American Journal of Nephrology最新文献

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.

Introduction: Podocyte injury has been proven to be a major cause for poor renal outcomes after acute kidney injury (AKI). However, clinical trial data are still limited. This study aimed to explore the clinical correlations between podocyte injury and renal outcomes in hospitalized AKI patients.

Method: This retrospective study analyzed data on 52 AKI patients who were histologically diagnosed with acute tubular necrosis or acute interstitial nephritis from six centers throughout China between January 2012 and June 2023. Patients were classified into two groups based on the degree of foot process fusion: ≤50% (mild podocyte injury group) and >50% (severe podocyte injury group). The outcomes were post-AKI new-onset proteinuria and incident CKD.

Results: Among 52 AKI patients (14 male; median age, 49 [30, 56] years), 28 (53.8%) had mild podocyte injury; 24 (46.2%) had severe podocyte injury. After 12-month follow-up, 16 (57.1%) had post-AKI new-onset proteinuria, and 5 (17.9%) had post-AKI incident CKD in mild podocyte injury group. Twenty (83.3%) had post-AKI new-onset proteinuria, and 14 (58.3%) had post-AKI incident CKD in severe podocyte injury group. Patients with more severe foot process fusion exhibited significantly higher incidences of post-AKI new-onset proteinuria (83.3% vs. 57.1%, p = 0.041) and incident CKD (58.3% vs. 17.9%, p = 0.003) at 12 months following AKI. The degree of foot process fusion (95% CI 1.013∼3.88, p = 0.048) and proteinuria at 3 months (95% CI 1.309∼5.443, p = 0.015) were identified as independent risk factors for post-AKI new-onset proteinuria at 12 months. The degree of foot process fusion (95% CI 1.026∼14.196, p = 0.048), and the presence of partial renal pathological features, including tubular atrophy (95% CI 1.012∼5.958, p = 0.030), interstitial inflammation (95% CI 1.005∼6.846, p = 0.039), interstitial fibrosis (95% CI 1.110∼6.075, p = 0.043) were independent risk factors for post-AKI incident CKD at 12 months. Kaplan-Meier analysis shows severe podocyte injury group had worst renal survival, including post-AKI new-onset proteinuria (p = 0.0066) and incident CKD (p = 0.0455).

Conclusion: The degree of podocyte injury is an independent risk factor for post-AKI new-onset proteinuria and incident CKD in patients, and patients with more severe podocyte injury exhibit a higher incidence of post-AKI new-onset proteinuria and incident CKD.

Introduction: It remains a big challenge to identify patients who are at high risk of developing severe acute kidney injury (AKI) after cardiac surgery. This study investigated the clinical utility of urinary cytokeratin 20 (uCK20), a novel biomarker reflecting severity of histological acute tubular injury, for identifying patients at risk of developing severe AKI.

Methods: This prospective multicenter cohort study enrolled a test set comprising 413 patients who underwent cardiac surgery at 5 centers and a validation set comprising 131 patients at an external center. uCK20 and six reported renal tubular injury biomarkers were measured within 6 h after cardiopulmonary bypass (CPB). The primary outcome was severe AKI after surgery. The secondary outcome was major adverse kidney events within 30 days (MAKE30).

Results: In test set, 54 patients (13.1%) reached the primary endpoint. Levels of uCK20 peaked at 4 h after CPB and remained elevated for 5 days after surgery in patients with severe AKI. After multivariable adjustment, the highest tertile of uCK20 was associated with a 67-fold higher risk of the primary outcome and 29-fold higher risk of the secondary outcome. For predicting the primary and the secondary outcomes, uCK20 at 4 h after CPB had area under the curves (AUCs) of 0.86 (95% confidence interval [CI]: 0.81-0.91) and 0.85 (95% CI: 0.78-0.92), outperforming some reported kidney injury biomarkers. Adding uCK20 to the clinical variables enhanced the predicting ability for severe AKI with an AUC of 0.90 (95% CI: 0.85-0.94) and largely improved the risk reclassification. The ability of uCK20 in predicting the primary and the secondary outcomes was further confirmed in an external validation set.

Conclusion: Urinary CK20 predicted early the risk of severe AKI and MAKE30 with excellent performances in patients undergoing cardiac surgery.

Introduction: Diabetes, kidney disease, and cardiovascular disease have complex interactions and coexistences that significantly worsen a patient's overall health. Previous research results have shown that SGLT2i hypoglycemic drugs can not only effectively control blood sugar in diabetic patients but also protect the kidneys and heart. This study further focuses on diabetic patients with kidney disease to explore the effectiveness of using SGLT2i hypoglycemic drugs in avoiding heart-related complications or death.

Methods: This is a multicenter retrospective cohort study using the Taipei Medical University Clinical Research Database (TMUCRD) as the data source. This study selected patients who suffered from both type 2 diabetes and chronic kidney disease from 1 January 2008 to 31 December 2020, as the research team. Integrated or separate 4-point major adverse cardiovascular events (4P-MACE) and mortality were the outcomes of this study. The Kaplan-Meier curves method and Cox proportional hazard regression analysis were used to explore the association between each influencing factor and the outcome.

Results: A total of 5,005 patients with type 2 diabetes and CKD were included in this study, of which 524 patients were stably treated with SGLT2i, 3,952 patients were treated with DPP4i, and 529 patients were treated with TZD. The results showed that the SGLT2i user group had a significantly lower risk of 4P-MACE compared with the SGLT2i nonuser group (hazard ratio [HR]: 0.68, 95% CI [0.49, 0.95], p = 0.024). The SGLT2i group had a significantly lower risk of cardiovascular mortality compared with the DPP4i and TZD groups (HR: 0.37, 95% CI [0.21, 0.65], p < 0.001; HR: 0.42, 95% CI [0.20, 0.90], p = 0.025).

Conclusion: This study found that for patients with both diabetes and kidney disease, SGLT2i is a better option than other oral hypoglycemic medications because it can significantly avoid the occurrence of heart-related complications. The results of this study can be used as a reference for clinical medication selection practice.