Journal of The American Society of Nephrology最新文献

Background: Diabetic nephropathy is a primary cause of kidney failure. Persistent hyperglycemia causes metabolic perturbations epigenetically dysregulating gene expression in renal cells, thereby leading to diabetic nephropathy pathogenesis. On analyzing the GEO database by using machine learning algorithms, our preliminary results demonstrated that growth arrest and DNA damage-inducible 45α (GADD45α) might serve as key regulators in diabetic nephropathy. Furthermore, emerging evidence has shown that R-loops, the three-stranded DNA-RNA structures, are crucial to gene expression during diabetic nephropathy. Therefore, this study aimed to investigate the role of GADD45α in diabetic nephropathy by modulating epigenetic alterations through interaction with R-loops.

Methods: A diabetic mouse model was established by injecting streptozotocin intraperitoneally into mice. Kidney histology and biochemical markers were analyzed in wild-type, GADD45α knockout, and renal tubule-specific GADD45α-overexpressing mice. The GADD45α lentivirus was used to induce the overexpression of GADD45α in HK-2 cells, while high-glucose treatment was applied to verify the mechanisms in vitro.

Results: GADD45α expression was reduced in kidneys of diabetic nephropathy, correlating with kidney dysfunction. GADD45α knockout worsened kidney injuries, while overexpression mitigated them. Mechanistically, GADD45α interacted with R-loops on the STEAP4 promoter, recruiting TET1 to activate STEAP4 transcription. Deficiency in the GADD45α-R-loop pathway exacerbated mitochondrial injury, disrupted lipid metabolism, and increased oxidative stress in diabetic nephropathy.

Conclusions: Deficiency of GADD45α exacerbates diabetic nephropathy by interacting with R-loops and inhibiting STEAP4 promoter demethylation. Targeting the GADD45α-R-loop pathway offers therapeutic potential against diabetic nephropathy.

Background: Cognitive dysfunction in hemodialysis (HD) patients is associated with decreased regional cerebral oxygenation (rSO2). Intradialytic exercise improves cognitive function; nonetheless, the acute effect of intradialytic exercise on cerebral circulation remains unknown. This study aimed to evaluate the acute effect of intradialytic exercise on rSO2 during HD.

Methods: This single-center, open-label, randomized crossover trial included 20 HD patients. Patients received the control condition as usual care and the intradialytic exercise condition in random order. The intradialytic exercise condition involved the performance of anaerobic threshold-intensity interval exercise for 35 min. Cerebral oxygenation (rSO2, oxygenated hemoglobin, deoxygenated hemoglobin, and total hemoglobin) in the prefrontal cortex was measured using near-infrared spectroscopy during HD. Cardiovascular responses, including the heart rate, cardiac index, mean arterial pressure, and blood gas, were also assessed. The two conditions were compared using two-way repeated-measures analysis of variance.

Results: The analysis included 16 patients, four of whom were excluded because of artifacts in the cerebral oxygenation data. The rSO2 (P<0.001), oxygenated hemoglobin (P<0.001), and total hemoglobin (P=0.004) showed significant interactions and were significantly increased at end of exercise (rSO2 1.3%, 95%CI [0.5, 2.1]; oxygenated hemoglobin 0.01 mM, 95%CI [0.00, 0.02]; total hemoglobin 0.01 mM, 95%CI [0.00, 0.03]) and 15-min after exercise (rSO2 1.1%, 95%CI [0.2, 2.0]; oxygenated hemoglobin 0.01 mM, 95%CI [0.00, 0.03]; total hemoglobin 0.02 mM, 95%CI [0.00, 0.03]) in the intradialytic exercise condition compared with the control condition. The rSO2 at the end of HD in the control condition was significantly decreased compared with that during pre-HD (-1.5%, 95%CI [-2.7, -0.3]), but not in the intradialytic exercise condition (-1.2%, 95%CI [-2.8, 0.5]).

Conclusions: Intradialytic exercise significantly increased rSO2 during and after exercise and improved rSO2 to the same extent as pre-dialysis.

Background: A family history of health conditions may reflect shared genetic and/or environmental risk. It is not well known to what extent family history impacts outcomes among patients with chronic kidney disease (CKD). Herein, we studied the associations of family history of CKD, diabetes, and other conditions with common comorbidities and kidney disease progression among patients with CKD.

Methods: We carried out an observational study of two prospective CKD cohorts, 2,573 adults and children from the Cure Glomerulopathy Network (CureGN) and 3,939 Chronic Renal Insufficiency Cohort (CRIC) adult participants. Self-reported first-degree family history of CKD, diabetes, and other common diseases were tested for associations with the risk of comorbidities and CKD progression using multivariable models.

Results: Family history of common comorbid conditions was associated with higher risk of these conditions in the context of CKD, including approximately by over 3-fold for diabetes (adjusted OR 3.37, 95% C.I. 2.73-4.15), 48% for cancer (adjusted OR 1.48, 95% C.I. 1.05-2.09), and 69% for cardiovascular disease (adjusted OR 1.69, 95% C.I. 1.36-2.10 in combined cohorts). While polygenic risk score for CKD was associated with kidney disease progression (adjusted HR 1.11, 95% C.I. 1.06-1.16 in combined cohorts), family history of kidney disease was not an independent risk factor for disease progression in the context of existing CKD. In contrast, family history of diabetes was significantly associated with a higher risk of CKD progression independently of diabetes occurrence, or polygenic risk score for diabetes (adjusted HR 1.19, 95% C.I. 1.05-1.35 in combined cohorts).

Conclusions: Broad collection of family history in the context of CKD improved clinical risk stratification. Family history of diabetes was consistently associated with a higher risk of CKD progression independently of diabetes status or polygenic risk score for diabetes in both cohorts.

Background: Cystatin C has entered mainstream clinical care as a measure of kidney function, joining serum creatinine which has been used for almost a century. But many physicians notice that eGFRCr and eGFRCys values can differ considerably. Hospitalization with critical illness is known to acutely decrease eGFRdiff (eGFRCys - eGFRCr). However, whether this effect occurs in all-cause hospitalizations and persists after hospitalization is unknown.

Methods: Among 5,599 adult participants in the Chronic Renal Insufficiency Cohort (CRIC) study with serum creatinine and cystatin C measurements, we estimated the association of six categories of total days of hospitalization between annual study visits (never hospitalized, hospitalized <7 days, 7-<14 days, 14-<28 days, 28-<42 days, and ≥ 42 days) and changes in eGFRCr, eGFRCys, and eGFRdiff between those study visits.

Results: Compared to no hospitalization between study visits, increasing days of hospitalization were associated with decreases in eGFRCys (e.g., -3.30 [95% CI -5.48, -1.13] ml/min/1.73m2 for ≥ 42 days of hospitalization, test for trend p<0.001), while eGFRCr remained relatively stable (e.g., -1.12 [-2.77, 0.53] ml/min/1.73m2 for ≥ 42 days of hospitalization, test for trend p=0.21). The differential effect resulted in eGFRdiff becoming progressively more negative with more total days of hospitalization (test for trend p<0.001).

Conclusions: Prolonged or repeated hospitalization was associated with larger decreases in eGFRCys compared to eGFRCr on measurements months after hospital discharge.

Background: Cardiovascular-Kidney-Metabolic (CKM) syndrome highlights the interconnected nature of metabolic diseases, chronic kidney disease, and cardiovascular diseases, representing a significant and growing public health burden. This study aimed to quantify the global burden of CKM syndrome by examining its key components, including high body mass index (BMI), diabetes, chronic kidney disease, atrial fibrillation and flutter, lower extremity peripheral arterial disease, ischemic heart disease, and stroke.

Methods: Data were derived from the Global Burden of Disease (GBD) 2021 platform, which provided estimates for incidence, prevalence, mortality, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life years (DALYs). A decomposition analysis was performed to assess the contributions of population growth, aging, and epidemiological changes to the burden of CKM syndrome. A NORDPRED model was employed to project future trends in DALYs, YLLs, and YLDs through 2046.

Results: Globally, ischemic heart disease and stroke were the major contributors to the CKM syndrome-related burden in 2021. Regions with a middle Socio-Demographic Index (SDI), such as Southeast Asia and the Western Pacific, experienced the largest burden. However, age-standardized DALY rates were inversely related to SDI, with regions of lower SDI exhibiting higher rates. From 1990 to 2021, DALYs for the seven key components of CKM syndrome increased, primarily driven by population growth and aging. However, age-standardized DALY rates varied across components, with stroke (-38.7% [95% uncertainty interval (UI): -43.4% to -34.0%]), peripheral arterial disease (-30.1% [-33.5% to -27.2%]), and ischemic heart disease (-28.8% [-32.5% to -25.2%]) showing a declining trend, while diabetes (38.2% [29.7% to 47.0%]) and high BMI (25.5% [16.6% to 33.7%]) exhibited an increasing trend. Further projection analysis suggested a consistent trend in the changes in CKM syndrome-related burden from 2022 to 2046, with increases ranging from 55.9% for stroke to 105.7% for atrial fibrillation and flutter.

Conclusions: The findings of this study highlight the substantial and growing CKM syndrome-related burden, emphasizing the urgent need for comprehensive and targeted interventions.

Background: Kidney fibrosis, the excessive accumulation and dysregulated remodeling of the extracellular matrix, is the principal pathophysiological process in chronic kidney disease (CKD). Protein L-isoaspartyl/D-aspartyl methyltransferase (PCMT1) is crucial in repairing post-translational modifications of L-isoaspartyl residues, which are important for extracellular matrix proteins because of their low turnover rate and susceptibility to accelerating factors. This study aimed to reveal a novel role of PCMT1 in kidney fibrosis.

Methods: Kidney tissues from mice and humans were evaluated for PCMT1 expression and its association with fibrosis and kidney function. PCMT1's effects on the TGF-β1/Smad signaling were analyzed, and its functional role was assessed in tubule-specific Pcmt1 knockout murine models of kidney fibrosis. The ability of secreted PCMT1 to repair L-isoaspartyl residues on the ectodomain of transforming growth factor beta receptor 2 (TGFBR2) was investigated through immunoprecipitation, gene lentivirus overexpression or knockout, and post-translational modification mass spectrometry.

Results: PCMT1 expression was decreased in the tubules of human kidney biopsies from patients with CKD and murine fibrosis models. Renal tubule-specific PCMT1 deficiency in murine kidney fibrosis models worsened tubular injury, extracellular matrix protein deposition, myofibroblast activation, and TGF-β1/Smad signaling overactivation. Mechanistically, PCMT1 was unconventionally secreted and enzymatically inhibited TGF-β1-induced extracellular matrix protein deposition in vitro. PCMT1 interacted with TGFBR2, reversing N63 deamination on its ectodomain, which triggered TGFBR2 ubiquitination and degradation. PCMT1 supplementation in kidneys decreased TGFBR2 levels, attenuated TGF-β1/Smad overactivation, and impeded the profibrotic process.

Conclusions: Our study highlights the importance of PCMT1 in maintaining extracellular matrix homeostasis and mitigating kidney fibrosis by regulating TGFBR2 deamination and its protein stability, suppressing the TGF-β1/Smad signaling.