Kidney Diseases最新文献

Introduction: Hydroxychloroquine (HCQ) is recommended for Chinese patients with immunoglobulin A nephropathy (IgAN). This study aimed to investigate the pharmacokinetics of HCQ in the treatment of IgAN and its relationship with therapeutic efficacy.

Methods: This prospective study included 49 IgAN patients treated with HCQ, who were divided into effective and ineffective groups based on HCQ treatment efficacy after 6 months, defined as a reduction in proteinuria of at least 50% from baseline. The concentrations of HCQ and its metabolites were measured by high-performance liquid chromatography-tandem mass spectrometry. The relationships between the concentrations of HCQ and its metabolites and therapeutic efficacy were analyzed using linear correlation analysis and logistic regression. Receiver operating characteristic (ROC) curves were generated to evaluate the predictive value of HCQ and its metabolite concentrations.

Results: Following 6 months of treatment with HCQ, patients in the effective group exhibited increased concentrations of HCQ (p = 0.022) and desethylchloroquine (DCQ) (p = 0.015). The results of the Spearman's correlation analysis indicated a positive correlation between alterations in proteinuria and concentrations of HCQ (r = 0.328, p < 0.05) and DCQ (r = 0.267, p < 0.05). Univariate and multivariate logistic regression analyses indicated that efficacy was significantly correlated with HCQ (odds ratio 1.008, 95% CI: 1.001-1.014) and DCQ (odds ratio 1.064, 95% CI: 1.010-1.121) concentrations. ROC curves indicated that an HCQ concentration of 442.6 ng/mL and a DCQ concentration of 42.7 ng/mL exhibited the optimal capacity to predict efficacy (p < 0.05).

Conclusion: The blood concentrations of HCQ and its metabolite DCQ may be significant factors for evaluating therapeutic efficacy in IgAN patients.

Introduction: Renal anemia is a common complication among patients with non-dialysis chronic kidney disease (ND-CKD), and there remains an unmet need for more efficient and convenient daily oral medications to improve patient outcomes. This study aimed to evaluate the efficacy and safety of enarodustat, a hypoxia-inducible factor-prolyl hydroxylase inhibitor, in treating anemia for ND-CKD patients.

Methods: This phase 3 study was conducted at 48 centers across China, enrolling 156 ND-CKD patients. Participants were randomly randomized in a 2:1 ratio to receive either enarodustat or placebo for an initial 8-week double-blind period, followed by a 16-week open-label period during which all patients received enarodustat.

Results: The primary endpoint was the mean change in hemoglobin (Hb) levels from baseline to the average level during weeks 7-9. Secondary endpoints focused on Hb concentration or treatment pattern, while exploratory endpoints assessed iron metabolism-related parameters. The mean (±SD) change in Hb levels from baseline to weeks 7-9 was 15.99 (±9.46) g/L in the enarodustat group, compared to -0.14 (±8.08) g/L in the placebo group, resulting in a mean difference of 16.00 (±1.54) g/L (p < 0.001). During weeks 7-9, 85.3% of patients in the enarodustat group achieved Hb levels ≥100 g/L with 86.0% maintaining this level during weeks 21-25. In the first 4 weeks, the Hb increased by 11.82 (±9.56) g/L in the enarodustat group. By week 9, the mean change in hepcidin level was -42.94 (±37.56) ng/mL in the enarodustat group, compared to +4.58 (±33.34) ng/mL in the placebo group. Enarodustat also improved other iron-related parameters and reduced the need for iron supplements. The safety profile of enarodustat was well tolerable with adverse events comparable to those of the placebo.

Conclusion: Enarodustat effectively corrected renal anemia with a manageable safety profile. Its once-daily oral administration offers convenience that may enhance the adherence. Enarodustat shows the potential as a promising therapy for anemic patients with ND-CKD.

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.