Kidney & blood pressure research最新文献

Introduction: MicroRNAs have been increasingly recognized for their roles in cardiovascular diseases. Among these microRNAs, miR-214 was reported to be involved in hypertension. However, the role of endothelial miR-214 in hypertension is still unknown. The aim of this study was to determine the role of cell-specific miR-214 on regulating blood pressure, as well as the potential mechanisms.

Methods: We detected the levels of miR-214 in hypertensive mice and cultured mouse aortic endothelial cells (MAECs). In addition, mouse miR-214 inhibitor, miR-214 mimics, vascular endothelial cell-specific miR-214-deficient mice, smooth muscle cell-specific miR-214-deficient mice, renal proximal tubule cell-deficient mice, and various cellular and molecular techniques were employed to define the role of miR-214 in Ang II-induced hypertension.

Results: In mice and MAECs, Ang II significantly enhanced miR-214 levels, and anti-miR-214 markedly attenuated Ang II hypertension in line with enhanced eNOS/p-eNOS in aorta. Then, we generated vascular endothelial cell-specific miR-214 knockout mice and found an antihypertensive phenotype in endothelial miR-214 conditional knockout mice after Ang II treatment. In normotensive animals and MAECs, exogenous miR-214 administration reduced eNOS expression at protein and mRNA levels; in contrast, anti-miR-214 played an opposite role in regulating eNOS. By luciferase assay, our results confirmed that eNOS was a direct target gene for miR-214 in endothelial cells. However, smooth muscle cell-specific or renal tubular cell-specific deletion of miR-214 did not alter Ang II-induced hypertension.

Conclusion: Our findings suggested that endothelial miR-214 promoted Ang II hypertension by targeting eNOS in mice, which increased the understanding on the pathogenic mechanism of hypertension.

Background: Intradialytic hypotension (IDH) occurs suddenly and without warning, although it is generally reversible. While ultrafiltration rate, cardiac function, and vascular resistance have been widely studied, more attention should be given to venous blood return to the heart in relation to blood stagnation. Both existing literature and clinical observations suggest that as a hemodialysis session progresses, the vascular bed of the liver expands, reducing venous return to the heart. This decrease in cardiac output may further increase hepatic blood volume, potentially playing a central role in the development of IDH.

Summary: This review explores the role of reduced venous return to the heart, caused by liver blood stagnation, as a key contributor to IDH.

Key messages: We tentatively name this pathophysiological mechanism "liver circulation jam." The clinical significance of this concept requires validation through future research.

Introduction: In the past, elevated blood pressure was considered an exclusion criterion for living kidney donation because of concerns about premature kidney failure. Hypertension leads to complement deposits and renal fibrosis in the kidney. Therefore, the aim of this study was to investigate whether increased complement deposits and fibrosis can be observed in grafts of hypertensive compared to normotensive living donors.

Methods: Zero-time renal biopsies from 238 living donors (52 hypertensive) and the corresponding 1-year protocol biopsies were examined for complement deposits of C1q, C3c, and MASP-2. Findings were compared to kidney biopsies from patients with hypertensive nephropathy. Further, renal fibrosis was visualized by Sirius red staining, scored semiquantitatively, and compared to biopsies from deceased donors and kidneys with hypertensive nephropathy. Additionally, zero-time biopsies from hypertensive (n = 6) and normotensive (n = 5) living donors were analyzed for expression of fibrosis-associated genes by multiplex mRNA analysis and compared to zero-time biopsies (n = 6) from deceased donors.

Results: In all zero-time biopsies from living donors, complement deposits were minimal for C1q, C3c, and MASP-2 compared to samples with hypertensive nephropathy, regardless of whether the donor was hypertensive or normotensive. In 1-year protocol biopsies, complement deposits were unchanged, while renal fibrosis was slightly but not significantly increased in hypertensive compared to normotensive living donors. Gene expression data showed that the 11 zero-time biopsies from hypertensive and normotensive living donors clustered together and were clearly separated from the deceased donor biopsies.

Conclusion: The use of kidneys from hypertensive living donors appears to have no or little effect on renal complement deposits and fibrosis 1 year after transplantation.

Introduction: Fibroblast growth factor 23 (FGF23) has emerged as an important endocrine regulator of renal phosphate and vitamin D metabolism and as a factor implicated in pathophysiological processes in further organs, including the heart. In myocardial infarction, elevations of plasma FGF23 can be observed that may be related to left ventricular hypertrophy or fibrosis. A critical event in the development of myocardial infarction and thrombosis is platelet aggregation due to thromboxane A2 (TxA2) formation. We studied whether TxA2 is a regulator of FGF23.

Methods: Experiments were performed in rat UMR-106 osteoblast-like cells and differentiated mouse MC3T3-E1 cells upon exposure to TxA2, pharmacological manipulation of TxA2 signaling, or co-incubation with platelets isolated from healthy volunteers. Fgf23 transcripts were analyzed by qRT-PCR and FGF23 protein by enzyme-linked immunosorbent assay.

Results: As a result, TxA2 or stable TxA2 receptor agonists I-BOP or U46619 significantly suppressed Fgf23 gene expression, an effect abrogated by TxA2 receptor antagonist SQ29548. TxA2 signaling also down-regulated FGF23 protein concentration in the cell culture supernatant. Co-incubation of UMR-106 cells with freshly isolated human thrombocytes activated by thrombin, but not with non-activated platelets or thrombin alone, significantly lowered Fgf23 gene expression in UMR-106 cells.

Conclusion: Taken together, TxA2 signaling suppresses FGF23 production in UMR-106 and MC3T3-E1 bone cells. TxA2-dependent regulation of FGF23 synthesis may be particularly relevant for common diseases associated with enhanced platelet aggregation.

Objective: The objective was to explore bone metabolism in chronic kidney disease (CKD) and its correlation with nutritional indicators and to identify risk factors for abdominal aortic calcification (AAC).

Methods: This cross-sectional study enrolled 148 adults (>18 years) with CKD stages 3-5 (stage 3: n = 13, stage 4: n = 15, stage 5: n = 120 including dialysis and non-dialysis patients) between May 2018 and May 2021. Participants met strict criteria: confirmed CKD diagnosis per Kidney Disease Outcomes Quality Initiative guidelines, stable nutritional status without malabsorption disorders, and no vitamin K antagonist use. Exclusion criteria included acute kidney injury, transplant recipients, malignancies, and thyroid/parathyroid disorders. Using convenience sampling, we assessed correlations between nutritional/mineral markers via Pearson's analysis and identified intima-media thickness (IMT)/AAC risk factors through binary logistic regression.

Results: Positive correlations were observed between serum calcium and 25-hydroxyvitamin D (25-[OH]D), haemoglobin, albumin (Alb), prealbumin (PAlb) and serum magnesium. Negative correlations were found with blood urea nitrogen (BUN), serum creatinine (SCr), the estimated glomerular filtration rate (eGFR), serum phosphorus, and intact parathyroid hormone (iPTH). Serum phosphorus was positively correlated with BUN, SCr, uric acid, cystatin C (CysC), calcium-phosphate product (Ca × P), iPTH, PAlb, and serum magnesium and negatively correlated with eGFR and 25-(OH)D. Parathyroid hormone levels were positively correlated with BUN, SCr, CysC, Ca × P, Alb, and PAlb and negatively correlated with eGFR and 25-(OH)D. Logistic regression identified age, sex, and diabetes as independent risk factors for IMT, and age, dialysis vintage, and low Alb as risk factors for AAC. Significant differences in AAC were found for sex, dialysis vintage, cholesterol, high-density lipoprotein, and serum calcium levels.

Conclusion: Calcium-phosphorus metabolism plays a role in vascular calcification in CKD, with age, diabetes, dialysis vintage, lipid levels, and low Alb levels contributing to this process.

Introduction: Chronic kidney disease (CKD) is classified according to the estimated glomerular filtration rate (eGFR), but kidney volume (KV) can also provide meaningful information. Very few radiomics (RDX) studies on CKD have utilized computed tomography (CT). This study aimed to determine whether non-enhanced computed tomography (NECT)-based RDX can be useful in evaluation of patients with CKD and to compare it with KV.

Methods: The NECT scans of 64 subjects with impaired kidney function (defined as <60 mL/min/1.73 m2) and 60 controls with normal kidney function were retrospectively analyzed. Kidney segmentations, volume measurements, and RDX features extraction were performed. Machine-learning models using RDX were constructed to classify the kidneys as having structural markers of impaired or normal function.

Results: The median KV in the impaired kidney function group was 114.83 mL vs. 159.43 mL (p < 0.001) in the control group. There was a statistically significant strong positive correlation between KV and eGFR (rs = 0.579, p < 0.001) and a strong negative correlation between KV and serum creatinine level (rs = -0.514, p < 0.001). The KV-based models achieved the best area under the curve (AUC) of 0.746, whereas the RDX-based models achieved the best AUC of 0.878.

Conclusions: RDX can be useful in identifying patients with impaired kidney function on NECT. RDX-based models outperformed KV-based models. RDX has the potential to identify patients with a higher risk of CKD based on imaging, which, as we believe, can indirectly support clinical decision-making.

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.