Kidney Diseases最新文献

Introduction: This study aims to explore the contribution of neutrophil extracellular traps (NETs) to kidney stones.

Methods: The microarray data from GSE73680 and bioinformatic analysis were applied to identify differentially expressed genes in patients with kidney stones. A rat model of kidney stones was established through ethylene glycol and ammonium chloride administration. The plasma was collected for examining cf-DNA, DNase I, MPO-DNA, H3Cit and NE. Superoxide dismutase, malondialdehyde, creatinine, blood urea nitrogen, and calcium were examined through biochemical analysis. MPO, H3Cit, and NE in kidney tissues were detected via immunofluorescence staining. Cell apoptosis was evaluated through TUNEL assays. HE, Periodic Acid-Schiff and Von Kossa staining were applied to determine histological structure, calcium deposits and stone formation in the kidneys. Neutrophil elastase inhibitor Sivelestat (SIVE) was administrated for NET suppression in rats.

Results: A total of 403 differentially expressed genes including 270 upregulated and 133 downregulated genes were identified between renal papillary tissues with Randall's plaque and normal tissues. Gene ontology enrichment, KEGG pathway and protein-protein interaction network analysis of these dysregulated genes were performed. Moreover, increased NET markers including cf-DNA, DNase I, MPO-DNA, H3Cit and NE and calcium deposits were observed in patients with kidney stones. Subsequently, we established a rat model of kidney stones. We found that NET formation was significantly elevated in kidney stone rats, and renal tubular injury and apoptotic cells were enhanced as kidney stones developed. Strikingly, we found that suppression of NETs via SIVE could significantly reduce calcium deposits and apoptotic cells and alleviate tubular injury, thus improving kidney function.

Conclusion: NETs drive the formation of kidney stones, thus aggravating kidney injury. Our study identifies NETs as a potential diagnostic and therapeutic biomarker for nephrolithiasis.

Introduction: Patients with acute mountain sickness (AMS) due to hypoxia at high altitudes often exhibit abnormal water metabolism. Hypoxia-inducible factors (HIFs) are major regulators of adaptive responses to hypoxia. As transcription factors, HIFs are involved in the regulation of erythropoiesis, iron metabolism, angiogenesis, energy metabolism, and cell survival by promoting the transcriptional expression of hundreds of target genes. Roxadustat, a novel drug for the treatment of anemia associated with chronic kidney disease (CKD), acts by inhibiting the degradation of HIFs to increase their protein levels. However, the clinical use of roxadustat is frequently associated with peripheral edema, suggesting the involvement of HIFs in regulating the body's water balance possibly by modulating water reabsorption in the kidney.

Methods: We first evaluated the effect of hypoxia (8% O₂) on mouse urine output. We then performed in vitro experiments using hypoxia (1% O₂) and roxadustat on mouse primary proximal tubular cells (mPTCs). The quantitative polymerase chain reaction, Western blot, and immunofluorescence were used to assess AQP1 mRNA and protein expression levels. Luciferase, Chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift assay (EMSA) were used to investigate the transcriptional regulation of AQP1 by HIF1α.

Results: We found that mice exposed to hypoxia (8% O₂) had significantly reduced urine volume compared to mice exposed to normoxia (21% O₂). Hypoxia significantly elevated AQP1 expression at both mRNA and protein levels. In vitro experiments using mouse primary cultured proximal tubular cells (mPTCs) revealed that both hypoxia and roxadustat increased AQP1 expression. Mechanistically, overexpression of HIF1α, but not HIF2α, markedly increased AQP1 protein expression. Furthermore, the upregulation of AQP1 by hypoxia and roxadustat can be blocked by the HIF1α inhibitor PX-478 in mPTCs. Finally, we found that the AQP1 gene promoter contains a putative hypoxia response element and confirmed that AQP1 is a target gene of HIF1α using Luciferase reporter, ChIP, and EMSA assays.

Conclusion: This study demonstrates that hypoxia can reduce the urine volume of mice via upregulating AQP1 expression by HIF1α in the proximal tubular epithelial cells. Our findings also suggest a potential mechanism involved in water metabolism disorders in patients with AMS and in patients with CKD receiving roxadustat treatment.

Introduction: Despite the pivotal role of hepcidin in the development of anemia among the patients with chronic kidney disease (CKD), the association between serum hepcidin levels and CKD progression has been never investigated. We here hypothesized that elevation in serum hepcidin levels might be associated with the risk of incident end-stage kidney disease (ESKD) among the patients with pre-dialysis CKD.

Methods: A total of 2,109 patients with pre-dialysis CKD at stages 1 to pre-dialysis 5 were categorized into the quartiles by serum hepcidin levels. The study outcome was incident ESKD. The median duration of follow-up was 7.9 years.

Results: The analysis of the baseline characteristics revealed that unfavorable clinical features were in general associated with higher serum hepcidin levels. The cumulative incidence of ESKD was significantly differed by serum hepcidin levels, with the highest incidence in the 4th quartile (p < 0.001, by log-rank test). Cox regression analysis demonstrated that, compared to the 1st quartile, the risk of incident ESKD is significantly increased in the 4th quartile (adjusted hazard ratio 1.372, 95% confidence interval 1.070-1.759). Penalized spline curve analysis illustrated a linear, positive correlation between serum hepcidin levels and the risk of incident ESKD. Subgroup analyses revealed that the association is significantly more prominent in the patients with advanced CKD (i.e., estimated glomerular filtration rate <45 mL/min/1.73 m²).

Conclusion: Elevation in serum hepcidin levels is significantly associated with the risk of incident ESKD among the patients with pre-dialysis CKD.

Background: Precise regulation of cell-cell communication is vital for cell survival and normal function during embryogenesis. The Wnt protein family, a highly conserved and extensively studied group, plays a crucial role in key cell-cell signaling events essential for development and regeneration. Congenital anomalies of the kidney and urinary tract (CAKUT) represent a leading cause of chronic kidney disease in children and young adults, and include a variety of birth abnormalities resulting from disrupted genitourinary tract development during embryonic development. The incidence and progression of CAKUT may be related to the Wnt signal transduction mechanism.

Summary: This review provides a comprehensive overview of the classical Wnt signaling pathway's role in CAKUT, explores related molecular mechanisms and provides new targets and intervention methods for the future treatment of the disease.

Key messages: The Wnt signal is intricately engaged in a variety of differentiation processes throughout kidney development.

Background: Inherited kidney diseases (IKDs) in children pose unique diagnostic and therapeutic challenges. IKD significantly impact patient quality of life, morbidity, mortality, and cost to the healthcare system. With over 150 genetic abnormalities, they account for approximately 30% of cases requiring renal replacement therapy. There is an urgent need to advance both diagnosis and treatment strategies. In this review, we present recent advances in diagnosis and treatment for facilitating personalized treatment approaches.

Summary: The diagnostic landscape for IKDs have evolved significantly, emphasizing precise genetic identification and classification of these disorders. Recent advancements include the refinement of genetic testing techniques, such as whole exome sequencing, which has improved the accuracy of diagnosing specific diseases and facilitated early intervention strategies. Additionally, this review categorizes IKDs based on genetic abnormalities and clinical manifestations, enhancing understanding and management approaches. Finally, it summarizes the corresponding treatment, and lists the application of emerging therapeutic options such as gene therapy and organoids, which show promise in transforming treatment outcomes.

Key messages: This review summarizes the common types of IKDs in children, including their diagnosis and treatment advances, and provides an update on the status of gene therapy development for these disorders.

Introduction: Depression is a common psychiatric problem in maintenance hemodialysis (MHD) patients. Recent studies have begun to explore the relationship between body composition and depression. Phase angle (PhA), a core parameter for assessing body composition, has been observed to be associated with frailty and cognitive dysfunction. The aim of this study was to investigate the association between PhA and depression in MHD patients.

Methods: This multicenter, cross-sectional study included 843 MHD patients from seven dialysis centers in Shanghai, China. Depressive symptoms were evaluated using the Patient Health Questionnaire (PHQ-9), with a score of ≥10 indicating depression. PhA was measured by bioelectrical impedance analysis. Nutritional status was assessed by malnutrition inflammation score (MIS). Multivariable logistic regression models were used to investigate the association between PhA and depression. Restricted cubic spline (RCS) analysis was utilized to examine the association. Receiver operating characteristic curve was used to identify the cut-off value of PhA for depression.

Results: A total of 15.2% of patients (62.8% male, median age 66 years) had depression. Median PhA level (interquartile range) of depressed patients was 4.4° (3.9-4.9°) for males and 3.9° (3.2-4.7°) for females. There was a significant decrease in the prevalence of depression with increasing quartiles of PhA levels. In multivariable logistic regression analyses, after adjusting for age, sex, education level, spKt/V, dialysis vintage, Charlson comorbidity index, hemoglobin, and serum albumin, lower PhA levels (lowest quartile group) were significantly associated with depressive symptoms (adjusted odds ratio, 2.19; 95% confidence interval, 1.07 to 4.48), compared to higher PhA levels (highest quartile group). RCS analysis showed a relatively inverse linear association between PhA and depression. The optimal cut-off value of PhA for depression was 4.9° for males and 3.5° for females. Subgroup analyses validated the findings across patient characteristics, including age, sex, diabetes, education, and malnutrition.

Conclusion: Our findings indicated an inverse association between PhA and depressive symptoms in Chinese MHD patients, suggesting that PhA could serve as a valuable indicator for assessing the risk of depression in this population. Further studies are needed to explore the potential of PhA as a prognostic tool and its implications for intervention strategies.

Background: Mitophagy is a crucial process involved in maintaining cellular homeostasis by selectively eliminating damaged or surplus mitochondria. As the kidney is an organ with a high dynamic metabolic rate and abundant mitochondria, it is particularly crucial to control mitochondrial quality through mitophagy. Dysregulation of mitophagy has been associated with various renal diseases, including acute and chronic kidney diseases, and therefore a better understanding of the links between mitophagy and these diseases may present new opportunities for therapeutic interventions.

Summary: Mitophagy plays a pivotal role in the development of kidney diseases. Upregulation and downregulation of mitophagy have been observed in various kidney diseases, such as renal ischemia-reperfusion injury, contrast-induced acute kidney injury, diabetic nephropathy, kidney fibrosis, and several inherited renal diseases. A growing body of research has suggested that PINK1 and Parkin, the main mitophagy regulatory proteins, represent promising potential therapeutic targets for kidney diseases. In this review, we summarize the latest insights into how the progression of renal diseases can be mitigated through the regulation of mitophagy, while highlighting their performance in clinical trials.

Key message: This review comprehensively outlines the mechanisms of mitophagy and its role in numerous kidney diseases. While early research holds promise, most mitophagy-centered therapeutic approaches have yet to reach the clinical application stage.

Introduction: Malignant hypertension (mHTN) is a hypertensive emergency. Thrombotic microangiopathy (TMA) is a widespread complication of mHTN. Few studies have evaluated whether glomerular hematuria provides prognostic information for renal dysfunction in patients with mHTN-associated TMA.

Methods: This observational cohort study included 292 patients with mHTN-associated TMA based on renal biopsy. Propensity-score matching (PSM) analysis was conducted to adjust for clinical characteristics in a comparison between with and without glomerular hematuria. Cox regression was employed to identify risk factors for renal prognosis.

Results: A total of 70 patients with glomerular hematuria were compared to 222 patients with non-glomerular hematuria. After PSM, 67 pairs of patients with mHTN-associated TMA were matched. Patients with glomerular hematuria exhibited lower serum albumin levels, higher 24-h proteinuria, and a higher prevalence of glomerular sclerosis than those with non-glomerular hematuria. Glomerular hematuria was independently associated with deteriorated renal function compared with non-glomerular hematuria (HR: 0.51; 95% CI: 0.29-0.89, p = 0.019). This association remained significant after PSM (HR: 0.51; 95% CI: 0.28-0.91, p = 0.022). Additionally, glomerular hematuria was independently associated with renal replacement therapy (RRT) (HR: 3.14; 95% CI: 2.06-5.66, p < 0.001). This difference remained significant after PSM comparison (HR: 2.41; 95% CI: 1.34-4.33, p = 0.003). Furthermore, despite intensive blood pressure control, patients with glomerular hematuria experienced a higher incidence of RRT and a poorer recovery in renal function, specifically a 25% reduction of creatinine levels, compared to patients with non-glomerular hematuria.

Conclusion: Glomerular hematuria is significantly associated with an increased risk of adverse renal outcomes in patients with mHTN-associated TMA.

Background: The bone-vascular axis plays a key role in the pathogenesis of vascular calcification (VC) in patients with chronic kidney disease (CKD). Understanding and managing the role of the bone-vascular axis in CKD-mineral and bone disorder (CKD-MBD) is critical for preventing and treating associated complications, including osteoporosis, arterial calcification, and cardiovascular diseases. This study aimed to comprehensively summarize the role of bone metabolism markers in uremic VC.

Summary: The skeleton, as an endocrine organ, can regulate systemic metabolic processes by secreting various bioactive substances. These molecules can induce the transdifferentiation of vascular smooth muscle cells, promoting their transition to other functional states, thereby affecting vascular growth and remodeling.

Key messages: The prevalence of VC in individuals with CKD is notably high. CKD-associated VC is characterized by the widespread accumulation of hydroxyapatite within the arterial media, which occurs as a result of the transformation of smooth muscle cells into osteoblastic smooth muscle cells under the influence of uremic toxins. Osteoblasts and osteoclasts in bone tissue secrete mineral metabolic proteins, which can influence neighboring cells, primarily vascular smooth muscle cells, through paracrine signaling. Both circulating and osteocytic sclerostin can exert a protective effect by inhibiting wingless/integrated (WNT)-induced calcification. The therapeutic goal for CKD-MBD is to reduce production of sclerostin by decreasing the osteogenic transdifferentiation of vascular smooth muscle cells. Calciprotein particles act as a physiological agent for delivering calcium-phosphate the bone and inducing fibroblast growth factor-23 expression in osteoblasts.

Introduction: Ischemia-reperfusion injury (IRI) is detrimental to kidney transplants and may contribute to poor long-term outcomes of transplantation. Programmed cell death (PCD), a regulated cell death form triggered by IRI, is often indicative of an unfavorable prognosis following transplantation. However, given the intricate pathophysiology of IRI and the considerable variability in clinical conditions during kidney transplantation, the specific patterns of cell death within renal tissues remain ambiguous. Consequently, accurately predicting the outcomes for transplanted kidneys continues to be a formidable challenge.

Methods: Eight Gene Expression Omnibus datasets of biopsied transplanted kidney samples post-IRI and 1,548 PCD-related genes derived from 18 PCD patterns were collected in our study. Consensus clustering was performed to identify distinct IRI subtypes based on PCD features (IRI PCD subtypes). Differential enrichment analysis of cell death, metabolic signatures, and immune infiltration across these subtypes was evaluated. Three machine learning algorithms were used to identify PCD patterns related to prognosis. Genes associated with graft loss were screened for each PCD type. A predictive model for graft loss was constructed using 101 combinations of 10 machine learning algorithms.

Results: Four IRI subtypes were identified: PCD-A, PCD-B, PCD-C, and PCD-D. PCD-A, characterized by high enrichment of multiple cell death patterns, significant metabolic paralysis, and immune infiltration, showed the poorest prognosis among the four subtypes. While PCD-D involved the least kind of cell death patterns with the features of extensive activation of metabolic pathways and the lowest immune infiltration, correlating with the best prognosis in the four subtypes. Using various machine learning algorithms, 10 cell death patterns and 42 PCD-related genes were identified as positively correlated with graft loss. The predictive model demonstrated high sensitivity and specificity, with area under the curve values for 0.5-, 1-, 2-, 3-, and 4-year graft survival at 0.888, 0.91, 0.926, 0.923, and 0.923, respectively.

Conclusion: Our study explored the comprehensive features of PCD patterns in transplanted kidney samples post-IRI. The prediction model shows great promise in forecasting graft loss and could aid in risk stratification in patients following kidney transplantation.