Kidney & blood pressure research最新文献

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 calcifications (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, FGF-23, α-Klotho, osteoprotegerin, TRAP5b, sclerostin, Matrix-Gla-Protein (both dephosphorylated-uncarboxylated and total-uncarboxylated) and 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 iPTH, hsCRP, 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.

Introduction: Milan hypertensive strain (MHS) of rat represents as one of the ideal rat models to study the genetic form of hypertension associated with aberrant renal salt reabsorption. In contrast to Milan normotensive strain (MNS), MHS rats possess missense mutations in three adducin genes and develop hypertension at 3 months old due to upregulation of sodium-chloride cotransporter (NCC). At pre-hypertensive stage (23-25 days old), MHS rats show enhanced protein abundance of Na+-K+-2Cl- cotransporter (NKCC2) but retain blood pressure comparable to MNS probably through enhanced GFR and reduced NCC and α-subunit of epithelial sodium channel (α-ENaC) expressed in distal convoluted tubule (DCT) and collecting duct (CD).

Methods: In the present study, mRNA and protein expressions of ion transporters in thick ascending limb of Henle's loop (TAL) of young MHS rats were investigated.

Results: Protein abundance of core-glycosylated form of renal outer medullary potassium channel (ROMK) in inner stripe of outer medulla (ISOM) is remarkably increased in MHS rats at prehypertensive stage. Furthermore, basolaterally expressed Na+-K+-ATPase and Barttin were upregulated.

Discussion/conclusion: These results may indicate that in TAL of MHS rats at this age, both total NKCC2 and core-glycosylated ROMK are upregulated in tandem potentially to balance the luminal potassium concentration. On the basolateral side, upregulation of Na+-K+-ATPase and CLC-Ka/b may energize the excretion of sodium and chloride out from the cells. These data may suggest the interplay of apical and basolateral ion transporters in TAL for the modulation of TAL function in favor of enhancing the transepithelial sodium reabsorption, although this seems compensated by NCC and ENaC expressed at the downstream nephron segments in young MHS rats.

Introduction: The morbidity and mortality of acute kidney injury (AKI) are increasing. Epigenetic regulation and immune cell infiltration are thought to be involved in the 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 2367 DEGs were obtained, including 1180 upregulated and 1187 downregulated genes in IRI-AKI kidney associated with the cell structure, proliferation, molecule binding/interaction, and signaling pathways such as the leucocyte 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: Maternal undernutrition (MUN) induced low birth weight (LBW) neonates are susceptible to the development of high blood pressure and kidney disease later in life, although the underlying pathological causes remain unclear. The study here investigated the role of renal oxidative stress, impairment of vascular function and altered sensitivity to angiotensin II as factors that contribute to these pathologies in aged LBW mice.

Methods: LBW offspring were generated using a combined protein and caloric restricted MUN mouse model. The resulting LBW offspring were examined one year after birth for mean arterial blood pressure (carotid artery catheterization), renal blood flow (laser-doppler flowmetry), glomerular filtration rate (sinistrin clearance), vasoreactivity (myograph), renal vascular density (CD31 staining), and reactive oxygen species (ROS) (ROS probes). Immunoblotting examined Ang II type 1 receptor (AT1R), soluble guanylate cyclase and antioxidant systems. Pharmacological agents delivered to animals included the soluble guanylate cyclase stimulator δ-aminolevulinic acid (ALA), the AT1R inhibitor losartan, the antioxidant ethyl pyruvate (EP) and the Toll-like Receptor 4 inhibitor TAK242.

Results: After one year, mean arterial blood pressure was increased, while renal blood flow, glomerular filtration rate, vascular reactivity, renal vascular density and soluble guanylate cyclase were all reduced in the LBW aged adult. All four pharmacological agents improved mean arterial blood pressure, renal blood flow, glomerular filtration rate, vascular density, and vascular reactivity. Renal ROS was increased in the LBW adult, but was reduced by ALA, EP and TAK242 treatment. AT1R was upregulated in the LBW adult, while soluble guanylate cyclase was decreased, an effect reversed by ALA treatment. Endogenous antioxidant systems, including SOD1, catalase and glutathione were downregulated in the LBW adult.

Conclusion: MUN induced LBW mice experience increased Ang II sensitivity and oxidative stress. The increased Ang II sensitivity and ROS generation influences vascular density and reactivity, which drives an increase in mean arterial blood pressure, and a concomitantly decrease in renal blood flow and glomerular filtration. Pharmacological intervention that inhibits AT1R, enhances levels of soluble guanylate cyclase, reduces ROS, or inhibits toll-like receptor 4 improves vascular and renal function in the LBW adult.

Introduction: Inflammation plays a key role in chronic kidney disease (CKD). Monocyte-to-lymphocyte ratio (MLR) is a novel inflammatory marker. The purpose of this study was to evaluate the relationship between MLR and inflammation in CKD patients.

Methods: In total, 1809 subjects were recruited from Wanzhai Town, Zhuhai City, between December 2017 and March 2018 for a cross-sectional survey. Patients were categorized based on the absence (hypersensitive C-reactive protein (hsCRP) level ≦ 3 mg/L) or presence (hsCRP level > 3 mg/L) of inflammation. Logistic regression models and MLR quartiles were used to explore the relationship between MLR and inflammation in CKD patients.

Results: Among 1809 subjects, 403 (22.2%) had CKD. Significant differences in systolic blood pressure, estimated glomerular filtration rate, white blood cell (WBC), neutrophil, monocyte, MLR, and Interleukin-6 (IL-6) levels were observed between noninflammatory group and inflammatory group. The highest MLR quartile had higher Scr, WBC, neutrophil, monocyte, IL-6, and hsCRP values and lower eGFR and lymphocyte values. Comparing the lowest quartile of MLR, the OR (95% CI) of inflammation risk in the highest quartile was 2.30 (1.24-4.27) after adjustment for confounding factors. The area under the curve of MLR for predicting inflammation was 0.631. The cutoff point for the MLR was 0.153.

Conclusion: A high MLR was significantly and independently associated with inflammation in patients with CKD, making MLR a potential marker for inflammation in this demographic. MLR may also predict the severity of CKD.

Background: Aldosterone, through its genomic and non-genomic effects, plays an important role in cardiovascular and renal injury. Steroidal mineralocorticoid receptor antagonists (MRAs) are fundamental to offset the aldosterone-mediated cardiorenal damage, but side effects may limit their use in a substantial proportion of patients. On the other hand, non-steroidal mineralocorticoid receptor antagonists (NS-MRA) showed improved selectivity and safety profile. However, interfering with the MRA could only partially inhibit aldosterone mediated effect both because of escaping mechanisms and potential non-genomic activity.

Summary: Inhibiting aldosterone synthesis could be a promising strategy to abolish aldosterone-mediated cardiovascular side effects. Aldosterone is primarily synthesized by the CYP11B2 enzyme, which is very similar to CYP11B1, a key enzyme involved in glucocorticoid production. Lack of specificity for CYP11B2 and consequent off-target effects hampered the development of first-generation aldosterone synthase inhibitors (ASIs). The subsequent development of highly specific ASIs led to successful clinical trials in patients with resistant and uncontrolled hypertension.

Key messages: A recent randomized clinical trial showed a significant benefit of ASIs in patients with chronic kidney disease and albuminuria. However, further outcome based clinical trials are needed to confirm the promising role of ASIs in cardiorenal damage.

Introduction: Chronic kidney disease (CKD) is closely linked to high blood pressure (HBP) which is its leading cause in developing countries. Hypertension affect 1.2 billion people worldwide. However, a significant portion of individuals with HBP are undiagnosed and their kidney function is even less known. The objective of this study was to determine the prevalence and associated factors of chronic kidney disease among three sub-groups of blood pressure status (normotensive, diagnosed hypertension and undiagnosed hypertension) individuals.

Patients and methods: We conducted a cross-sectional study in the general population of three northern regions in Senegal using a two-level cluster sampling method. The sample was constituted with a precision of 5% and a power of 80%, with an additional 10% attrition margin. Individuals aged 18 - 80 years were included in the study after consent. Pregnant women, hospitalized persons within the past three months, patients with general or urinary symptoms within the past seven days and individuals undergoing renal replacement therapy were excluded. Investigators collected Clinical and biological data at participants' homes using a modified version of the WHO's STEPwise questionnaire. Samples were collected for biochemical analysis (serum creatinine, lipid profile and blood sugar). Estimated GFR was calculated using the CKD-EPI 2021 formula.

Results: A total of 2441 participants were included in the study with a mean age of 45.4 +/- 16.0 years and a sex ratio M/F of 0.4. The Overall prevalence of HBP and CKD were respectively 52.0% and 17.8%. Three out of every five hypertensive patients were undiagnosed. Chronic kidney disease was more frequent among known hypertensive patients (30.5%) compared to individuals with undiagnosed hypertension (19.1%) and normotensive individuals (10.9%). Multivariate analysis showed that CKD was associated with older age and female sex.

Conclusion: Undiagnosed hypertension is common among populations in northern Senegal. A high prevalence of CKD was found among both diagnosed and undiagnosed individuals with hypertension. Extending strategies for early detection and management in the general population could help prevent or reduce morbidity and mortality associated with CKD.

Introduction: Individuals with chronic kidney disease (CKD) are at increased risk for thrombotic events and bleeding. Acetylsalicylic acid (ASA), an effective antiplatelet agent, is one of the most frequently used medications for both primary and secondary prevention of cardiovascular disease (CVD). However, it can also contribute to bleeding events due to its inherent antiplatelet effect. The objective of this study was to determine the characteristics of CKD patients at increased risk for bleeding under ASA therapy.

Methods: This retrospective analysis included patients with non-dialysis dependent CKD who were treated with ASA for primary prevention of CVD for at least 3 consecutive months and did not receive anti-coagulants or anti-platelets. Data were collected from electronic medical records from January 2014 to December 2018. CKD diagnosis was based on an estimated glomerular filtration rate of <60 ml/min/1.73 m2. CKD patients who experienced major bleeding events during ASA therapy (bleeding group) vs. all others (control group) were compared. Additional outcomes included first documented non-fatal cardiovascular event and all-cause mortality.

Results: Of the 900 adult CKD patients included in this analysis, 82 (9.1%) had a major bleeding event during 31.6±25.9 months of follow-up. The most common bleeding site was gastrointestinal (52 cases, 63.4% of major bleeding events). Patients who had a major bleeding event were older (76.5±10 vs. 74±10.3 years, P=0.038). On multivariate analysis, age was the most important predictor of major bleeding event (odds ratio 1.029, 95% confidence interval 1.004-1.056).

Conclusions: Given its controversial efficacy in primary prevention of CVD in CKD patients, characterizing those at increased risk for bleeding under ASA therapy is important in the era of tailored medicine. Age, CKD stage and cardiovascular risk are key factors to consider regarding the safety and effectiveness of ASA for CKD patients.

Introduction: Interstitial cells are crucial to the development of kidney structure and function, although the mechanism underlying their role in it remains unclear to date. Our previous study identified cell clusters in human fetal kidney tissue, and we further analyzed the interstitial cell cluster within this context.

Methods: We extracted the barcoded cDNA from tissue samples and prepared spatial transcriptome libraries. Sequencing data was quality-checked, normalized, and clusters were identified using Seurat. Single-cell and spatial data were integrated using MIA and cell types were deconvoluted. DEGs in interstitial cells were identified and functionally annotated using DAVID. CellPhoneDB was used to predict ligand-receptor interactions between cell types.

Results: The results of the present study revealed that this cluster of interstitial cells appeared to be scattered in the junction between the cortical and medullary regions. The subsequent KEGG pathway analysis revealed that the differentially expressed genes (DEGs) in this cluster of interstitial cells were involved in the WNT signaling pathway. The Gene Ontology (GO) analysis revealed that these DEGs were involved in multiple pathways associated with kidney development, with six of the genes (NKD2, TCF21, WNT5A, WNT4, MDK, and SFRP1) associated with kidney development exhibiting significant upregulation. Accordingly, it was inferred that these interstitial cells might be involved in regulating epithelial cell differentiation, ureteral bud development, and morphogenesis. The subsequent cell-cell communication analysis revealed that the cellular crosstalk was primarily regulated mainly by ligand-receptor pairs. Additionally, 17 genes reported to be associated with kidney disease were focused on, and these genes were found to be predominantly expressed in a single cell type.

Conclusion: In summary, the present study revealed the characteristics of a previously identified cluster of interstitial cells in the kidney tissue, thereby providing fresh insights into the process of kidney development.

Introduction: This study aimed to explore the correlation between the extent of fundus damage and the severity strategies for chronic kidney disease (CKD).

Methods: We collected data from 118 CKD patients, including general information, renal function indicators, and fundoscopic examination results. The stages of CKD and degrees of fundus lesions were graded. SPSS 25.0 software facilitated the analysis of correlations using Kendall's tau-b correlation analysis and ordinal regression analysis.

Results: Statistically significant differences were observed among multiple CKD stages in the distribution of age, systolic blood pressure, diastolic blood pressure, hemoglobin, total cholesterol, homocysteine, cystatin C, serum creatinine, blood urea, eGFR, 24-hour urine protein, urine microalbumin, urine microalbumin/urine creatinine, and blood β2 microglobulin, complement C3. Notably, the levels of cytokeratin 19 fragment and transforming growth factor β significantly increased in all CKD stages. Kendall's tau-b correlation analysis revealed a significant positive correlation between CKD stage and fundus lesion grade. Ordinal regression analysis indicated that sex differences, total cholesterol levels, and hemoglobin levels were significant predictors of fundus lesion risk. Compared with patients at stage 5 CKD, the risk of fundus damage significantly lower in patients in stage 2 and stage 3, further demonstrating a positive correlation between renal function deterioration and increased risk of fundus damage.

Conclusions: Routine fundus screening and early intervention for fundus lesions are vital for assessing CKD deterioration, providing new directions for future related research.