Kidney & blood pressure research最新文献

Introduction: Our recent findings revealed that CACNA1D D307G mutation participates in the early-onset hypertension.

Methods: We used the CRISPR/Cas9 technique to generate the Cacna1d D307G mutation rat model and investigated the effects of Cacna1d D307G mutation on blood pressure (BP) and renal function. Rats fed normal-salt diet had normal plasma aldosterone levels but higher plasma ET-1 and mildly elevated systolic BP (SBP) in D307G and G307G rats compared with the wild type (WT) until 24 weeks. Renal function and renal histopathology did not significantly differ among the three groups.

Results: When fed high-salt diet (HSD), D307G and G307G rats showed more sensitivity to HSD. The results showed a further increase in SBP than in WT rats. Plasma and vascular endothelin-1 (ET-1) level and cortex and renal artery endothelin type A (ETA) receptor protein expression were significantly increased. Enhanced renal injury was also noted as indicated by an increased ratio of kidney weight/body weight, elevated urinary protein and albumin/creatinine ratio, higher kidney injury molecule-1 (KIM-1) levels, advanced fibrosis and apoptosis, and inflammation. Further experiments revealed a reduction in urinary sodium excretion and creatinine clearance. Higher protein expression of renal cortex epithelial sodium channel α subunit (αENaC) was confirmed in D307G and G307G rats fed HSD. However, a selective ETA receptor blockade (ABT-627) could partially reverse the increased SBP, increased serum KIM-1 level, upregulated renal cortex protein expression of αENaC, and reduced urinary sodium excretion with reduced creatinine clearance in D307G rats fed HSD.

Conclusion: Activation of the ET-1/ETA system in D307G mutation rats might have contributed to increased sensitivity to salt loading, augmented hypertension, and exacerbated the renal injury.

Introduction: Kallistatin, a serine protease inhibitor, has been implicated in cardiovascular and renal protection. This study investigates its association with clinical characteristics and outcomes in long-term kidney transplant recipients (KTRs).

Methods: In this longitudinal observational cohort study, we enrolled 101 KTRs between September 2016 and October 2017. The median (interquartile range) time post-transplant was 52 (36-97) months, and the follow-up time was 83 (41-85) months. All patients had documented graft function of ≥24 months and no record of acute rejection or active or chronic infection at presentation. Serum kallistatin and high-sensitivity interleukin-6 were measured at baseline using commercially available enzyme-linked immunosorbent assays. A control group of 32 healthy volunteers was also recruited.

Results: Higher serum kallistatin levels were observed in KTRs compared to healthy controls (15.9 vs. 13.8 µg/mL; p = 0.007). Concentrations were lower in diabetic versus non-diabetic KTR (14.8 vs. 16.4 µg/mL; p = 0.021). A significant interaction between diabetic status and body mass index indicated a positive association with kallistatin levels only in diabetic KTRs (p = 0.046). Linear mixed models assessing estimated glomerular filtration rate (eGFR) change over time showed improved fit after kallistatin was included in a base model with age, sex, and baseline eGFR (p = 0.024). Cox regression showed that higher kallistatin levels were associated with an increased risk of graft loss (HR: 1.120; p = 0.049), but also remained independent of time after transplantation (HR: 1.147; p = 0.030). No association was observed for all-cause mortality. The best performance was estimated for kallistatin models adjusting for time post-transplant (c-index 0.779) and diabetic status (c-index 0.707).

Conclusion: This study highlights the complex interactions between kallistatin, renal function, and cardiometabolic status in stable, long-term KTRs. Higher kallistatin levels are associated with an increased risk of graft loss in non-diabetic patients while showing a protective effect in diabetic patients. These findings support integrated management of cardio-reno-metabolic health in KTRs.

Introduction: This study aimed to assess the long-term renal prognosis of patients with hypertensive nephropathy (HN) diagnosed through renal biopsy, utilizing the random survival forest (RSF) algorithm.

Methods: From December 2010 to December 2022, HN patients diagnosed by renal biopsy in Xijing Hospital were enrolled and randomly divided into training set and testing set at a ratio of 7∶3. The study's composite endpoint was defined as a ≥50% decline in estimated glomerular filtration rate (eGFR), end-stage renal disease, or death. RSF and Cox regression were used to establish a renal prognosis prediction model based on the factors screened by the RSF algorithm. The Concordance index (C-index), integrated Brier score, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were used to evaluate discrimination, calibration, and risk classification, respectively.

Results: A total of 225 patients were included in this study, with 72 (32.0%) patients experiencing combined events after a median follow-up of 29.9 (16.6, 52.1) months. Six eligible variables (overall chronicity grade of renal pathology, eGFR, high-density lipoprotein cholesterol, hematocrit, monocyte, and stroke volume) were selected from clinical data and introduced into the RSF model. The RSF model had a higher C-index in both the training set (0.904 [95% CI: 0.842-0.938] vs. 0.831 [95% CI: 0.768-0.894], p < 0.001) and the testing set (0.893 [95% CI: 0.770-0.944] vs. 0.841 [95% CI: 0.751-0.931], p = 0.021) compared to the Cox model. NRI and IDI indicated that the RSF model outperformed the Cox model regarding risk classification.

Conclusion: In this study, the RSF algorithm was employed to identify the risk factors affecting the prognosis of HN patients, and a clinical prognostic RSF model was constructed to predict the adverse outcomes of HN patients based on renal pathology. Compared to the traditional Cox regression model, the RSF model offers superior performance and can provide valuable new insights for clinical diagnosis and treatment strategies.

Introduction: Several population-based studies have highlighted an association between stroke and dementia. Alzheimer's disease (AD)-related dementia and vascular dementia are the most common causes of dementia, with clear pathophysiological mechanisms for the latter. Given the ongoing debate surrounding the link between stroke and AD, a systematic meta-analysis was performed to determine their relationship and the possible influence of some moderators (sex, age, and region).

Methods: We searched five databases (ISI Web of Science, Scopus, PubMed, Elsevier ScienceDirect, and Google Scholar) with no initial publication date restriction, and the last search was conducted in 2022. We included longitudinal population-based studies assessing the stroke-AD association, selecting those with reported effect sizes, standardized AD diagnosis, and an AMSTAR score ≥9. Case reports, reviews, animal studies, and non-English publications were also excluded. The meta-analysis, conducted using Comprehensive Meta-Analysis 3.1, presented pooled log odds ratios (LogOR) with 95% confidence intervals, heterogeneity analysis (Cochran's Q, I2), and moderator analyses by age, sex, and region.

Results: The meta-analysis included 3 meta-analyses and 12 primary studies, comprising a total of 14,207 stroke cases and 1,952 AD cases. Our analysis revealed a significant association between ischemic stroke (IS), hemorrhagic stroke (HS), and microinfarcts (MI) and the risk of AD. Despite some heterogeneity across studies, no significant differences were observed in the stroke-AD association based on age, sex, or region.

Conclusion: Our study describes the risk of AD in patients with episodes of stroke (IS, HS, and MI) and suggests that the risk of AD may be higher in stroke patients than in matched controls without stroke incidence. Moreover, the moderator analysis supports the robustness of our results. The link between stroke and AD suggests that stroke may accelerate cognitive decline. This calls for tighter vascular control and indicates worse prognosis in dementia progression.

Background: The FLOT regimen, a combination of fluorouracil, leucovorin, oxaliplatin, and docetaxel, is a standard treatment for gastric and esophagogastric junction cancers, but concerns exist about its potential renal toxicity. The exact prevalence and severity of renal toxicity need to be well documented, and this knowledge gap could impact the optimal use of the FLOT regimen in clinical practice. We aimed to evaluate the renal toxicity profile of the FLOT regimen with a specific focus on acute kidney disease (AKD) onset in a real-life setting and explore associated risk factors.

Methods: We conducted a multicenter retrospective study involving 96 patients treated with preoperatory FLOT. The incidence of AKD and potential risk factors were identified.

Results: AKD occurred in 3 patients (incidence rate of 0.0122 cases/month of follow-up). Oral antidiabetic agents and prostate hypertrophy emerged as significant predictors of AKD.

Conclusion: AKD is uncommon in patients treated with the preoperatory FLOT regimen. Our findings highlight the importance of diligent renal function monitoring and appropriate preventive strategies in patients undergoing FLOT treatment. These results encourage the conduction of further studies and clinical experience in larger populations and patients with lower baseline estimated glomerular filtration rate.

Introduction: Cisplatin-induced acute kidney injury (Cis-AKI) is a significant cause of renal damage, characterized by tubular injury, ferroptosis, and oxidative stress. While therapeutic options for Cis-AKI remain limited, identifying novel targets to prevent kidney injury is critical. This study focuses on GALNT14, a gene associated with ferroptosis, and its potential role in mitigating Cis-AKI.

Methods: The Limma package was used to analyze differentially expressed genes (DEGs) between the saline and cisplatin groups. The weighted correlation network analysis (WGCNA) was performed to discover the co-expressed modules and hub genes linked with Cis-AKI. The hub genes were then put into String database to create a network of protein-protein interactions. The FerrDb database was used to acquire genes related to ferroptosis, which were then screened for their association with CiS-AKI. The role of GALNT14 was examined in vitro using HK-2 renal tubular cells and in vivo in a Cis-AKI murine model.

Results: Totally, 1,201 DEGs in intravenous (iv) administration group were retrieved. The 806 genes were obtained from intersection WGCNA and DEGs. Ultimately, we identified 4 genes (ALOX5, CD44, GALNT14, and ASNS) that may play important roles in the regulation of ferroptosis in Cis-AKI. The mRNA expression level of GALNT14 exhibited the most notable difference between Cis-AKI and the control group. In vitro, GALNT14 overexpression in HK-2 cells reduced renal injury and ferroptosis markers, including KIM1, NGAL, and FSP1, while increasing GPX4 expression. Conversely, silencing GALNT14 exacerbated Cis-AKI-induced injury. In vivo, GALNT14 overexpression in Cis-AKI mice attenuated kidney injury, reduced ferroptosis markers, and reversed pathological alterations such as tubular dilatation and loss of brush border.

Conclusion: GALNT14 inhibits Cis-AKI by regulating tubular ferroptosis, demonstrating its potential as a therapeutic target for kidney injury. Our findings suggest that GALNT14 could be an effective strategy for preventing Cis-AKI and improving renal function in kidney injury-related diseases.

Introduction: Chronic kidney disease (CKD) is an important risk factor for cardiovascular disease and mortality. However, data on the prediction of long-term adverse outcomes in advanced predialysis CKD patients are lacking.

Methods: We studied the factors associated with mortality and major adverse cardiovascular and cerebrovascular events (MACCEs, including cardiovascular death, myocardial infarction, stroke, and coronary revascularization) in a cohort of 210 patients with non-dialysis CKD stages 4-5 during a 5-year follow-up. The participants underwent stress ergometry testing to study maximal exercise capacity (Wmax%), a plain lateral abdominal radiograph to study abdominal aortic calcification score (AAC) and laboratory tests including cardiac troponin T (TnT) and N-terminal pro-B-type natriuretic peptide (ProBNP). Furthermore, a dichotomous composite covariate was created and explored by combining ProBNP and Wmax% using the cut-offs determined with the Youden index. The associations between covariates of interest and study outcomes were explored using multivariable Cox proportional hazards models adjusted with age, sex, coronary artery disease (CAD), and incident kidney transplantation (KTx).

Results: Median age at baseline was 65 (52-73) years and eGFR 12 (10-15) mL/min/1.73 m2, 34.8% were female, and 44.8% had diabetes. Altogether 67 (31.9%) patients died during follow-up, and 65 (31.0%) were observed with a MACCE. In separate multivariable Cox proportional hazards models adjusted for age, gender, CAD, and KTx, Wmax% (HR 0.983 [95% CI: 0.968-0.999], p = 0.019), TnT (HR 1.004 [95% CI: 1.002-1.005], p < 0.001), and ProBNP (HR 1.036 per 1,000 ng/L [95% CI: 1.014-1.059], p = 0.002) were independently associated with mortality. In similarly adjusted multivariable Cox models, Wmax% (HR 0.977 [95% CI: 0.962-0.992], p = 0.003), TnT (HR 1.004 [95% CI: 1.002-1.005], p < 0.001), and ProBNP (HR 1.034 per 1,000 ng/L [95% CI: 1.010-1.058], p = 0.006) were independently associated with the occurrence of MACCE during follow-up. AAC was associated with the risk of an incident MACCE (HR 1.080 [95% CI: 1.028-1.135], p = 0.002) but, surprisingly, not with mortality (HR 1.046 [95% CI: 0.994-1.101], p = 0.083). Finally, in participants with Wmax ≤50% and ProBNP ≥1,270 ng/L, the risk of mortality (HR 8.760 [95% CI: 4.730-16.222], p < 0.001) and MACCE (HR 3.293 [95% CI: 1.850-5.862], p < 0.001) was significantly greater than those with Wmax >50% and/or ProBNP <1,270 ng/L.

Conclusion: Wmax% and ProBNP separately and together as a composite risk factor may serve as important predictors of long-term all-cause mortality and MACCE in patients with CKD stages 4-5 not undergoing dialysis at baseline.

Introduction: Urine samples could partially reflect the renal condition and could provide possible mechanism of high-risk factor for the long-term development of chronic kidney disease (CKD) caused by prematurity.

Methods: Urine samples were collected from preterm infants (gestational age <28 weeks) when their corrected gestational weeks reached ≥37 weeks. In addition, urine samples were collected from full-term infants beyond 3 days after birth as the control group. The urine proteome was investigated by using liquid chromatography-tandem mass spectrometry analysis, and subsequent bioinformatics analysis was performed. Differentially expressed proteins were validated using ELISA.

Results: A total of 2,634 proteins were identified, 366 proteins were highly expressed in the preterm group, while 102 proteins were enriched in the full-term group. Based on functional analysis, proteins enriched in preterm group were implicated in structure organization, cell adhesion, and extracellular part, while proteins enriched in urine of the full-term group were implicated in the immune response. Kidney inherent cells accelerated into urine have been examined in preterm infants group. Each of the top 20 differentially expressed proteins enriched in the urine of preterm infants was used as a keyword for literature retrieval, ultimately leading to the selection and validation of CDH6 and CDH11 through ELISA. Both proteins were found to be more abundant in the urine of preterm infants than in that of full-term infants.

Conclusion: The present study provides differences in urine protein profiles between preterm and full-term infants and a new potential explanation for the high risk of CKD development caused by preterm birth.

Introduction: Diabetic nephropathy (DN) is a common complication in diabetic patients, and the pathological mechanism has not been fully understood. PIAS2, as a counter-regulator of the JAK2/STAT3 signaling pathway, may play a crucial role in DN. This study aimed to investigate the expression of PIAS2 in high glucose-induced podocytes and the protective effect against podocyte cell injury.

Methods: Human kidney podocytes were cultured under normal glucose (5.5 mm) and high glucose (30 mm) conditions. The expression of PIAS2 was detected by RT-qPCR and Western blotting. Subsequently, the effects of PIAS2 overexpression in high glucose-induced human podocytes were evaluated through the determination of cell viability, apoptosis, and secretion of inflammatory cytokines. Recombinant human IL-6 was used as an agonist of the JAK2/STAT3 signaling pathway to further validate the mechanism of the effects of PIAS2 in high glucose-induced human podocytes.

Results: High glucose treatment significantly increased the expression levels of PIAS2 in human podocytes. Overexpression of PIAS2 significantly reversed high glucose-induced human podocyte injury, evidenced by increased cell viability, reduced cell apoptosis, decreased expression of pro-apoptotic proteins Bax and cleaved caspase-3, increased expression of the antiapoptotic protein Bcl-2, and reduced secretion of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. Additionally, IL-6 significantly reversed the protective effects of PIAS2 on high glucose-induced human podocytes.

Conclusion: PIAS2 plays a protective role in DN by inhibiting JAK2/STAT3 signaling pathway to alleviate high glucose-induced podocyte injury. PIAS2 may be a potential new target in the treatment of DN.

Introduction: High sodium and low potassium intake are associated with cardiovascular disease. This meta-analysis investigates the combined effect of dietary sodium and potassium intake (Na+/K+-ratio), on cardiovascular outcome.

Methods: We systematically searched MEDLINE and Embase databases (1946-2024) for randomized controlled trials and cohort studies reporting the association between estimated diet Na+/K+-ratio and cardiovascular events or mortality in adults. Two authors screened articles, extracted data, and assessed risk of bias (ROBINS-E tool). We pooled results using random-effects models and compared outcomes across the general population, patients with chronic kidney disease, and those with a history of cardiovascular disease. The study was registered in PROSPERO (ID: CRD42024450279).

Results: Twenty-four studies were included. Participants were 59 ± 11 years old, 49 ± 22% were men and the estimated dietary Na+/K+-ratio was 2.0 ± 0.6 mmol/mmol. The risk of bias was low in 9% of the studies, high in 39% of the studies and 52% of the studies were appraised as some concerns. Higher estimated diet Na+/K+-ratio was associated with a higher risk for cardiovascular events and mortality (hazard ratio 1.10 [95% confidence interval: 1.06-1.16]), which was apparent in the general population and subjects with a history of cardiovascular disease. In patients with chronic kidney disease, only limited data were available.

Conclusion: Higher estimated diet Na+/K+-ratio is associated with a higher incidence of cardiovascular events and mortality in both the general population and patients with a cardiovascular disease history.