Effects of correcting metabolic acidosis on muscle mass and functionality in chronic kidney disease:a systematic review and meta-analysis

Metabolic acidosis unfavourably influences the nutritional status of patients with non-dialysis dependent chronic kidney disease (CKD) including the loss of muscle mass and functionality, but the benefits of correction are uncertain. We investigated the effects of correcting metabolic acidosis on nutritional status in patients with CKD in a systematic review and meta-analysis. A search was conducted in MEDLINE and the Cochrane Library from inception to June 2023. Study selection, bias assessment, and data extraction were independently performed by two reviewers. The Cochrane risk of bias tool was used to assess the quality of individual studies. We applied random effects meta-analysis to obtain pooled standardized mean difference (SMD) and 95% confidence intervals (CIs). We retrieved data from 12 intervention studies including 1995 patients, with a mean age of 63.7 ± 11.7 years, a mean estimated glomerular filtration rate of 29.8 ± 8.8 mL/min per 1.73 m2, and 58% were male. Eleven studies performed an intervention with oral sodium bicarbonate compared with either placebo or with standard care and one study compared veverimer, an oral HCl-binding polymer, with placebo. The mean change in serum bicarbonate was +3.6 mEq/L in the intervention group and +0.4 mEq/L in the control group. Correcting metabolic acidosis significantly improved muscle mass assessed by mid-arm muscle circumference (SMD 0.35 [95% CI 0.16 to 0.54], P &lt; 0.001) and functionality assessed with the sit-to-stand test (SMD −0.31 [95% CI −0.52 to 0.11], P = 0.003). We found no statistically significant effects on dietary protein intake, handgrip strength, serum albumin and prealbumin concentrations, and blood urea nitrogen. Correcting metabolic acidosis in patients with CKD improves muscle mass and physical function. Correction of metabolic acidosis should be considered as part of the nutritional care for patients with CKD.</p

SCN5A Mutations in Brugada Syndrome Are Associated with Increased Cardiac Dimensions and Reduced Contractility

BACKGROUND: The cardiac sodium channel (Na(v)1.5) controls cardiac excitability. Accordingly, SCN5A mutations that result in loss-of-function of Na(v)1.5 are associated with various inherited arrhythmia syndromes that revolve around reduced cardiac excitability, most notably Brugada syndrome (BrS). Experimental studies have indicated that Na(v)1.5 interacts with the cytoskeleton and may also be involved in maintaining structural integrity of the heart. We aimed to determine whether clinical evidence may be obtained that Na(v)1.5 is involved in maintaining cardiac structural integrity. METHODS: Using cardiac magnetic resonance (CMR) imaging, we compared right ventricular (RV) and left ventricular (LV) dimensions and ejection fractions between 40 BrS patients with SCN5A mutations (SCN5a-mut-positive) and 98 BrS patients without SCN5A mutations (SCN5a-mut-negative). We also studied 18 age/sex-matched healthy volunteers. RESULTS: SCN5a-mut-positive patients had significantly larger end-diastolic and end-systolic RV and LV volumes, and lower LV ejection fractions, than SCN5a-mut-negative patients or volunteers. CONCLUSIONS: Loss-of-function SCN5A mutations are associated with dilatation and impairment in contractile function of both ventricles that can be detected by CMR analysis

Serum magnesium and the risk of death from coronary heart disease and sudden cardiac death

Background-Low serum magnesium has been implicated in cardiovascular mortality, but results are conflicting and the pathway is unclear. We studied the association of serum magnesium with coronary heart disease (CHD) mortality and sudden cardiac death (SCD) within the prospective population-based Rotterdam Study, with adjudicated end points and long-term follow-up. Methods and Results-Nine-thousand eight-hundred and twenty participants (mean age 65.1 years, 56.8% female) were included with a median follow-up of 8.7 years. We used multivariable Cox proportional hazard models and found that a 0.1 mmol/L increase in serum magnesium level was associated with a lower risk for CHD mortality (hazard ratio: 0.82, 95% CI 0.70-0.96). Furthermore, we divided serum magnesium in quartiles, with the second and third quartile combined as reference group (0.81-0.88 mmol/L). Low serum magnesium (=0.80 mmol/L) was associated with an increased risk of CHD mortality (N=431, hazard ratio: 1.36, 95% CI 1.09-1.69) and SCD (N=217, hazard ratio: 1.54, 95% CI 1.12-2.11). Low serum magnesium was associated with accelerated subclinical atherosclerosis (expressed as increased carotid intima-media thickness: +0.013 mm, 95% CI 0.005-0.020) and increased QT-interval, mainly through an effect on heart rate (RR-interval: -7.1 ms, 95% CI -13.5 to -0.8). Additional adjustments for carotid intima-media thickness and heart rate did not change the associations with CHD mortality and SCD. Conclusions-Low serum magnesium is associated with an increased risk of CHD mortality and SCD. Although low magnesium was associated with both carotid intima-media thickness and heart rate, this did not explain the relationship between serum magnesium and CHD mortality or SCD. Future studies should focus on why magnesium associates with CHD mortality and SCD and whether intervention reduces these risks

Cystic renal-epithelial derived induced pluripotent stem cells from polycystic kidney disease patients

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, leading to kidney failure in most patients. In approximately 85% of cases, the disease is caused by mutations in PKD1. How dysregulation of PKD1 leads to cyst formation on a molecular level is unknown. Induced pluripotent stem cells (iPSCs) are a powerful tool for in vitro modeling of genetic disorders. Here, we established ADPKD patient-specific iPSCs to study the function of PKD1 in kidney development and cyst formation in vitro. Somatic mutations are proposed to be the initiating event of cyst formation, and therefore iPSCs were derived from cystic renal epithelial cells rather than fibroblasts. Mutation analysis of the ADPKD iPSCs revealed germline mutations in PKD1 but no additional somatic mutations in PKD1/PKD2. Although several somatic mutations in other genes implicated in ADPKD were identified in cystic renal epithelial cells, only few of these mutations were present in iPSCs, indicating a heterogeneous mutational landscape, and possibly in vitro cell selection before and during the reprogramming process. Whole-genome DNA methylation analysis indicated that iPSCs derived from renal epithelial cells maintain a kidney-specific DNA methylation memory. In addition, comparison of PKD1+/− and control iPSCs revealed differences in DNA methylation associated with the disease history. In conclusion, we generated and characterized iPSCs derived from cystic and healthy control renal epithelial cells, which can be used for in vitro modeling of kidney development in general and cystogenesis in particular

GFAP isoforms control intermediate filament network dynamics, cell morphology, and focal adhesions

Glial fibrillary acidic protein (GFAP) is the characteristic intermediate filament (IF) protein in astrocytes. Expression of its main isoforms, GFAPα and GFAPδ, varies in astrocytes and astrocytoma implying a potential regulatory role in astrocyte physiology and pathology. An IF-network is a dynamic structure and has been functionally linked to cell motility, proliferation, and morphology. There is a constant exchange of IF-proteins with the network. To study differences in the dynamic properties of GFAPα and GFAPδ, we performed fluorescence recovery after photobleaching experiments on astrocytoma cells with fluorescently tagged GFAPs. Here, we show for the first time that the exchange of GFP–GFAPδ was significantly slower than the exchange of GFP–GFAPα with the IF-network. Furthermore, a collapsed IF-network, induced by GFAPδ expression, led to a further decrease in fluorescence recovery of both GFP–GFAPα and GFP–GFAPδ. This altered IF-network also changed cell morphology and the focal adhesion size, but did not alter cell migration or proliferation. Our study provides further insight into the modulation of the dynamic properties and functional consequences of the IF-network composition

Patient-reported outcomes in autosomal inherited bleeding disorders: A systematic literature review

AIM: Currently, it is unknown which patient-reported outcomes are important for patients with autosomal inherited bleeding disorders. Therefore, the purpose of this study is to systematically review the available literature assessing patient-reported outcomes and their measurement methods in autosomal inherited bleeding disorders. METHODS: The Embase, Medline ALL, Web of Science Core Collection, Cochrane Central Register of Controlled Trails and Google Scholar databases were searched from inception until 14 August 2020. Studies on patient-reported outcomes in patients with von Willebrand disease, inherited platelet function disorders and coagulation factor deficiencies were included. RESULTS: Twenty-one articles met the inclusion criteria. Three studies were assessed as having poor quality, and therefore a high risk of bias. Nineteen studies had fair quality rating. Different measurements methods were used, ranging from predefined to self-developed questionnaires. The majority of included studies focused on von Willebrand disease. Patients with von Willebrand disease reported lower health-related quality of life compared to the general population. Overall, this trend was especially visible in the following domains: vitality, physical and social functioning and pain. Women with inherited bleeding disorders scored lower on health-related quality of life compared to men, especially women with heavy menstrual bleeding. Patients with joint bleeds or heavy menstrual bleeding reported an increased level of pain. CONCLUSION: Patients with autosomal inherited bleeding disorders report lower health related quality of life, especially those with joint bleeds or heavy menstrual bleeding. Numerous measurement methods are used in patients with autosomal inherited bleeding disorders, highlighting the need for studies using established, standardized measurement methods

K+-induced natriuresis is preserved during Na+ depletion and accompanied by inhibition of the Na+-Cl- cotransporter

During hypovolemia and hyperkalemia, the kidneys defend homeostasis by Na+ retention and K+ secretion, respectively. Aldosterone mediates both effects, but it is unclear how the same hormone can evoke such different responses. To address this, we mimicked hypovolemia and hyperkalemia in four groups of rats with a control diet, low-Na+ diet, high-K+ diet, or combined diet. The low-Na+ and combined diets increased plasma and kidney ANG II. The low-Na+ and high-K+ diets increased plasma aldosterone to a similar degree (3-fold), whereas the combined diet increased aldosterone to a greater extent (10-fold). Despite similar Na+ intake and higher aldosterone, the high-K+ and combined diets caused a greater natriuresis than the control and low-Na+ diets, respectively (P < 0.001 for both). This K+-induced natriuresis was accompanied by a decreased abundance but not phosphorylation of the Na+-Cl- cotransporter (NCC). In contrast, the epithelial Na+ channel (ENaC) increased in parallel with aldosterone, showing the highest expression with the combined diet. The high-K+ and combined diets also incr