development. Nowadays, a trend toward an older age at EC initiation has been observed globally, probably due to the convenience of disposable diaper use in daily life. The study aimed to identify potential risk factors for disposable diaper dependence (DDD) and evaluate whether an early/proper EC can reduce the risk of DDD among children in China. Methods: A cross-sectional study was performed on 13,500 children in mainland China from October 2019 to March 2020. An anonymous questionnaire was used to collect information including the sociodemographic characteristics, details about DDD and EC, and the effect of DDD on the quality of life of children. Data were analyzed by SPSS and R software. Results: The overall prevalence of DDD was 4.17% (4.31% in boys; 4.02% in girls) and decreased with age, from 8.71% at 2 years to 0.73% at 6 years (χ 2 trend = 210.392, P < 0.001). In univariable analysis, age, location or EC were associated with DDD. Four independent factors-age, location (urban), caregivers with high education levels (junior college or above) and delayed EC (after 12 months of age)-were identified to be significantly associated with DDD risk in logistic regression model. Compared with EC onset after 12 months of age, EC onset before 12 months of age was associated with a 79.6% (model 2) reduction in DDD. Four independent factors were selected to establish the nomogram for DDD based on the results of logistic regression analysis. The C-index (0.770) and the AUC (>0.7) indicated satisfactory discriminative ability of the nomogram. The calibration diagrams showed favorable consistency between the prediction of the nomogram and actual observations. Conclusion: Our findings indicate the joint contribution of age, location, caregivers' education level and EC to DDD in Chinese preschool-aged children. Timely cessation of the use of disposable diapers and early/proper EC may help to reduce the risk of DDD in children.

METTL3/N6-methyladenosine/ miR-21-5p promotes obstructive renal fibrosis by regulating inflammation through SPRY1/ERK/NF-κB pathway activation.

Renal fibrosis induced by urinary tract obstruction is a common clinical occurrence; however, effective treatment is lacking, and a deeper understanding of the mechanism of renal fibrosis is needed. Previous studies have revealed that miR-21 impacts liver and lung fibrosis progression by activating the SPRY1/ERK/NF-kB signalling pathway. However, whether miR-21 mediates obstructive renal fibrosis through the same signalling pathway has not been determined. Additionally, studies have shown that N6-methyladenosine (m6 A) modification-dependent primary microRNA (pri-microRNA) processing is essential for maturation of microRNAs, but its role in the maturation of miR-21 in obstructive renal fibrosis has not yet been investigated in detail. To address these issues, we employed a mouse model of unilateral ureteral obstruction (UUO) in which the left ureters were ligated for 3, 7 and 14 days to simulate the fibrotic process. In vitro, human renal proximal tubular epithelial (HK-2) cells were transfected with plasmids containing the corresponding sequence of METTL3, miR-21-5p mimic or miR-21-5p inhibitor. We found that the levels of miR-21-5p and m6 A modification in the UUO model groups increased significantly, and as predicted, the SPRY1/ERK/NF-kB pathway was activated by miR-21-5p, confirming that miR-21-5p plays an important role in obstructive renal fibrosis by enhancing inflammation. METTL3 was found to play a major catalytic role in m6 A modification in UUO mice and drove obstructive renal fibrosis development by promoting miR-21-5p maturation. Our research is the first to demonstrate the role of the METTL3-m6 A-miR-21-5p-SPRY1/ERK/NF-kB axis in obstructive renal fibrosis and provides a deeper understanding of renal fibrosis.

Mechanism and Priority of Botulinum Neurotoxin A versus Sacral Neuromodulation for Refractory Overactive Bladder: A Review.

BACKGROUND: The treatment of common overactive bladder (OAB) has reached a consensus, but there is not a clear answer to the treatment of refractory OAB (ROAB). ROAB is defined as nonresponsive to treatment with behavioural and oral therapies. The disease can influence the physical and mental health of patients, cause poor quality of life, and create an urgent socio-economic burden. With the advancement of medical treatment, the treatment of OAB has improved significantly in the last 2 decades, especially ROAB, by the usage of botulinum neurotoxin A (BoNT-A) and sacral neuromodulation (SNM). Many studies have demonstrated their effectiveness and safety. However, which therapy is the optimal method remains unclear for patients with ROAB, and the exact mechanism involved in the procedures is still unknown. SUMMARY: This review is to clarify the mechanisms, advantages, and disadvantages of SNM and BoNT-A in treatment of ROAB, and determine whether there is an order effect of SNM and BoNT-A in managing ROAB. Key Messages: BoNT-A and SNM mainly act on the peripheral nervous system and central nervous system, respectively. But BoNT-A and SNM may partly act on the central and peripheral nervous systems, separately. SNM may be a better choice than BoNT-A in the long time. At the same time, BoNT-A and SNM can treat the ROAB as the first and next steps, and the sequence of both would not affect the effectiveness of each other.