Clinical and Experimental Nephrology最新文献

Background: Renoprotective effects of sodium glucose transporter 2 (SGLT2) inhibitors, including dapagliflozin, were observed in randomized controlled trials (RCTs). The suspected underlying mechanism is a correction of hyperfiltration, observed as an "initial dip". Whether SGLT2 inhibitors can attenuate the rate of decline in the estimated glomerular filtration rate (eGFR) in clinical settings, even when considering the pre-treatment decline rate, is unknown. Although several RCTs identified an association between the initial dip and long-term renal prognoses, a conclusion has not been reached.

Methods: We collected the eGFR data of patients for whom dapagliflozin was initiated in our hospital and then calculated their eGFR slopes before and after the start of the treatment. We investigated the changes in the eGFR slopes (ΔeGFR slope) and the association between the ΔeGFR slope and the initial dip. Risks for rapid eGFR decliners (eGFR slope < - 3 mL/min/1.73 m²/year) were also examined.

Results: The eGFR slope was significantly milder after dapagliflozin treatment (p < 0.01). A deeper initial dip was associated with a milder rate of eGFR decline (adjusted beta: - 0.29, p < 0.001). Dapagliflozin treatment reduced the proportion of rapid eGFR decliners from 52.9 to 14.7%, and a smaller initial dip was identified as a significant risk for post-treatment rapid eGFR decline (adjusted odds ratio: 1.73, p < 0.05).

Conclusions: Compared to before the administration of dapagliflozin, the rate of eGFR decline was significantly milder after its administration. The initial dip was significantly associated with long-term renoprotective effects and may be a useful predictor of treatment response.

Background: Methyltransferase 14 (METTL14) mediated N6-methyladenine (m6A) RNA methylation and progestin and AdipoQ receptor family member 3 (PAQR3) are reported to be involved in diabetic nephropathy (DN) progression. Here, we explored whether the effects of PAQR3 on DN was associated with METTL14-induced m6A and their relationship with macrophage-related exosomes in DN progression.

Methods: Human glomerular endothelial cells (GECs) were incubated in high glucose (HG) condition to mimic DN condition in vitro. Exosomes were isolated from M1 macrophages and co-cultured with GECs. qRT-PCR and western blotting detected the levels of genes and proteins. Cell functions were determined using cell counting kit-8 assay and flow cytometry. ELISA analysis detected inflammatory factors, and oxidative stress was evaluated by measuring reactive oxygen species and malondialdehyde. The m6A modification profile was determined by methylated RNA immunoprecipitation assay and the interaction was verified by dual-luciferase reporter assay.

Results: HG elevated PAQR3 expression levels in GECs. PAQR3 silencing reversed HG-induced viability arrest, apoptosis, inflammatory response, and oxidative stress. M1 macrophage co-culture could suppress HG-induced GEC injury. PAQR3 was packaged into M1 macrophage-derived exosomes, and M1 macrophages regulated HG-induced GEC injury by secreting PAQR3 into cells via exosomes. Mechanistically, METTL14 induced PAQR3 m6A modification. METTL14 was enriched in M1 macrophage-derived exosomes. METTL14 knockdown in M1 macrophage-derived exosomes protected GEC from HG-induced viability arrest, apoptosis, inflammation and oxidative stress by regulating PAQR3.

Conclusion: Exosomal METTL14 derived from M1 macrophages promoted HG-induced apoptosis, inflammation and oxidative stress in GECs by mediating PAQR3 m6A modification.

Background: CKD currently affects 8.2% to 9.1% of the global population and the CKD mortality rate has increased during recent decades, making it necessary to identify new therapeutic targets. This study investigated the role of nicotinamide N-methyltransferase (NNMT) in renal fibrosis following ischemia-reperfusion injury (IRI), a key factor in chronic kidney disease (CKD) progression.

Methods: We established a mouse model with a knockdown of NNMT to investigate the impact of this enzyme on renal fibrosis after unilateral IRI. We then utilized histology, immunohistochemistry, and metabolomic analyses to investigate fibrosis markers and sphingolipid metabolism in NNMT-deficient mice. We also utilized an Nnmt lentivirus interference vector or an Nnmt overexpression plasmid to transfect mouse kidney proximal tubule cells, stimulated these cells with TGF-β1, and then measured the pro-fibrotic response and the expression of the methylated and unmethylated forms of Sphk1.

Results: The results demonstrated that reducing NNMT expression mitigated fibrosis, inflammation, and lipid deposition, potentially through the modulation of sphingolipid metabolism. Histology, immunohistochemistry, and metabolomic analyses provided evidence of decreased fibrosis and enhanced sphingolipid metabolism in NNMT-deficient mice. NNMT mediated the TGF-β1-induced pro-fibrotic response, knockdown of Nnmt decreased the level of unmethylated Sphk1 and increased the level of methylated Sphk1 in renal tubular epithelial cells.

Conclusions: Our findings suggest that NNMT functions in sphingolipid metabolism and has potential as a therapeutic target for CKD. Further research is needed to elucidate the mechanisms linking NNMT to sphingolipid metabolism and renal fibrosis.

Background: Fibrosis is a common final pathway leading to end-stage renal failure. As the renal medulla and cortex contain different nephron segments, we analyzed the factors associated with the progression of renal medullary and cortical fibrosis.

Methods: A total of 120 patients who underwent renal biopsy at Kawashima Hospital between May 2019 and October 2022 were enrolled in this retrospective study. Renal medullary and cortical fibrosis and stiffness were evaluated using Masson's trichrome staining and shear wave elastography, respectively. Maximum urine osmolality in the Fishberg concentration test was also examined.

Results: Medullary fibrosis was positively correlated with cortical fibrosis (p < 0.0001) and log-converted urinary β2-microglobulin (MG) (log urinary β2-MG) (p = 0.022) and negatively correlated with estimated glomerular filtration rate (eGFR) (p = 0.0002). Cortical fibrosis also correlated with log urinary β2-MG, eGFR, and maximum urine osmolality. Multivariate analysis revealed that cortical fibrosis levels (odds ratio [OR]: 1.063) and medullary stiffness (OR: 1.089) were significantly associated with medullar fibrosis (≧45%). The severe fibrosis group with both medullary fibrosis (≧45%) and cortical fibrosis (≧25%) had lower eGFR and maximum urine osmolality values and higher urinary β2-MG levels than the other groups.

Conclusions: Patients with disorders involving both renal medullary and cortical fibrosis had decreased maximum urine osmolality but had no abnormalities in the urinary concentrating capacities with either condition. Renal medullary and cortical fibrosis were positively correlated with urinary β2-MG, but not with urinary N-acetyl-beta-D-glucosaminidase.

Background: Angiogenesis and inflammation are key events leading to peritoneal morphologic alteration and ultrafiltration failure in patients undergoing peritoneal dialysis (PD). The current study aims to explore the role of ADAM17 in the angiogenetic and inflammatory responses of endothelial cells.

Methods: Human umbilical vein endothelial cells (HUVECs) were cultured and treated with a high glucose-containing medium. In parallel experiments, the expression of ADAM17 in HUVECs was inhibited by SiRNA interference. The mRNA and protein expression of ADAM17, GRO-α and CXCR2 were assessed by qPCR and Western blotting, respectively. The concentrations of GRO-α, VEGF, IL-6 and TNF-α in the cellular supernatants were determined by ELISA. Tube formation and migration of HUVECs were evaluated by Matrigel and transwell migration apparatus.

Results: High glucose increased the expression of ADAM17, CXCR2 and GRO-α in cultured HUVECs. RNA silencing of ADAM17 abolished high glucose-mediated increase of GRO-α and CXCR2, which were accompanied by reduced secretion of VEGF, IL-6, TNF-α, as well as tube formation and cell migration in HUVECs.

Conclusions: Inhibition of ADAM17 ameliorates high glucose-induced angiogenic and inflammatory responses in endothelial cells partly through down-regulation of GRO-α/CXCR2 expression.

Background: The effects of tonsillectomy combined with steroid pulse (TSP) therapy for IgA nephropathy (IgAN) are little known. Therefore, we examined the effects of TSP therapy on the kidney outcomes of IgAN in a large, nationwide cohort study in Japan.

Methods: Between 2002 and 2004, 632 IgAN patients with ≥ 0.5 g/day proteinuria at diagnosis were divided into three groups with mild (0.50-0.99 g/day; n = 264), moderate (1.00-1.99 g/day, n = 216), or severe (≥ 2.00 g/day; n = 153). Decline in kidney function and urinary remission were compared among the three groups after TSP therapy, corticosteroid (ST) therapy, or conservative therapy during a mean follow-up of 6.2 ± 3.3 years. 10.6% and 5.9% of patients in the ST and conservative therapy group underwent tonsillectomy.

Results: The rate of urinary remission at the final observation was significantly higher in the TSP therapy group than in the ST or conservative therapy groups (mild proteinuria: 64%, 43%, and 41%; moderate proteinuria: 51%, 45%, and 28%; severe proteinuria: 48%, 30%, and 22%, respectively). In contrast, the rate of a 50% increase in serum creatinine was lower in groups TSP therapy, than ST or conservative therapy (mild proteinuria: 2.1%, 10.1% and 16.7%; moderate proteinuria: 4.8%, 8.8% and 27.7%; severe proteinuria: 12.0%, 28.9% and 43.1%, respectively). In multivariate analysis, TSP therapy significantly prevented a 50% increase in serum creatinine levels compared with conservative therapy in groups with moderate and severe proteinuria (hazard ratio, 0.12 and 0.22, respectively).

Conclusion: TSP significantly increased the rate of proteinuria disappearance and urinary remission in IgAN patients with mild-to-moderate urinary protein levels. It may also reduce the decline in kidney function in patients with moderate-to-severe urinary protein levels.

Background: Elevated serum alkaline phosphatase (ALP) levels are a risk factor for all-cause mortality in hemodialysis patients. Traditionally in Japan, ALP measurements were conducted using the JSCC method, which yields higher ALP measurement values than the IFCC method, mainly due to its increased sensitivity to intestinal ALP.

Methods: Serum total ALP levels before and after switching the assay method from JSCC to IFCC were compared among different blood types in 521 hemodialysis patients (Study 1). The association between ALP levels measured by the JSCC method and 7-year mortality was analyzed, including blood types and liver function parameters as covariates, in 510 hemodialysis patients (Study 2).

Results: ALP levels measured by the JSCC method were approximately three times higher than those measured by the IFCC method, with significant elevation in patients with blood types B and O compared to those with blood types A and AB. Similarly, ALP levels measured by the IFCC method were significantly higher in patients with blood types B and O compared to those with blood types A and AB (Study 1). The highest tertile of ALP levels showed a significantly increased risk of all-cause mortality, even after adjusting for patient background. However, this significance disappeared when serum liver function-related or inflammatory markers were included as covariates (Study 2).

Conclusion: ALP levels measured by the JSCC method are associated with life prognosis, but caution should be exercised due to their elevation in patients with blood types B and O and in those with hepatic dysfunction or inflammation.

Background: Previous reports highlighted the efficacy of hemofiltration utilizing isotonic sodium bicarbonate solution as replacement fluid for severe metabolic acidosis. This approach corrects metabolic acidosis by eliminating chloride and supplementing bicarbonate. Here, we present the results of an in vitro study aimed at determining the effect of Isotonic sodium bicarbonate-based Continuous HemoDiafiltration (IBB-CHDF).

Methods: Conventional Continuous HemoDiaFiltration (CHDF) and IBB-CHDF utilized aqueous solutions mimicking blood's electrolyte composition. To assess the efficacy and safety, we compared serial changes in pH, HCO₃^-, Na⁺, and K⁺ concentrations. Blood flow rate was 100 mL/min, and the dialysis fluid flow rate maintained 1.0 L/h for both CHDF and IBB-CHDF. Replacement flow rates ranged from 0.5 to 1.5 L/h for CHDF and 0.1 to 1.5 L/h for IBB-CHDF.

Results: At a replacement flow rate of 0.5 L/h with IBB-CHDF, bicarbonate increased from 14.7 mEq/L to within the physiological range (25.9 mEq/L), whereas in conventional CHDF, the post-treatment bicarbonate concentration did not increase (16.5 mEq/L). The maximum bicarbonate concentration achieved was 22.0 mEq/L at a replacement flow rate of 1.5 L/h in conventional CHDF. Notably, in IBB-CHDF, the sodium concentration remained constant at 150 mEq/L, 10 mEq/L higher than conventional CHDF, and did not escalate despite increasing the replacement flow rate.

Conclusion: IBB-CHDF effectively corrects metabolic acidosis without inducing sodium and water overload by eliminating excess chloride while providing bicarbonate.

Background: We investigated the roles of renal volumetry and histological features in the assessment of preoperative and postoperative renal function in living kidney donors (LKDs) including high-risk marginal donors (MDs).

Methods: We included 128 LKDs who underwent donor nephrectomy at our institution between 2006 and 2022. Clinical and radiographic data were retrospectively obtained from medical charts. Renal volume parameters were calculated using preoperative computed tomography images. Tissues obtained from allograft biopsies were examined. MDs were defined according to the Japanese guidelines and compared with standard donors (SDs).

Results: LKDs were divided into 89 SDs and 39 MDs. Renal volumetry parameters did not differ significantly between the two groups, while interstitial inflammation and interstitial fibrosis/tubular atrophy were significantly higher in MDs (P = 0.031 and P = 0.041). In the multivariate analysis, age < 60 years (P = 0.036), body mass index > 25 (P = 0.031), and residual kidney volume/body surface area (RKV/BSA; P = 0.002) were independent factors for poor preservation of renal function. Subgroup analysis of the MDs revealed that RKV/BSA (P = 0.0096), residual measured glomerular filtration rate (GFR) (P = 0.0005), and arteriosclerosis (P = 0.045) were associated with poor preservation of renal function. Furthermore, the risk of graft loss was significantly higher for kidneys donated from MDs (P = 0.0019).

Conclusions: RKV/BSA can be a reliable screening and prognostic tool for selection of LKDs, including MDs, and RKV/BSA, measured GFR, and histological findings such as arteriosclerosis can be used to establish clearer MD criteria for optimal personalized follow-up after surgery.