Brain microbleeds are increased in chronic kidney disease (CKD) and their presence increases risk of cognitive decline and stroke. We examined the interaction between CKD and brain microhemorrhages (the neuropathological substrate of microbleeds) in mouse and cell culture models and studied progression of microbleed burden on serial brain imaging from humans. Mouse studies: Two CKD models were investigated: adenine-induced tubulointerstitial nephritis and surgical 5/6 nephrectomy. Cell culture studies: bEnd.3 mouse brain endothelial cells were grown to confluence, and monolayer integrity was measured after exposure to 5-15% human uremic serum or increasing concentrations of urea. Human studies: Progression of brain microbleeds was evaluated on serial MRI from control, pre-dialysis CKD, and dialysis patients. Microhemorrhages were increased 2-2.5-fold in mice with CKD independent of higher blood pressure in the 5/6 nephrectomy model. IgG staining was increased in CKD animals, consistent with increased blood-brain barrier permeability. Incubation of bEnd.3 cells with uremic serum or elevated urea produced a dose-dependent drop in trans-endothelial electrical resistance. Elevated urea induced actin cytoskeleton derangements and decreased claudin-5 expression. In human subjects, prevalence of microbleeds was 50% in both CKD cohorts compared with 10% in agematched controls. More patients in the dialysis cohort had increased microbleeds on follow-up MRI after 1.5 years. CKD disrupts the blood-brain barrier and increases brain microhemorrhages in mice and microbleeds in humans. Elevated urea alters the actin cytoskeleton and tight junction proteins in cultured endothelial cells, suggesting that these mechanisms explain (at least in part) the microhemorrhages and microbleeds observed in the animal and human studies.
BackgroundSpirituality may influence how patients cope with their illness.ObjectivesWe assessed whether spirituality may influence adherence to management of outpatients with heart failure.MethodsCross sectional study enrolling consecutive ambulatory heart failure patients in whom adherence to multidisciplinary treatment was evaluated. Patients were assessed for quality of life, depression, religiosity and spirituality utilizing validated questionnaires. Correlations between adherence and psychosocial variables of interest were obtained. Logistic regression models explored independent predictors of adherence.ResultsOne hundred and thirty patients (age 60 ± 13 years; 67% male) were interviewed. Adequate adherence score was observed in 38.5% of the patients. Neither depression nor religiosity was correlated to adherence, when assessed separately. Interestingly, spirituality, when assessed by both total score sum (r = 0.26; p = 0.003) and by all specific domains, was positively correlated to adherence. Finally, the combination of spirituality, religiosity and personal beliefs was an independent predictor of adherence when adjusted for demographics, clinical characteristics and psychosocial instruments.ConclusionSpirituality, religiosity and personal beliefs were the only variables consistently associated with compliance to medication in a cohort of outpatients with heart failure. Our data suggest that adequately addressing these aspects on patient’s care may lead to an improvement in adherence patterns in the complex heart failure management.
Angiotensinogen (AGT) gene polymorphisms have been linked to increased risk of hypertension, but the data remain controversial. In this study we review the most commonly investigated polymorphisms at the AGT locus (other than M235T) and provide summary estimates regarding their association with essential hypertension, while addressing heterogeneity, as well as publication biases. Data on 26 818 subjects from 46 studies for the 4 most-studied AGT variants (T174M in exon 2 and 3 promoter variants: A-6G, A-20C, and G-217A) were meta-analyzed. Statistically significant associations with hypertension were identified for the T174M (odds ratio [OR]: 1.19; 95% CI: 1.07 to 1.33; P=0.002) and G-217A (OR: 1.37; 95% CI: 1.17 to 1.59; P=0.00006) polymorphisms. A dual but consistent effect was observed for the -20C allele, which was associated with a decreased risk of hypertension in populations of mixed and European ancestries (OR: 0.64; 95% CI: 0.44 to 0.92; P=0.02 and OR: 0.77; 95% CI: 0.65 to 0.91; P=0.003, respectively), but with a 24% increase in the odds of hypertension in Asian subjects (OR: 1.24; 95% CI: 1.04 to 1.48; P=0.02). No association of the A-6G variant with hypertension was detected. Current studies support the notion that single variants at the AGT might modulate the risk of hypertension but indicate caution in interpreting these results because of the putative presence of publication bias and gene-environment interactions.
Highlights The effect of LCZ696 (Sacubitril/valsartan) against cardiorenal syndrome is proposed. LCZ696 more improved CKD related heart failure than valsartan therapy alone. LCZ696 attenuated CKD related cardiac hypertrophy and fibrosis and aortic fibrosis. Effects of LCZ696 for heart are mediated by anti-inflammation and oxidative stress. LCZ696 also improved indicators of mitochondrial mass/function. AbstractBackground: Chronic kidney disease (CKD) is associated with cardiac hypertrophy, fibrosis and
Activated fibroblasts are deemed the main executors of organ fibrosis. However, regulation of the pathologic functions of these cells is poorly understood. PDGF receptor (PDGFR) is highly expressed in activated pericytes, a main source of fibroblasts. Studies using a PDGFR promoter-driven Cre system to delete v integrins in activated fibroblasts identified these integrins as core regulators of fibroblast activity across solid organs, including the kidneys. Here, we used the same PDGFR-Cre line to isolate and study renal fibroblasts We found that renal fibroblasts express threev integrins, namely v1, v3, and v5. Blockade of v1 prevented direct binding of fibroblasts to the latency-associated peptide of TGF-1 and prevented activation of the latent TGF- complex. Continuous administration of a recently described potent small molecule inhibitor of v1, compound 8, starting the day of unilateral ureteral obstruction operation, inhibited collagen deposition in the kidneys of mice 14 days later. Compound 8 also effectively attenuated renal failure, as measured by BUN levels in mice fed an adenine diet known to cause renal injury followed by fibrosis. Inhibition of v1 integrin could thus hold promise as a therapeutic intervention in CKD characterized by renal fibrosis.
Although the prevalence of Fabry disease was very low in our study (0.36%), routine screening of male hemodialysis patients would enable earlier identification of many other affected relatives in their families who might benefit from specific clinical treatment.
These findings do not support the hypothesis that the enhanced ACE activity associated with the D allele might promote a significantly worse prognosis in patients with ADPKD.
In chronic kidney disease (CKD), the gut microbiome is altered and bacterial-derived uremic toxins promote systemic inflammation and cardiovascular disease. Ferric citrate complex is a dietary phosphate binder prescribed for patients with end-stage kidney disease to treat hyperphosphatemia and secondary hyperparathyroidism. Iron is an essential nutrient in both microbes and mammals. This study was undertaken to test the hypothesis that the large iron load administered with ferric citrate in CKD may significantly change the gut microbiome. Male Sprague-Dawley rats underwent 5/6 nephrectomy to induce CKD. Normal control and CKD rats were randomized to regular chow or a 4% ferric citrate diet for 6 weeks. Fecal and cecal microbial DNA was analyzed via 16S ribosomal RNA gene sequencing on the Illumina MiSeq system. CKD rats had lower abundances of Firmicutes and Lactobacillus compared with normal rats and had lower overall gut microbial diversity. CKD rats treated with ferric citrate had improved hemoglobin and creatinine clearance and amelioration of hyperphosphatemia and hypertension. Ferric citrate treatment increased bacterial diversity in CKD rats almost to levels observed in control rats. The tryptophanase-possessing families Verrucomicrobia, Clostridiaceae, and Enterobacteriaceae were increased by ferric citrate treatment. The uremic toxins indoxyl sulfate and p-cresyl sulfate were not increased with ferric citrate treatment. Verrucomicrobia was largely represented by Akkermansia muciniphila, which has important roles in mucin degradation and gut barrier integrity. In summary, ferric citrate therapy in CKD rats was associated with significant changes in the gut microbiome and beneficial kidney and blood pressure parameters.
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