Nephron最新文献

Background: The progression of diabetic nephropathy (DN) is closely associated with lipid accumulation. Diosgenin (Dio) plays a beneficial role in the lipid metabolism associated with multiple diseases. Thus, the mechanism underlying Dio's function in DN associated with aberrant lipid accumulation warrants further investigation.

Methods: To model DN in vitro, HK-2 cells were treated with high glucose (HG) and palmitic acid. Cell viability was evaluated using MTT assay. The triglyceride (TG) content in HK-2 cells was measured using a commercial assay kit. The formation of lipid droplets in HK-2 cells was observed using Oil Red O staining. The expression levels of mRNA and protein were detected using RT-qPCR and western blot, respectively. The DNA methylation of FOXO1 was assessed using MSP. The interaction between DNMT1 and the FOXO1 promoter was confirmed by ChIP assay.

Results: Dio treatment reduced TG levels and lipid droplet formation in HK-2 cells co-treated with HG and palmitic acid. Simultaneously, the levels of miR-148b-3p and FOXO1 were increased by Dio, while Dio decreased the expression levels of DNMT1 and SREBP-2. Meanwhile, miR-148b-3p can bind to DNMT1, which in turn inhibits the expression of FOXO1 by mediating the DNA methylation of FOXO1. In addition, FOXO1 negatively regulates the expression of SREBP-2 by interacting with the SREBP-2 promoter. MiR-148b-3p inhibition or silencing of FOXO1 abolished the inhibitory effect of Dio on TG production and lipid droplet formation. This effect was further exacerbated by the downregulation of DNMT1. FOXO1 overexpression may counteract the promotive effects of miR-148b-3p inhibitor on lipid accumulation.

Conclusion: Dio treatment reduced TG production and lipid droplet formation in HK-2 cells during the progression of DN by modulating the miR-148b-3p/DNMT1/FOXO1/SREBP-2 axis. This finding provides new evidence supporting the therapeutic potential of Dio for DN.

Introduction: Sepsis-associated acute kidney injury (SA-AKI) is a common complication of sepsis. miR-340-5p has been identified as an effective biomarker of various human diseases. As the downstream target, the involvement of lysine (K)-specific demethylase 4C (KDM4C) in SA-AKI would help interpret the regulatory mechanism of miR-340-5p. The significance of miR-340-5p in the onset and progression of SA-AKI was evaluated to provide a potential therapeutic target for SA-AKI.

Methods: This study enrolled 64 healthy individuals (control) and 159 sepsis patients (92 SA-AKI and 67 non-AKI) and collected urine samples. The urine level of miR-340-5p was analyzed by PCR, and a series of statistical analyses were conducted to assess the clinical significance of miR-340-5p in the occurrence and development of SA-AKI. The injured renal tubular epithelial cells were established with LPS induction. The roles of miR-340-5p in cellular processes were evaluated.

Results: Increasing urine miR-340-5p discriminated SA-AKI patients from healthy individuals (AUC = 0.934) and non-AKI sepsis patients (AUC = 0.806) sensitively. Additionally, elevated miR-340-5p could predict the adverse prognosis (HR = 5.128, 95% CI = 1.259-20.892) and malignant development of SA-AKI patients. In vitro, lipopolysaccharide (LPS) also induced an increased level of miR-340-5p and significant cell injury in the renal tubular epithelial cell; silencing miR-340-5p could alleviate the suppressed proliferation, migration, and invasion caused by LPS. In mechanism, miR-340-5p negatively regulated KDM4C, which mediated the function of miR-340-5p.

Conclusion: miR-340-5p served as a diagnostic and prognostic biomarker of SA-AKI and regulated renal tubular epithelial cell injury via modulating KDM4C.

Background: Kidney disease poses a significant global health challenge, marked by a rapid decline in renal function due to a variety of causative factors. A crucial element in the pathophysiology of kidney disease is the dysregulation of epithelial cells, which are vital components of renal tissue architecture. The integrity and functionality of these cells are largely dependent on tight junctions (TJ) proteins, complex molecular structures that link adjacent epithelial cells. These TJ not only confer cellular polarity and maintain essential barrier functions but also regulate epithelial permeability.

Summary: TJ proteins are pivotal in their traditional role at cell junctions and in their non-junctional capacities. Recent research has shifted the perception of these proteins from mere structural elements to dynamic mediators of kidney disease, playing significant roles in various renal pathologies. This review explores the multifaceted roles of TJ proteins, focusing on their functions both within and external to the renal epithelial junctions. It highlights how these proteins contribute to mechanisms underlying kidney disease, emphasizing their impact on disease progression and outcomes.

Key messages: TJ proteins have emerged as significant players in the field of nephrology, not only for their structural role but also for their regulatory functions in disease pathology. Their dual roles in maintaining epithelial integrity and mediating pathological processes make them promising therapeutic targets for kidney disease. Understanding the intricate contributions of TJ proteins in kidney pathology offers potential for novel therapeutic strategies, aiming to modulate these proteins to halt or reverse the progression of kidney disease.

Background: This study aimed to assess the prognostic significance of serum ferritin levels in sepsis-associated acute kidney injury (SA-AKI) and their correlation with short-term mortality. Despite the established predictive value of serum ferritin in various serious diseases, its specific prognostic relevance in SA-AKI remains unexplored. Therefore, this study seeks to fill this research gap by investigating the association between serum ferritin levels and short-term mortality in patients with SA-AKI.

Methods: This retrospective cohort study utilized clinical data from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database, including all patients with SA-AKI admitted to the intensive care unit for the first time. The relationship between serum ferritin levels and 28-day mortality was explored using restricted cubic splines. Kaplan-Meier curves and Cox regression models were employed to evaluate the association between serum ferritin levels and mortality. Subgroup and sensitivity analyses were performed to verify the robustness of the results.

Results: In this study, a total of 878 patients (486 males and 392 females) with a median age of 63.7 years were enrolled. The results indicated that increasing serum ferritin levels were linearly associated with a gradual increase in 28-day mortality rates. Specifically, patients in the highest quartile of serum ferritin had significantly higher 28-day mortality compared to those in the reference group (the first quartile of ferritin levels). After adjusting for various factors, the fully adjusted hazard ratio was 1.92 (95% CI: 1.24-2.96, p = 0.003).

Conclusion: In patients with SA-AKI, higher serum ferritin levels are associated with an increased 28-day mortality rate.

The development of the human kidney leads to the establishment of nephron endowment through a process influenced by both genetic and environmental factors. There is individual variability regarding nephron endowment and factors including aging and pathological conditions contribute to the decline in the number of nephrons, impacting renal function. Genetic determinants, such as mutations in crucial developmental genes like Pax2, and epigenetic mechanisms mediated by key enzymes including sirtuin 3, play critical roles in the regulation of the number of nephrons, with implications for kidney disease susceptibility. Sexual dimorphism significantly influences kidney development and function, with the number of nephrons being significantly lower in females, consistent with lower female birth weight, which is considered a surrogate for nephron endowment. Also, although females have fewer nephrons, they experience a slower decline in GFR compared to males. Gender disparity in chronic kidney disease progression has been attributed to factors such as metabolism, oxidative stress, renal hemodynamics, and sex hormones. Understanding the complexities of nephron endowment variability, genetic determinants, and sexual dimorphism in kidney development and function is crucial for elucidating the mechanisms underlying individual kidney disease susceptibility and progression. Further research in this field holds promise for the development of personalized approaches to kidney disease prevention, management, and treatment.

Introduction: IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory disease that can affect nearly every organ system, including blood vessels and the kidney. IgG4-related vascular lesions mainly involve the aorta, and the dominant renal manifestation is tubulointerstitial nephritis (TIN). Here, we report a case of IgG4-RD demonstrating extensive abdominal periarteritis and membranous nephropathy (MN).

Case presentation: The patient was a 71-year-old man with peptic ulcer who developed nephrotic syndrome, with a low serum albumin level (1.8 g/dL), massive urinary protein (6.1 g/day), and high serum IgG4 level (435 mg/dL). Computed tomography images revealed soft tissue mass around the medium-sized abdominal arteries. Renal pathological findings showed MN and focal infiltration of numerous IgG4-positive cells in the interstitium. The findings of high serum IgG4 levels, periarteritis, and focal inflammation with rich IgG4-positive plasma cells led to the diagnosis of IgG4-RD. We chose low-dose steroid therapy to prevent the recurrence of the peptic ulcer and aneurysm formation in the affected arteries, which can occur with medium to high doses of prednisolone. We successfully controlled IgG4-related periarteritis and kidney disease without relapse or complications.

Conclusion: The varied clinical manifestations of IgG4-RD sometimes make the diagnosis challenging. However, clinicians should diagnose IgG4-RD based on serological, radiological, and pathological evaluations because, without appropriate therapy, IgG4-RD can lead to irreversible organ failure caused by swelling, obstruction, or fibrosis of the organs.

Alport syndrome (AS) is a hereditary kidney disorder of type IV collagen caused by pathogenic variants in the COL4A3, COL4A4 and COL4A5 genes. Previously several cases of digenic AS, caused by two pathogenic variants in two of the three COL4A genes, have been reported. Patients with digenic AS may present with a more severe phenotype compared to patients with single variants, depending on the percentage affected type IV trimeric collagen chain. We report a newly discovered case of trigenic AS. A 52-year-old female presented with hematuria at the age of 24 years and developed hypertension by the age of 30. Over the years she developed chronic kidney disease; the most recent eGFR was 44ml/min/1.73m2. She has symmetric high-tone sensorineural hearing loss. Full genetic analysis revealed a heterozygous pathogenic variant c.2691del in COL4A3, a heterozygous pathogenic variant c.1663dup in COL4A4, and a complete heterozygous deletion of COL4A5. We describe the first patient with AS caused by pathogenic variants in all three COL4A genes, designated trigenic AS. This case report emphasizes the importance of examining all three COL4A genes, even in patients with a mild Alport phenotype, for optimal follow-up of the patient and adequate genetic counseling of family members.

Introduction: In pediatric kidney patients, where clinical presentation is often not fully developed, and renal biopsy is too risky or inconclusive, it may be difficult to establish the underlying pathology. In cases such as these, genetic diagnosis may be used to guide treatment, prognosis, and counseling. Given the large number of genes involved in kidney disease, introducing next-generation sequencing with extended gene panels as part of the diagnostic algorithm presents a viable solution.

Methods: A cohort of 87 consecutive independent cases (83 children and 4 terminated pregnancies) with renal disease was recruited. Exome sequencing with MiSeq or NovaSeq 6000 (Illumina) platforms and analysis of extended gene panels were used for genetic testing.

Results: Depending on the presenting pathology, the cases were grouped as patients with glomerular disease, ciliopathies, congenital anomalies, renal electrolyte imbalances, and chronic/acute kidney disease. The overall diagnostic yield was approximately 42% (37 out of 87), with most disease-causing mutations found in COL4A3, COL4A4, COL4A5, and PKHD1 genes. A change or clarification of preliminary diagnosis or adjustment of initial treatment plan based on the results of the genetic testing was made for approximately one-third of the children with meaningful genetic findings (11 out of 37).

Discussion: Our results prove the value of targeted exome sequencing as a non-invasive, versatile, and reliable diagnostic tool for pediatric renal disease patients. Providing genetic diagnosis will help for a better understanding of disease etiology and will give the basis for optimal clinical management and insightful genetic counseling.

Introduction: Sodium-glucose cotransporter 2 inhibitors (SGLT2Is) have beneficial effects on the renal function of chronic kidney disease (CKD) patients, although the types of patients suitable for this treatment remain unclear.

Methods: A retrospective observational study was conducted on CKD patients who were treated with SGLT2I in our department from 2020 to 2023. The estimated glomerular filtration rate (eGFR) just before treatment was defined as the baseline and the difference between pre-and post-treatment eGFR slopes were used to compare the improvement of renal function. Logistic regression analysis was used to evaluate the independent factors for its improvement.

Results: A total of 128 patients were analyzed (mean age: 67.2 years; number of women: 28 [22%]). The mean eGFR was 42.1 mL/min/1.73 m2, and urine protein was 0.66 g/gCr. The eGFR slopes of patients with an eGFR <30 mL/min/1.73 m2 were improved significantly after treatment (-0.28 to -0.14 mL/min/1.73 m2/month, p < 0.001) but were worsened in patients with an eGFR ≥30 mL/min/1.73 m2. Logistic analysis for the improvement in eGFR slopes showed that women (odds ratio [OR], 5.63; 95% confidence interval [CI], 1.16-27.3; p = 0.03), use of mineralocorticoid receptor antagonists (OR, 11.79; 95% CI, 1.05-132.67; p = 0.012) and rapid decline of eGFR before treatment (OR, 12.8 per mL/min/1.73 m2/month decrease in eGFR; 95% CI, 3.32-49.40; p < 0.001) were significant independent variables.

Conclusion: SGLT2Is may have beneficial effects, especially for rapid decliners of eGFR, including advanced CKD.

Introduction: The association between magnesium level and progression to acute kidney disease (AKD) in acute kidney injury (AKI) patients was not well studied. With AKI transition to AKD, the burden of the disease on mortality, morbidity, and healthcare costs increases. Serum magnesium disturbances are linked with a decline in renal function and increased risk of death in CKD and hemodialysis patients. This study aims to assess the significance of magnesium derangements as a risk factor for the progression of AKI to AKD in critically ill patients.

Methods: This study was conducted among patients with AKI admitted to the intensive care units at Mayo Clinic from 2007 to 2017. Serum magnesium at AKI onset was categorized into five groups of <1.7, 1.7-1.9, 1.9-2.1, 2.1-2.3, and ≥2.3 mg/dL, with 1.9-2.1 mg/dL as the reference group. AKD was defined as AKI that persisted >7 days following the AKI onset. Logistic regression was used to evaluate the association between magnesium and AKD.

Results: Among 20,198 critically ill patients with AKI, the mean age was 66 ± 16 years, and 57% were male. The mean serum magnesium at AKI onset was 1.9 ± 0.4 mg/dL. The overall incidence of AKD was 31.4%. The association between serum magnesium and AKD followed a U-shaped pattern. In multivariable analysis, serum magnesium levels were associated with increased risk of AKD with the odds ratio of 1.17 (95% CI: 1.07-1.29), 1.13 (95% CI: 1.01-1.26), and 1.65 (95% CI: 1.48-1.84) when magnesium levels were <1.7, 2.1-2.3, and ≥2.3 mg/dL, respectively.

Conclusion: Among patients with AKI, magnesium level derangement was an independent risk for AKD in critically ill AKI patients. Monitoring serum magnesium and proper correction in critically ill patients with AKI should be considered an AKD preventive intervention in future trials.