American Journal of Nephrology最新文献

Introduction: Albuminuria is an independent risk factor for renal interstitial fibrosis and induces G2/M phase arrest in proximal tubular epithelial cells. Although protein overload disrupts fatty acid metabolism, the mechanistic link to cell cycle arrest remains unclear. This study investigates the role of NIMA-related kinase 10 (NEK10), a serine/threonine kinase implicated in cell cycle regulation, in mediating albumin-induced lipid dysregulation and G2/M arrest, which exacerbate tubulointerstitial fibrosis.

Methods: Human renal tubular cells (HK-2) were exposed to 10 mg/mL bovine serum albumin (BSA) for 24-48 h. In vivo, NEK10 was knocked down using recombinant adenovirus (rAAV-shNEK10) in unilateral ureteral obstruction (UUO) mice treated with BSA. Clinically, NEK10 expression was assessed via immunohistochemistry in kidney biopsies from chronic kidney disease (CKD) patients with varying urinary protein levels.

Results: BSA-exposed HK-2 cells showed lipid droplet accumulation, reduced ATP levels, impaired fatty acid oxidation, and increased G2/M phase arrest. These effects coincided with upregulated NEK10 expression and ERK1/2 phosphorylation. NEK10 knockdown in UUO mice attenuated BSA-induced renal fibrosis, lipid accumulation, and tubular injury. In CKD patients, elevated NEK10 expression correlated with higher urinary protein levels (>3.5 g/24 h) and interstitial fibrosis.

Conclusion: Our findings identify NEK10 as a critical regulator of albumin-induced metabolic dysfunction and cell cycle arrest, suggesting therapeutic targeting of NEK10 may mitigate fibrosis in proteinuric kidney diseases.

Introduction: Inhaled fine and ultrafine particulate matter may affect organs other than the lung, including the kidney. Recent studies have consistently shown the possibility of air pollution in highly polluted countries to be nephrotoxic. However, in countries like Australia, where air quality generally adheres to or remains below the WHO standards, the subtle yet consequential impacts of chronic exposure to seemingly safe levels of traffic PM2.5, are a subject of increasing significance. However, how such exposures in the peri-pregnancy period affect kidney health in mothers and the offspring is unclear, which formed the aims of this study.

Methods: Female Balb/c mice were exposed to PM2.5 (5 μg/day) delivered nasally for 6 weeks prior to mating, during gestation and lactation (PM group). In a subgroup, PM2.5 was switched to saline from mating until offspring were weaned to model mothers moving to areas with clean air. Kidneys were analysed in dams and adult offspring at 13 weeks of age.

Results: PM2.5 induced oxidative stress without histological changes in the dam's kidney. However, male PM offspring displayed in utero underdevelopment, characterised by reduced body weight and kidney-to-body weight at birth compared to control offspring, and lower glomerular numbers, with a marked increase in albuminuria, glomerulosclerosis, inflammation, oxidative stress, and mitochondrial injury. Female PM offspring had delayed postnatal development, lower glomerular numbers, increased glomerulosclerosis, and oxidative stress injury markers. Removal of PM2.5 from conception significantly reduced DNA oxidation and kidney damage in the offspring.

Conclusion: There is no safe level of ambient PM2.5 for kidney health when exposed in utero. Maternal PM2.5 exposure equally impacts the kidney health of male and female offspring. Removal of PM2.5 from conception was overall protective to the offspring.

Introduction: Patients with primary membranous nephropathy (PMN) are at high risk of developing venous thromboembolic events (VTEs), while neutrophils are involved in the onset of VTEs in PMN remains unclear.

Methods: The association of neutrophils with VTEs was retrospectively analyzed in a large cohort of patients with PMN. Plasma cell-free DNA (cfDNA) levels were evaluated in PMN patients with and without VTEs. In addition, we established a rat model of passive Heymann nephritis (PHN) by immunization with sheep anti-rat Fx1A serum. The inferior vena cava (IVC) was ligated to establish the deep vein thrombosis model. Thrombus weight and length were evaluated at 4 h after IVC stenosis in rats. GSK484 was administered via intraperitoneal injection to assess the role of NETosis inhibition in thrombosis formation in PHN rats.

Results: Circulating neutrophils in PMN patients with VTEs were significantly higher than in patients without VTEs. Neutrophil counts were positively correlated with the activity of factor IX, factor XI, protein C, protein S, and AT-III (r = 0.328, p = 0.002; r = 0.378, p < 0.001; r = 0.380, p < 0.001; r = 0.243, p = 0.029; r = 0.254, p = 0.020). In multivariate logistic regression, neutrophils were the independent risk factors for VTEs in PMN patients (OR = 1.608, 95% CI: 1.293-2.000; p < 0.05). Significantly increased plasma levels of cfDNA were detected in PMN patients, especially in PMN patients with VTEs, relative to controls. In animal experiments, the plasma cfDNA levels elevated significantly after IVC stenosis in PHN rats, and GSK484 decreased the plasma cfDNA levels in PHN rats with IVC stenosis. Four hours after IVC stenosis surgery, thrombi formed in PHN rats were both longer and heavier compared to those observed in control rats, and GSK484 administration significantly inhibits the thrombus formation in PHN rats.

Conclusion: This study preliminarily indicated that neutrophils were involved in the hypercoagulation state and increased thrombosis propensity in PMN, offering novel insights into the pathogenesis of thrombosis formation in PMN and potential therapeutic targets for its management.

Introduction: Acute kidney injury (AKI) is a common clinical condition where cellular senescence plays a crucial role in its progression. Previous studies have suggested that DOT1L plays a pivotal role in cellular senescence, yet its specific mechanisms in regulating AKI cellular senescence remain unclear.

Methods: This study utilized a glycerol-induced in vivo AKI model and employed the DOT1L-specific inhibitor EPZ004777 (EPZ) to suppress DOT1L function. Aging staining, periodic acid-Schiff staining, and Masson staining were employed to assess renal aging, injury, and interstitial fibrosis. In vitro experiments utilized doxorubicin-treated human renal tubular epithelial (HK-2) cells to establish an AKI cellular senescence model. EPZ was used to inhibit DOT1L, evaluating its impact on cellular senescence. High-throughput miRNA sequencing was performed to analyze differential expression of miRNAs downstream of DOT1L, and DOT1L overexpression and dual luciferase reporter gene experiments were conducted to explore interactions among DOT1L, miR-222-5p, and Wnt family member 9B (WNT9B).

Results: The results demonstrated that in vivo inhibition of DOT1L significantly reduced cellular senescence and improved renal tubular injury and interstitial fibrosis. In the doxorubicin-induced HK-2 cell model, DOT1L inhibition markedly decreased cellular senescence and lowered mRNA and protein levels of senescence markers while alleviating cell cycle arrest. DOT1L inhibition notably upregulated miR-222-5p expression and suppressed WNT9B expression, with opposite effects observed with DOT1L overexpression.

Conclusion: DOT1L regulates cellular senescence through the miR-222-5p/WNT9B pathway in AKI. These findings suggest that DOT1L may serve as a potential therapeutic target to mitigate the progression of AKI to chronic kidney disease.

Introduction: As a concept recently proposed by the American Heart Association (AHA), cardiovascular-kidney-metabolic (CKM) syndrome is characterized by the interplay of cardiovascular, renal, and metabolic dysfunctions. However, previous studies constantly focused on the cardiovascular outcomes, and there is scarce evidence addressing the association between chronic systemic inflammation and long-term changes in kidney function in the progression of CKM syndrome. This study aimed to investigate the association between the systemic inflammation and worsening renal function (WRF) in individuals with CKM syndrome.

Methods: A cohort of 39,944 outpatients with regular follow-up visits at Fuqing City Hospital from 2014 to 2021 was analyzed. WRF was defined as an absolute increase in serum creatinine of ≥26.5 μmol/L (≥0.3 mg/dL) with a relative increase of ≥25% from baseline during the first year of follow-up. Three logistic regression models were constructed to evaluate the associations between systemic immune inflammation index (SII), systemic inflammatory response index (SIRI), and WRF. Restricted cubic spline (RCS) regression was utilized to illustrate the relationship between SII, SIRI, and WRF. Additionally, we explored this correlation through segmented linear regression as part of our threshold analysis.

Results: A total of 10,361 individuals (25.9%) experienced WRF within the first year. Higher levels of SII and SIRI were significantly associated with increased odds of WRF across all CKM stages. After adjusting for multiple conventional variables, SII remained an independent predictor for WRF (OR: 1.298, 95% CI: 1.181-1.427, p < 0.001). Similarly, SIRI also demonstrated a significant positive correlation with WRF (OR: 1.026, 95% CI: 1.021-1.030, p < 0.001). The RCS analysis also revealed a dose-response relationship, indicating higher quartiles of SII and SIRI correlating with greater odds of WRF. Further analysis revealed significant interactions between SII, SIRI, and CKM stages, particularly at stages 4 (p < 0.001 for both). Subgroup analysis suggested that this association between SII, SIRI, and WRF was more prominent in the early stage of CKM. The threshold effect analysis demonstrated that for ln transformed SII, a threshold of above 5.565 indicated significant correlation with WRF (OR: 1.277), while for SIRI, the threshold of 2.34 showed a strong correlation below it (OR: 1.330).

Conclusion: Both SII and SIRI were associated with the risk of WRF in individuals with CKM. This association seemed more prominent in the early stage of CKM.

Introduction: Non-alcoholic fatty liver disease (NAFLD) has emerged as a potential indicator for cardio-metabolic risk. However, clinical implications of NAFLD in patients with chronic kidney disease (CKD) are still elusive. We investigated to explore the association between NAFLD and adverse clinical outcomes among patients with CKD.

Methods: In this national population-based retrospective cohort study, we analyzed 816,857 individuals who underwent National Health Insurance Service health examinations and had an estimated glomerular filtration rate of 15-59 mL/min/1.73 m2. The main predictor was the fatty liver index (FLI), a surrogate marker for NAFLD. The primary outcome was a composite cardiovascular or kidney events, which were examined combined or separately.

Results: During a median follow-up of 7.7 (IQR, 6.4-9.6) years, the composite outcome events occurred in 74,266 (9.1%) individuals. Among these, there were 55,525 (6.8%) cardiovascular events and 22,961 (2.8%) kidney events, respectively. Compared to FLI of <30, the hazard ratio (HRs; 95% confidence intervals [CIs]) for the composite outcome were 1.16 (1.14-1.18) and 1.30 (1.26-1.33) for the FLIs of 30-59 and ≥60, respectively. The corresponding HRs for cardiovascular events were 1.21 (95% CI, 1.18-1.23) and 1.36 (95% CI, 1.31-1.40), respectively. Furthermore, FLIs of 30-59 and ≥60 were associated with an 11% (HR, 1.11; 95% CI, 1.07-1.15) and 24% (HR, 1.24; 95% CI, 1.17-1.30) increased risk of kidney events, respectively.

Conclusions: NAFLD was associated with higher risk of adverse clinical outcomes in individuals with CKD. These findings suggest that NAFLD, as assessed by the FLI, can serve as a predictor of cardiovascular and kidney events in CKD population.

Introduction: Although both patients with kidney failure (KF) receiving hemodialysis (HD) and kidney transplantation (KT) recipients (KTRs) have a high risk of bladder cancer, how this risk changes in the transition from dialysis to KT is unknown. In this study, we aimed to investigate the risk of bladder cancer in KTRs and patients on HD.

Methods: This was a nationwide longitudinal cohort study of 66,547 participants from the National Health Insurance Service cohort who started HD for patients with KF or who received KT from 2002 to 2020. The primary outcome was the diagnosis of bladder cancer, which was defined as the composite of diagnostic codes and either hospitalization or ≥2 outpatient visits for bladder cancer.

Results: During mean follow-ups of 4.2 and 7.9 years in the HD and KT groups, respectively, the incidence rates of bladder cancer were 1.1/1,000 and 0.3/1,000 person-years, respectively. In the time-dependent multivariable Cox models, compared to patients on HD, the adjusted hazard ratio (aHR) for bladder cancer among KTRs was 0.36 (95% confidence interval [CI], 0.21-0.60; p < 0.001). Among men, this aHR was 0.29 (95% CI, 0.15-0.55; p < 0.001); however, no statistically significant association between the kidney replacement therapy modality and the risk of bladder cancer was observed among women. Landmark analysis performed to avoid immortal time bias by redefining time zero as a specific landmark time (2 and 5 years after HD initiation or KT) revealed similar results.

Conclusion: The risk of bladder cancer was significantly lower among KTRs than that among patients receiving HD, particularly among men.

Introduction: Acute kidney injury associated with the consumption of Beni-koji CholesteHelp supplements, which contain red yeast rice (Beni-Koji), has become a significant public health concern in Japan. While renal biopsy findings from several case reports have suggested tubular damage, no definitive causal relationship has been established, and the underlying mechanisms of kidney injury remain poorly understood. The complexity of identifying toxic substances in supplements containing various bioactive compounds makes conventional investigative approaches both time-consuming and challenging. This highlights an urgent need to establish a reliable platform for assessing organ-specific toxicity in such supplements. In this study, we utilized a kidney organoid model derived from adult rat kidney stem cells (KS cells) to assess the potential tubular toxicity of these supplements.

Methods: KS cell clusters were cultured in three-dimensional system supplemented with growth factors to promote kidney organoids. The organoids were subsequently exposed to Beni-koji CholesteHelp supplements or cisplatin, followed by histological and molecular analyses to evaluate structural impacts.

Results: Established organoids had the kidney-like structures including tubular-like structures and glomerulus-like structures at the tips of multiple tubules. Treatment with Beni-koji CholesteHelp supplements induced significant tubular damage in the organoids, characterized by epithelial cell thinning, structural disruption, and increase in cleaved-caspase 3-positive apoptotic tubular cells, similar to the organoids treated with cisplatin.

Conclusion: These findings provide the first evidence suggesting that certain toxicants in specific batches of Beni-koji CholesteHelp supplements cause direct renal tubular injury. This KS cell-based organoid system represents a cost-effective, reproducible, and technically simple platform for nephrotoxicity screening.

Introduction: Recent experimental studies have reported that fibroblast growth factor 23 (FGF23) inhibits erythropoiesis by suppressing erythropoietin (EPO) production and downregulating the EPO receptor. Conversely, either endogenous or exogenous EPO has been shown to stimulate FGF23 production. However, little is known about the relationships between FGF23, erythropoiesis-stimulating agent (ESA) treatment, ESA resistance, and endogenous EPO in hemodialysis patients.

Methods: We analyzed cross-sectional data from a cohort of 654 maintenance hemodialysis patients. We examined the associations of intact or C-terminal FGF23 with ESA treatment, ESA resistance index (ERI), hemoglobin, C-reactive protein, and endogenous EPO levels using linear regression models. EPO was measured only in patients not receiving ESAs.

Results: A total of 458 patients (70%) were treated with ESAs. The median EPO concentration in non-ESA users was 7.8 (interquartile range, 5.3-14.4) mIU/mL. The median levels of intact and C-terminal FGF23 were 1,598 (interquartile range, 548-4,586) pg/mL and 38.7 (interquartile range, 14.0-127.6) pmol/L, respectively, in non-ESA users and 1,955 (interquartile range, 573-5,264) pg/mL and 41.4 (interquartile range, 13.9-116.8) pmol/L, respectively, in ESA users. After adjustment for potential confounders, higher ESA dose was associated with higher FGF23 levels measured by both intact and C-terminal assays. Higher C-terminal FGF23 was also associated with higher ERI, lower hemoglobin, and higher endogenous EPO, but no such associations were observed for intact FGF23 levels.

Conclusions: Both intact and C-terminal FGF23 showed similar associations with ESA dose, but they showed different patterns of association with other parameters related to anemia. Further research is needed to elucidate the mechanisms underlying these different associations.

Introduction: Maintaining renin-angiotensin-aldosterone system inhibition (RAASi) in advanced chronic kidney disease (CKD) to delay CKD progression is still controversial. This is due to potential side effects associated with RAASi, such as a decline in glomerular filtration rate (GFR) and hyperkalemia. This study aimed to examine the effect of RAASi on progression of advanced CKD to kidney failure (estimated glomerular filtration rate [eGFR] <15 mL/min/1.73 m2, CKD stage 5) in a real-life outpatient cohort.

Methods: This single-center retrospective observational study presents data from 954 individuals with advanced CKD (eGFR 15-30 mL/min/1.73 m2), comparing 806 RAASi with 511 control intervals over a median follow-up period of 19 months. The endpoint was defined as time to manifestation of kidney failure. Univariate and multivariate time-to-event analyses were performed to assess effects of RAASi on endpoint probabilities.

Results: Univariate time-to-event analysis did not show a significant difference in the median time to kidney failure between RAASi and control intervals (7.6 vs. 7.0 years, p = 0.74). Covariate-adjusted multivariate regression models also demonstrated no association between RAASi treatment and progression to kidney failure in patients with advanced CKD (hazard ratio 0.92 [95% CI: 0.67-1.23], p = 0.63).

Conclusion: RAASi has no significant impact on the time to kidney failure in patients with advanced CKD. Hence, this study supports maintenance of RAASi in advanced CKD, if used for extrarenal indications such as cardiovascular protection.