Kidney & blood pressure research最新文献

Introduction: An autosomal recessive hereditary disorder of the glyoxylate metabolism, primary hyperoxaluria (PH), causes an excess of oxalate to be formed in the body. Three genes have so far been found to cause the three forms of PH (I, II, and III). Overall, 10% of PH patients are type III and are caused by a mutation in the HOGA1 gene. Pathogenic variants responsible for the disease have been identified in several populations. In the present study, we are going to genetically analyze 14 Iranian patients who are suspicious of being affected with PH III.

Methods: We studied 14 patients from 11 unrelated Iranian families with a clinical diagnosis of hyperoxaluria disease. The kidney stone was detected in all patients. All of them had high levels of creatinine and oxalate in their urine. Sanger sequencing of the HOGA1 gene was performed in all 14 patients. Next-generation sequencing has also been performed on 1 patient who did not have any causative variants in the HOGA1 gene.

Results: We identified one homozygous likely pathogenic missense variant in the HOGA1 (c.266G>A).

Conclusion: This is the first report of analyzing the HOGA1 gene in Iranian patients suspicious of being affected with hyperoxaluria type III, which can expand our knowledge about this gene and its mutations.

Background: Fabry disease (FD) is an X-linked genetic condition caused by variants in the GLA gene, leading to a deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A) and the accumulation of complex glycosphingolipids such as globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3). The systemic disorder primarily affects the cardiovascular, renal, and nervous systems, resulting in decreased life expectancy. The timing of treatment initiation and optimal dosing play crucial roles in improving outcomes and quality of life in Fabry patients. Available FD treatments include enzyme replacement therapy with agalsidase alfa, aglasidase beta, and pegunigalsidase alfa, as well as oral chaperone therapy with migalastat, which can all stabilize or reduce the disease burden.

Summary: This review focuses exclusively on newly available drugs and future therapeutic approaches for treating FD, including migalastat, pegunigalsidase alfa, substrate reduction therapy (SRT), and gene therapy. Migalastat provides benefits such as oral administration and non-immunogenicity; however, it is only appropriate for patients with "amenable" GLA variants. The recently approved pegunigalsidase alfa is a pegylated form of α-Gal A manufactured in plant cell cultures, with apparent reduced immune response and prolonged circulating half-life. SRT (venglustat, lucerastat) reduces Gb3 synthesis, helping to normalize metabolic processes while offering certain advantages such as oral administration, non-immunogenic properties, and the possible crossing of the blood-brain barrier. Clinical trials in human and animal model studies are currently investigating ex vivo and in vivo gene therapy techniques, showing positive early outcomes.

Key messages: The ongoing development of novel treatments for FD suggests that patients will soon have access to a wider array of therapies, enabling more individualized care approaches. Although a definitive FD cure has not been achieved and the expense of combining therapies remains challenging, new therapeutic options such as gene and mRNA-based treatments show promise, though more research is needed.

Background: Chronic kidney disease (CKD) affects over 850 million people worldwide and is associated with significant morbidity and mortality. There has been recent expansion in treatment options to reduce CKD progression and cardiovascular risk, and it is essential that this translates into clinical practice.

Summary: The primary objectives of this review were to outline current CKD care models and associated care gaps and review the literature for alternative care models, with a focus on the early detection and management of CKD. Several care models have been proposed to improve CKD management including nurse-led, pharmacy-led, integrated care models and digital interventions, with mixed results.

Key messages: There is a need for ongoing health systems and implementation research to improve translation of evidence into practice in the management of CKD.

Introduction: Four different antihypertensive drug classes are equivalently recommended in the previous guidelines for first-line treatment of arterial hypertension (HTN). However, it is unclear, whether one of these drugs is more capable than the others to reach blood pressure (BP) control. We sought to compare response rates and BP control in these 4 classes.

Methods: Patients with newly diagnosed mild to moderate HTN on 24-h BP measurements (ABPM) were randomized in a 1:1:1:1 fashion to either perindopril, olmesartan, amlodipine, or hydrochlorothiazide (HCT). ABPM was completed at baseline (BL) and after 4 weeks of half dose (treatment period 1 [TP1]). If BP control was not reached after TP1, drug dose was doubled and another ABPM completed after 4 weeks (treatment period 2 [TP2]). Patients were classified as controlled if 24-h mean BP was <130/80 mm Hg, awake BP <135/85 mm Hg, and night BP <120/70 mm Hg, and as optimal if 24-h mean BP was 115-124/65-74 mm Hg.

Results: 88 patients were randomized: 20 (23%) to perindopril, 23 (26%) to olmesartan, 24 (27%) to amlodipine, and 21 (24%) to HCT. Median 24-h mean BP reduction from BL to TP1 was -11/-6 mm Hg and from TP1 to TP2 -4/-2 mm Hg. The highest BP reduction was reached with olmesartan (-15/-10 mm Hg), particularly for diastolic values, the lowest with HCT (-8/-1 mm Hg). 27% of patients reached systo-diastolic BP control, with the best control rate with perindopril and olmesartan (40 and 39%), the lowest with HCT (5%), and 21%/18% reached an optimal treatment goal for systolic/diastolic 24-h mean values, respectively, after TP1. Three additional participants (4%) reached BP control after TP2.

Conclusion: Initial antihypertensive monotherapy failed in most patients (73% uncontrolled, 21%/18% reached optimal treatment goal at TP1) even in low-risk patients, with efficacy varying by drug class (inhibitors of the renin-angiotensin-aldosterone system best, HCT least). These findings support guideline-recommended combination therapy.

Background: Renal damage in Fabry disease (FD) is a consequence of pathological and progressive glycosphingolipids accumulation, which occurs in different magnitudes among FD phenotypes, but is a constant renal tissue phenomenon in all patients with renal involvement. A significant correlation between plasma Lyso-Gb3 (Gb3 analog) and disease severity has been described but, there is lack of information from clinical studies regarding the correlation between Lyso-Gb3 and renal events in humans and, the few results have certain discrepancies. In clinical practice, it is necessary to have disease-specific biomarkers, non-invasive and useful in diagnosis, prognosis and therapeutic response. Evidence relating to the prognostic value of lyso-GL3 is mixed.

Summary: We reviewed the evidence on renal effect of plasma and/or urinary Lyso-Gb3 in FD patients and the usefulness as a biomarker of diagnostic and therapeutic response. Additionally, the in vitro renal effects of Lyso-Gb3 were reviewed. The literature search was conducted in PubMed, Embase, Scopus, Cochrane, and Google academic. Search terms were (Fabry disease + [Lyso-Gb3 or Lyso-GL3] + ["renal" or "kidney"]).

Inclusion criteria: (i) "in vitro" studies in which a direct effect of Lyso-Gb3 on kidney tissue has been studied, both in animals and/or humans; (ii) retrospective, cross-sectional, or prospective "in vivo" studies in which a correlation between Lyso-Gb3 and renal clinical events or renal function biomarkers has been studied.

Key messages: Ten studies presented evidence of "in vitro" renal damage due to Lyso-Gb3; 4 studies presented correlation between plasma Lyso-Gb3 and renal events in FD patients; and 3 studies reported correlation between urinary Lyso-Gb3 and renal events in FD patients.

Conclusion: The small number of publications and the methodological heterogeneity do not allow a statistical analysis of them. Regarding the "in vivo" and "in vitro" renal effects of Lyso-Gb3 in FD: There is evidence of harmful effects on renal cells in vitro due to Lyso-Gb3 but this evidence is not sufficient to use Lyso-Gb3 (neither plasma nor urinary) as a biomarker for monitoring renal damage in FD patients. Plasma Lyso-Gb3 is a useful biomarker in (i) FD diagnosis and (ii) stratification of phenotype and severity of FD. In FD "classic" patients receiving enzyme replacement therapy (ERT), it is useful to determine plasma Lyso-Gb3 periodically because an inconsistent reduction during ERT may indicate the formation of neutralizing anti-agalsidase antibodies.

Introduction: Patients with chronic kidney disease (CKD) often experience symptoms consistent with orthostatic hypotension (OH); however, not much is known about OH in this population. Therefore, study analyzed OH prevalence and risk according to renal function decline.

Methods: A community-based cohort study was conducted using data from the Korean Genome and Epidemiology Study (KoGES). OH prevalence was assessed at baseline and at a 2-year follow-up across three estimated glomerular filtration rate (eGFR) categories: high (≥90 mL/min/1.73 m2, G1), moderate (60-89 mL/min/1.73 m2, G2), and low (<60 mL/min/1.73 m2, G3).

Results: Among 9,597 participants, baseline OH, 2-year OH, and persistent OH were evaluated within each eGFR group: high (n = 6,743), moderate (n = 2,758), and low (n = 96). The low eGFR group demonstrated the highest prevalence of baseline OH (n = 52, p = 0.024) and 2-year OH (n = 42, p = 0.002). This group also exhibited the largest decline in systolic blood pressure at both baseline and follow-up. In adjusted logistic regression, participants aged <50 years with low eGFR had 3.54-fold higher odds of OH (p = 0.035). Additionally, adherence to a low-sodium diet was associated with increased 2-year OH prevalence across groups (p = 0.001).

Conclusion: The low eGFR group showed a higher baseline and follow-up OH prevalence. A low-sodium diet was also associated with elevated OH risk, underscoring the need for careful dietary management in patients with CKD.

Introduction: The morbidity and mortality of acute kidney injury (AKI) are increasing. Epigenetic regulation and immune cell infiltration are thought to be involved in AKI. However, the relationship between epigenetic regulation and immune cell infiltration in AKI has not been elucidated. This study was conducted to identify the differentially expressed genes (DEGs), differentially expressed RNA methylation genes (DEMGs), and infiltrated immune cells in the kidneys of ischemia-reperfusion induced-acute kidney injury (IRI-AKI) models and further explore their relationships in IRI-AKI.

Methods: This is a bioinformatic analysis using R programming language in 3 selected IRI-AKI datasets from the Gene Expression Omnibus (GEO) database, including 16 IRI-AKI kidney tissues and 10 normal kidney tissues. The DEGs were screened, and enrichment pathways were analyzed using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) database. The DEMGs and core DEMGs were identified using the R package. The ROC curve was plotted to predict disease occurrence of 7 core DEMGs. The correlation of 7 core DEMGs and other genes was analyzed using Pearson's correlation test. The gene set enrichment analysis (GSEA) of each DEMG was conducted using the R package. The upstream miRNAs and transcript factors of 7 core DEMGs were predicted based on the RegNetwork database and Cytoscape software. The STITCH database was used to predict the possible binding compounds of the 7 core DEMGs. Immune cell infiltration in kidney tissues between the IRI-AKI group and control group was evaluated using the R package.

Results: A total of 2,367 DEGs were obtained, including 1,180 upregulated and 1,187 downregulated genes in IRI-AKI kidney associated with the cell structure, proliferation, molecule binding/interaction, and signaling pathways such as the leukocyte migration and chemokine signaling pathways. Ten DEMGs were identified, with Ythdf1, Rbm15, Trmt6, Hnrnpc, and Dnmt1 being significantly upregulated, while Lrpprc, Cyfip2, Mettl3, Ncbp2, and Nudt7 were significantly downregulated in IRI-AKI tissues. The molecules interacting with 7 core DEMGs were identified. Significant changes in the infiltration of 8 types of immune cells were observed in IRI-AKI kidneys compared to normal controls. The significant correlation between 6 core DEMGs and the infiltration of immune cells was observed.

Conclusion: IRI may induce AKI through RNA methylation to regulate the expression of genes involved in immune cell infiltration.

Introduction: Cardiovascular (CV) diseases persist as the foremost cause of morbidity/mortality among chronic kidney disease (CKD) patients. This paper examines the values of coronary artery calcification (CAC) and biomarkers of CV on major adverse CV events (MACE)/CV death in a sample of 425 non-dialysis CKD patients.

Methods: At inclusion, patients underwent chest multidetector computed tomography for CAC scoring and biomarkers of CV risk including CRP, mineral metabolism markers, fibroblast growth factor-23 (FGF-23), α-Klotho, osteoprotegerin, tartrate-resistant acid phosphatase 5b (TRAP5b), sclerostin, matrix gla protein (both dephosphorylated uncarboxylated [dp-ucMGP] and total uncarboxylated), and growth differentiation factor-15 (GDF-15) were measured. Patients were followed for a median of 3.61 years (25th-75th percentiles = 1.92-6.70).

Results: Our results reported that CAC was a major independent factor of MACE/CV mortality showing a hazard ratio of 1.71 95% (confidence interval = 1.00-2.93) after adjustment for age, gender, diabetes, and history of CV events for patients with CAC >300. Interestingly, CAC effect was further enhanced in the presence of low levels of 25(OH) vitamin D3 or α-Klotho and high levels of intact parathyroid hormone (PTH), high-sensitive C reactive protein, FGF-23, osteoprotegerin, sclerostin, dp-ucMGP, or GDF-15.

Conclusion: CAC constitutes a significant CV risk, further exacerbated by inflammation, hyperparathyroidism, and regulation of bone molecules implicated in calcification progression. This finding aligns with the original concept of multiple hits. Consequently, addressing the detrimental environment that fosters plaque vulnerability, reducing chronic low-grade inflammation, and normalizing mineral metabolism markers (such as vitamin D and PTH) and bone-regulating molecules may emerge as a viable therapeutic strategy.

Background: Chronic kidney disease (CKD) is a global health concern, with renal fibrosis being a major pathological feature. Empagliflozin (Empa), a sodium-glucose co-transporter-2 inhibitor, has shown promise in protecting the kidney. This study aimed to investigate the effects of Empa on renal fibrosis in a nondiabetic CKD model and to elucidate the underlying mechanisms.

Methods: We established a CKD model using 5/6 nephrectomy (5/6 Nx) rats and divided them into three groups: placebo-treated sham surgery rats, placebo-treated 5/6 Nx rats, and Empa-treated 5/6 Nx rats. Kidney function was assessed by measuring blood urea nitrogen, serum creatinine, and urinary albumin-to-creatinine ratio. Renal fibrosis was evaluated histologically. Single-cell RNA sequencing (scRNA-seq) was performed to analyze intercellular communication networks and identify alterations in ligand-receptor pairs and signaling pathways involved in fibrosis.

Results: Empa treatment significantly improved kidney function and reduced renal interstitial fibrosis in 5/6 Nx rats. scRNA-seq revealed that Empa modulated the TGF-β signaling pathway, inhibited intercellular communication, and reduced the expression of fibrotic genes such as COLLAGEN, FN1, THBS, and LAMININ. Furthermore, Empa downregulated GRN gene expression, weakened signal transmission in the MIF pathway, consequently reduced the interaction between M2 macrophages and other cell types, such as endothelial cells, fibroblasts, and mesangial cells.

Conclusion: This study elucidates the potential mechanisms by which Empa slows the progression of renal fibrosis in nondiabetic CKD. By reducing the number of M2 macrophages and inhibiting signal transduction in both pro-inflammatory and fibrotic pathways, Empa modulates the intercellular communication network in renal cells, offering a promising therapeutic strategy for CKD management.

Objective: The objective of this study was to explore the value of Nutritional Risk Screening 2002 (NRS2002) and Subjective Global Assessment (SGA) scores in diagnosing malnutrition in patients with chronic kidney disease (CKD).

Methods: A retrospective analysis was conducted on 87 patients with CKD admitted to our hospital from July 2023 to July 2024. Patient demographics were collected, and patients were grouped based on age, using 60 years as the cut-off. Clinical data were collected, and the number of cases with malnutrition and normal nutrition assessed by NRS2002 and SGA scores was calculated for different age and gender groups of CKD patients. Spearman's rank correlation analysis was used to assess the correlation between NRS2002 scores, SGA scores, and clinical data among CKD patients of different genders. Binary multivariable logistic regression analysis was performed to analyze the influencing factors of malnutrition in CKD patients evaluated by NRS2002 scores and SGA scores.

Results: Among the CKD patients, 47.13% were classified as malnourished based on BMI, 65.52% based on NRS2002 scores, and 59.77% based on SGA scores. Correlation analysis showed a significant positive correlation between NRS2002 and SGA scores. Furthermore, NRS2002 scores and SGA scores exhibited a significant positive correlation with age (p < 0.001). Binary multivariable logistic regression analysis identified stage IV, age, BMI, RBC, Tp, PA, ALB, and GFR as significant factors associated with malnutrition in CKD patients.

Conclusion: The NRS2002 and SGA scores are valuable tools for diagnosing malnutrition in CKD patients. Early detection and management of malnutrition can improve patient outcomes in this population.