Clinical and Experimental Nephrology最新文献

Background: Contrast agents are known to increase the risk of radiocontrast-induced nephropathy (CIN), particularly in elderly, diabetic, or dehydrated patients. However, the exact molecular mechanisms leading to renal injury in CIN remain unclear. Probenecid (PBN), an organic anion transport inhibitor that also inhibits Pannexin1 channels, has been suggested as a potential therapeutic agent in certain nephropathy models. This study aimed to examine the protective effects of PBN in CIN. Additionaly, considering the roles of small RhoGTPases and Pannexin1 in nephropathy and their interactions, we investigated the relationship between these molecules in the same CIN rat model.

Methods: CIN was induced in male Wistar rats by a single intraperitoneal (ip.) injection of iohexol. The animals were treated with either saline (i.p) or PBN (150 mg/kg or 300 mg/kg, i.p) twice daily for 5 days following iohexol (3 g iodine/kg) administration. Kidney tissue samples were stained with hematoxylin and eosin to assess tubular injury. Immunohistochemical analysis was also performed to evaluate the expression of RhoA, Rac1, Pannexin1, and active Caspase-3.

Results: Iohexol caused tubular necrosis, dilatation, vacuolization and brush border loss, while high-dose PBN significantly reduced these changes. Rac1, Pannexin1 and active-Caspase 3 expressions were increased in CIN, while RhoA expression was decreased compared to control. High-dose PBN ameliorated these changes, but significant improvement was observed in RhoA expression.

Conclusions: These results indicate that PBN may protect against CIN through modulation of small Rho GTPases (increasing RhoA expressions or altered balance between RhoA and Rac1) and Pannexin1 channels in Wistar rats.

Background: Increased serum anti-nephrin antibody titers and co-localization of nephrin and IgG in kidney tissues have been reported in minimal change disease (MCD) and post-transplant recurrent focal segmental glomerulosclerosis (FSGS). These results indicate an association of anti-nephrin antibodies with nephrotic syndrome (NS); however, the exact relationship remains unclear. Herein, we evaluated nephrin/IgG co-localization in the glomeruli of patients with various kidney diseases, including monogenic NS, to clarify the association between idiopathic nephrotic syndrome (INS) and anti-nephrin antibodies.

Methods: IgG and nephrin co-localization was investigated in 52 kidney tissue biopsy samples, comprising INS in the active phase (n = 26; MCD, n = 19; FSGS, n = 7) and remission (n = 6), monogenic NS (n = 3), and other kidney diseases (n = 17). Double-immunofluorescence staining for nephrin/IgG was performed in unfixed frozen sections for 2 h at room temperature with Alexa Fluor-labeled nephrin/IgG cocktail antibodies. Nephrin/IgG co-localization was assessed using optical sectioning under a fluorescence microscope.

Results: Nephrin/IgG co-localization was observed in 81% (21/26, children: 15/17, adults: 6/9) of active INS cases, 84% (16/19) of MCD cases, and 71% (5/7) of FSGS cases. No co-localization was observed in NS with monogenic variants or other kidney diseases.

Conclusion: Nephrin/IgG co-localization in the kidney tissue is finding observed in active INS, strongly indicating an association between anti-nephrin antibodies and INS onset. The nephrin/IgG cocktail antibody is a rapid and effective approach for investigating INS pathogenesis that facilitates the differential diagnosis of immune-mediated NS from other kidney diseases, including monogenic NS.

Background: T50 calciprotein crystallization test (serum calcification propensity, T50) is a blood test which assesses the resistance of the serum to calcification stress in vitro. Because of its limited availability in clinical practice of chronic kidney disease, we aimed to develop equations for estimated T50 (eT50).

Methods: This was an observational study in 1,651 hemodialysis patients whose T50 was measured by the method Pasch et al. The data sets were divided into two groups for the derivation (N = 1,003) and validation (N = 648) of the equations. Logarithmically transformed values of measured T50 were regressed by relevant variables selected from 36 candidates based on the Akaike's Information Criteria.

Results: Because the initial model A included 19 variables, we developed simpler models B and C with 10 and 5 variables, respectively, for clinical use. All these models included serum phosphate, magnesium, sodium, chloride, and total ion binding capacity. When these equations were validated, the intercept, slope, and R² values were 1.130, 0.770, 0.596 for model A, 1.093, 0.782, and 0.597 for model B, and 0.979, 0.806, and 0.573 for model C, respectively. Multivariable-adjusted Fine-Gray analysis showed that a lower eT50 value by model A, B, or model C was an independent predictor of a higher risk of new cardiovascular events in the total cohort as the measured T50 was.

Conclusions: We developed three equations for eT50 from clinically available variables. These eT50 values may be useful if measured T50 is not available.

This article is part of a review series on water and electrolyte disorders, based on the annual "Electrolyte Winter Seminar" for early-career nephrologists in Japan. The seminar features interactive case-based discussions, some of which are included as self-assessment questions. The fifth installment addresses the management of hyperkalemia. Hyperkalemia frequently occurs in patients with chronic kidney disease (CKD) and can become life-threatening when severe, necessitating prompt treatment regardless of its underlying cause. Renin-angiotensin system inhibitors (RASi) are a recognized risk factor for hyperkalemia in CKD; however, discontinuing RASi in response to elevated potassium levels may adversely affect patient outcomes. Although there are no formal criteria distinguishing acute from chronic hyperkalemia, symptoms presentation and potassium levels offer a practical guide for clinical management. This review covers standard treatment strategies for severe (symptomatic or acute) hyperkalemia in emergency and inpatient settings and discusses how to manage mild-to-moderate (asymptomatic or chronic) cases in CKD patients while continuing RASi therapy.

Chronic kidney disease (CKD) is a global health burden associated with increasing mortality rates. Aging populations and declining fertility rates exacerbate this issue, particularly in countries such as Japan. Acute kidney injury (AKI) was previously considered temporary and reversible condition. However, in recent years, multiple studies on kidney diseases have shown that AKI survivors are at an increased risk of developing CKD. During the AKI-to-CKD transition, a subset of AKI-induced epigenetic alterations persists in cells, potentially driving the progression of tubulointerstitial fibrosis. Therefore, targeting epigenetic mechanisms may represent a promising therapeutic approach for preventing AKI-to-CKD transition. Among the epigenetic mechnisms involved, "hypoxic memory" plays a crucial role in this transition by inducing persistent epigenetic changes. Hypoxic memory induces DNA methylation, histone modification, changes in chromatin conformation, and long non-codingRNA (lncRNA) expression. Herein, we review the latest evidence on epigenetic memory in the AKI-to-CKD transition, identifying that the detailed mechanisms of epigenetic memory and temporal specificity are crucial for developing effective treatments.

Background: Maintenance therapy using immunosuppressive agents after rituximab can be effective for sustaining remission in childhood-onset refractory frequently relapsing nephrotic syndrome/steroid-dependent nephrotic syndrome (FRNS/SDNS). We evaluated the long-term outcome of mycophenolate mofetil (MMF) after rituximab.

Methods: We conducted a multicenter, retrospective cohort study of patients with childhood-onset refractory FRNS/SDNS who received MMF as maintenance therapy after a single dose of rituximab and were followed up ≥ 2 years at three pediatric renal centers. Relapses, additional treatment, risk factors for relapse, and adverse events were analyzed.

Results: We enrolled 106 patients, and the median follow-up was 7.2 years. Forty-seven (44%) patients had no relapse under MMF, and the 50% relapse-free survival was 3.2 years during MMF administration. Sixty-one (58%) patients required additional rituximab during the observation period. The mean annual number of relapses before the first rituximab treatment versus 1 year after rituximab initiation was 3.7 (standard deviation: 1.3) versus 0.4 (standard deviation: 0.8) times (p < 0.0001). Sixty-six of 74 (89%) patients could discontinue calcineurin inhibitors within 1 year after rituximab. MMF < 1000 mg/m² was an independent significant risk factor for the first relapse (p = 0.03). No fatal adverse events and 23 episodes of infection requiring hospitalization were observed during the study period.

Conclusions: MMF after a single dose of rituximab is safe and effective in achieving a long relapse-free period and discontinuing a calcineurin inhibitor in patients with refractory FRNS/SDNS.

Background: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. We aimed to explore the role of RNA binding motif protein 15 (RBM15) in high glucose (HG)-induced pyroptosis of renal tubular epithelial cell, thus providing theoretical knowledge and new targets for DN treatment.

Methods: HG-induced HK-2 cells were used to establish DN cell models. RBM15 expression was inhibited in HK-2 and detected. Cell viability was detected by cell counting kit-8. The levels of NLR family pyrin domain containing 3 (NLRP3), NLR family CARD domain containing 4 (NLRC4), gasdermin D (GSDMD)-N, and cleaved Caspase-1 were detected by Western blot assay. The levels of IL-1β and IL-18 were detected by enzyme linked immunosorbent assay. The enrichment of insulin-like growth factor 2 mRNA binding protein (IGF2BP2) and N6-methyladenosine (m6A) on NLRP3 and NLRC4 were analyzed by methylated RNA immunoprecipitation (MeRIP) and RIP. The stability of NLRP3 and NLRC4 mRNA was analyzed. The mechanism was verified by interfering NLRP3 and NLRC4 expression.

Results: RBM15 was highly expressed in HG-induced HK-2 cells. Inhibition of RBM15 reversed cell viability, inhibited inflammation, and alleviated pyroptosis. RBM15 promoted the expression of inflammasomes NLRP3 and NLRC4 through IGF2BP2-dependent m6A modification.

Conclusion: RBM15 promoted the expression of inflammasomes NLRP3 and NLRC4 through IGF2BP2-dependent m6A modification, thereby promoting pyroptosis.