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Biomedicines Jul 2023The combination effects of smoking (SMK) and hyperuricemia (HU) on renal arteriolosclerosis in patients with IgA nephropathy remain unknown. We examined the...
The combination effects of smoking (SMK) and hyperuricemia (HU) on renal arteriolosclerosis in patients with IgA nephropathy remain unknown. We examined the cross-sectional association between smoking (current or former) and renal arteriolar hyalinosis and wall thickening with or without HU [uric acid (UA) level ≥ 7 and ≥5 mg/dL in men and women] in 87 patients with IgA nephropathy who underwent renal biopsy. Arteriolar hyalinosis and wall thickening were assessed by the semiquantitative grading of arterioles. The SMK/HU subgroup showed the highest indices for hyalinosis and wall thickening, followed by the non-SMK/HU, SMK/non-HU, and non-SMK/non-HU subgroups. Multiple logistic analysis showed that SMK/HU, but not SMK/non-HU, was significantly associated with an increased risk of higher-grade renal arteriolar wall thickening. However, this did not occur with hyalinosis compared to non-SMK/non-HU. The adjusted odds ratio (95% confidence interval, value) for SMK/HU was 12.8 (1.36-119, < 0.05) for wall thickening. An association between SMK and renal arteriolar wall thickening might be prevalent only among patients with HU and in patients with IgA nephropathy. Further prospective studies are needed to determine whether patients with HU and SMK history exhibit rapid eGFR deterioration.
PubMed: 37509692
DOI: 10.3390/biomedicines11072053 -
Molecular Medicine Reports Apr 2021Hypertensive nephropathy is the most common complication of hypertension, and is one of the main causes of end‑stage renal disease (ESRD) in numerous countries. The... (Review)
Review
Hypertensive nephropathy is the most common complication of hypertension, and is one of the main causes of end‑stage renal disease (ESRD) in numerous countries. The basic pathological feature of hypertensive nephropathy is arteriolosclerosis followed by renal parenchymal damage. The etiology of this disease is complex, and its pathogenesis is mainly associated with renal hemodynamic changes and vascular remodeling. Despite the increased knowledge on the pathogenesis of hypertensive nephropathy, the current clinical treatment methods are still not effective in preventing the development of the disease to ESRD. Herbal medicine, which is used to relieve symptoms, can improve hypertensive nephropathy through multiple targets. Since there are few clinical studies on the treatment of hypertensive nephropathy with herbal medicine, this article aims to review the progress on the basic research on the treatment of hypertensive nephropathy with herbal medicine, including regulation of the renin angiotensin system, inhibition of sympathetic excitation, antioxidant stress and anti‑inflammatory protection of endothelial cells, and improvement of obesity‑associated factors. Herbal medicine with different components plays a synergistic and multi‑target role in the treatment of hypertensive nephropathy. The description of the mechanism of herbal medicine in the treatment of hypertensive nephropathy will contribute towards the progress of modern medicine.
Topics: Antihypertensive Agents; Hemodynamics; Herbal Medicine; Humans; Hypertension, Renal; Kidney Failure, Chronic; Nephritis; Oxidative Stress
PubMed: 33537809
DOI: 10.3892/mmr.2021.11873 -
Scientific Reports Nov 2022A practical research method integrating data-driven machine learning with conventional model-driven statistics is sought after in medicine. Although glomerular...
A practical research method integrating data-driven machine learning with conventional model-driven statistics is sought after in medicine. Although glomerular hypertrophy (or a large renal corpuscle) on renal biopsy has pathophysiological implications, it is often misdiagnosed as adaptive/compensatory hypertrophy. Using a generative machine learning method, we aimed to explore the factors associated with a maximal glomerular diameter of ≥ 242.3 μm. Using the frequency-of-usage variable ranking in generative models, we defined the machine learning scores with symbolic regression via genetic programming (SR via GP). We compared important variables selected by SR with those selected by a point-biserial correlation coefficient using multivariable logistic and linear regressions to validate discriminatory ability, goodness-of-fit, and collinearity. Body mass index, complement component C3, serum total protein, arteriolosclerosis, C-reactive protein, and the Oxford E1 score were ranked among the top 10 variables with high machine learning scores using SR via GP, while the estimated glomerular filtration rate was ranked 46 among the 60 variables. In multivariable analyses, the R value was higher (0.61 vs. 0.45), and the corrected Akaike Information Criterion value was lower (402.7 vs. 417.2) with variables selected with SR than those selected with point-biserial r. There were two variables with variance inflation factors higher than 5 in those using point-biserial r and none in SR. Data-driven machine learning models may be useful in identifying significant and insignificant correlated factors. Our method may be generalized to other medical research due to the procedural simplicity of using top-ranked variables selected by machine learning.
Topics: Humans; Machine Learning; Glomerular Filtration Rate; Nephrectomy; Linear Models; Hypertrophy
PubMed: 36351996
DOI: 10.1038/s41598-022-23882-7 -
Acta Neuropathologica Mar 2022Emerging evidence suggests that small vessel disease (SVD) is a risk factor for clinical dementia and may contribute to AD neuropathological changes. Watershed brain...
Emerging evidence suggests that small vessel disease (SVD) is a risk factor for clinical dementia and may contribute to AD neuropathological changes. Watershed brain regions are located at the most distal areas between arterial territories, making them vulnerable to SVD-related changes. We examined the association of pathologic markers of SVD, specifically arteriolosclerosis in watershed brain regions, with AD pathologic changes. Participants (N = 982; mean age-at-death = 90; 69% women) were enrolled as part of one of two cohort studies of aging and dementia. At autopsy, neuropathological evaluation included semi-quantitative grading of arteriolosclerosis pathology from 2 cortical watershed regions: the anterior watershed (AWS) and posterior watershed (PWS), densities for cortical β-amyloid and tau-tangle pathology, and other common age-related pathologies. Linear regression models examined the association of watershed arteriolosclerosis pathology with β-amyloid and tau-tangle burden. In follow-up analyses, available ex-vivo MRI and proteomics data in a subset of decedents were leveraged to examine the association of whole brain measure of WMH, as a presumed MRI marker of SVD, with β-amyloid and tau-tangle burden, as well as to examine the association of watershed arteriolosclerosis with proteomic tau. Watershed arteriolosclerosis was common, with 45% of older persons having moderate-to-severe arteriolosclerosis pathology in the AWS region, and 35% in the PWS. In fully adjusted models that controlled for demographics and common age-related pathologies, an increase in severity of PWS arteriolosclerosis was associated with a higher burden of tau-tangle burden, specifically neocortical tau burden, but not with β-amyloid. AWS arteriolosclerosis was not associated with β-amyloid or tau pathology. Ex-vivo WMH was associated with greater tau-tangle pathology burden but not β-amyloid. Furthermore, PWS arteriolosclerosis was associated with higher abundance of tau phosphopeptides, that promote formation of tau aggregates. These data provide compelling evidence that SVD, specifically posterior watershed arteriolosclerosis pathology, is linked with tau pathological changes in the aging brain.
Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Brain; Female; Humans; Male; Proteomics; tau Proteins
PubMed: 35044500
DOI: 10.1007/s00401-021-02397-x -
The American Journal of Pathology Nov 2021Alzheimer disease (AD) is the most common cause of dementia. Biological definitions of AD are limited to the cerebral burden of amyloid β plaques, neurofibrillary... (Review)
Review
Alzheimer disease (AD) is the most common cause of dementia. Biological definitions of AD are limited to the cerebral burden of amyloid β plaques, neurofibrillary pathology, and neurodegeneration. However, current evidence suggests that various features of small vessel disease (SVD) are part of and covertly modify both sporadic and familial AD. Neuroimaging studies suggest that white matter hyperintensities explained by vascular mechanisms occurs frequently in the AD spectrum. Recent advances have further emphasized that frontal periventricular and posterior white matter hyperintensities are associated with cerebral amyloid angiopathy in familial AD. Although whether SVD markers precede the classically recognized biomarkers of disease is debatable, post-mortem studies show that SVD pathology incorporating small cortical and subcortical infarcts, microinfarcts, microbleeds, perivascular spacing, and white matter attenuation is commonly found in sporadic as well as in mutation carriers with confirmed familial AD. Age-related cerebral vessel pathologies such as arteriolosclerosis and cerebral amyloid angiopathy modify progression or worsen risk by shifting the threshold for cognitive impairment and AD dementia. The incorporation of SVD as a biomarker is warranted in the biological definition of AD. Therapeutic interventions directly reducing the burden of brain amyloid β have had no major impact on the disease or delaying cognitive deterioration, but lowering the risk of vascular disease seems the only rational approach to tackle both early- and late-onset AD dementia.
Topics: Alzheimer Disease; Cerebral Small Vessel Diseases; Humans
PubMed: 34331941
DOI: 10.1016/j.ajpath.2021.07.004 -
Journal of Stroke and Cerebrovascular... Jun 2024Brain arterial diseases, including atherosclerosis, vasculitis, and dissections, are major contributors to cerebrovascular morbidity and mortality worldwide. These... (Review)
Review
INTRODUCTION
Brain arterial diseases, including atherosclerosis, vasculitis, and dissections, are major contributors to cerebrovascular morbidity and mortality worldwide. These diseases not only increase the risk of stroke but also play a significant role in neurodegeneration and dementia. Clear and unambiguous terminology and classification of brain arterial disease phenotypes is crucial for research and clinical practice.
MATERIAL AND METHODS
This review aims to summarize and harmonize the terminology used for brain large and small arterial phenotypes based on pathology studies and relate them to imaging phenotypes used in medical research and clinical practice.
CONCLUSIONS AND RESULTS
Arteriosclerosis refers to hardening of the arteries but does not specify the underlying etiology. Specific terms such as atherosclerosis, calcification, or non-atherosclerotic fibroplasia are preferred. Atherosclerosis is defined pathologically by an atheroma. Other brain arterial pathologies occur and should be distinguished from atherosclerosis given therapeutic implications. On brain imaging, intracranial arterial luminal stenosis is usually attributed to atherosclerosis in the presence of atherosclerotic risk factors but advanced high-resolution arterial wall imaging has the potential to more accurately identify the underlying pathology. Regarding small vessel disease, arteriosclerosis is ambiguous and arteriolosclerosis is often used to denote the involvement of arterioles rather than arteries. Lipohyalinosis is sometimes used synonymously with arteriolosclerosis, but less accurately describes this common small vessel thickening which uncommonly shows lipid. Specific measures of small vessel wall thickness, the relationship to the lumen as well as changes in the layer composition might convey objective, measurable data regarding the status of brain small vessels.
Topics: Humans; Cerebral Angiography; Cerebral Arteries; Cerebral Small Vessel Diseases; Intracranial Arteriosclerosis; Phenotype; Predictive Value of Tests; Prognosis; Risk Factors; Terminology as Topic
PubMed: 38395095
DOI: 10.1016/j.jstrokecerebrovasdis.2024.107642 -
Journal of Neuropathology and... Feb 2022Cerebral small vessel disease (SVD) causes lacunar stroke and vascular cognitive impairment in older people. The pathogenic pathways from vessel pathology to parenchymal...
Cerebral small vessel disease (SVD) causes lacunar stroke and vascular cognitive impairment in older people. The pathogenic pathways from vessel pathology to parenchymal damage in SVD are unknown. Neurofilaments are axonal structural proteins. Neurofilament-light (NfL) is an emerging biomarker for neurological disease. Here, we examined the high molecular weight form neurofilament-heavy (NfH) and quantified a characteristic pattern of peri-arterial (vasculocentric) NfH labeling. Subcortical frontal and parietal white matter from young adult controls, aged controls, and older people with SVD or severe Alzheimer disease (n = 52) was immunohistochemically labeled for hyperphosphorylated NfH (pNfH). The extent of pNfH immunolabeling and the degree of vasculocentric axonal pNfH were quantified. Axonal pNfH immunolabeling was sparse in young adults but a common finding in older persons (controls, SVD, or AD). Axonal pNfH was often markedly concentrated around small penetrating arteries. This vasculocentric feature was more common in older people with SVD than in those with severe AD (p = 0.004). We conclude that axonal pNfH is a feature of subcortical white matter in aged brains. Vasculocentric axonal pNfH is a novel parenchymal lesion that is co-located with SVD arteriopathy and could be a consequence of vessel pathology.
Topics: Aged; Aged, 80 and over; Biomarkers; Brain; Cerebral Small Vessel Diseases; Humans; Intermediate Filaments; White Matter
PubMed: 35086142
DOI: 10.1093/jnen/nlab134 -
Acta Neuropathologica Communications Aug 2023Cerebrovascular pathologies other than frank infarctions are commonly seen in aged brains. Here, we focus on multi-lumen vascular profiles (MVPs), which are...
Cerebrovascular pathologies other than frank infarctions are commonly seen in aged brains. Here, we focus on multi-lumen vascular profiles (MVPs), which are characterized by multiple vessel lumens enclosed in a single vascular channel. Little information exists on the prevalence, risk factors, and co-pathologies of MVPs. Therefore, we used samples and data from the University of Kentucky Alzheimer's Disease Research Center (n = 91), the University of Kentucky Pathology Department (n = 31), and the University of Pittsburgh Pathology Department (n = 4) to study MVPs. Age at death was correlated with MVP density in the frontal neocortex, Brodmann Area 9 (r = 0.51; p < 0.0001). Exploratory analyses were performed to evaluate the association between conventional vascular risk factors (e.g., hypertension, diabetes), cardiovascular diseases (e.g., heart attack, arrhythmia), and cerebrovascular disease (e.g., stroke); the only nominal association with MVP density was a self-reported history of brain trauma (Prevalence Ratio = 2.1; 95 CI 1.1-3.9, before correcting for multiple comparisons). No specific associations were detected between neuropathological (e.g., brain arteriolosclerosis) or genetic (e.g., APOE) variables and MVP density. Using a tissue clearing method called SeeDB, we provide 3-dimensional images of MVPs in brain tissue. We conclude that MVPs are an age-related brain pathology and more work is required to identify their clinical-pathological correlation and associated risk factors.
Topics: Humans; Aged; Brain; Neuropathology; Stroke; Brain Injuries, Traumatic; Aging
PubMed: 37641147
DOI: 10.1186/s40478-023-01638-2 -
Life Sciences Nov 2019The prevalence of dementia worldwide is growing at an alarming rate. A number of studies and meta-analyses have provided evidence for increased risk of dementia in... (Review)
Review
The prevalence of dementia worldwide is growing at an alarming rate. A number of studies and meta-analyses have provided evidence for increased risk of dementia in patients with metabolic syndrome (MS) as compared to persons without MS. However, there are some reports demonstrating a lack of association between MS and increased dementia risk. In this review, taking into account the potential role of individual MS components in the pathogenesis of MS-related cognitive dysfunction, we considered the underlying mechanisms in arterial hypertension, diabetes mellitus, dyslipidemia, and obesity. The pathogenesis of dementia in MS is multifactorial, involving both vascular injury and non-ischemic neuronal death due to neurodegeneration. Neurodegenerative and ischemic lesions do not simply coexist in the brain due to independent evolution, but rather exacerbate each other, leading to more severe consequences for cognition than would either pathology alone. In addition to universal mechanisms of cognitive dysfunction shared by all MS components, other pathogenetic pathways leading to cognitive deficits and dementia, which are specific for each component, also play a role. Examples of such component-specific pathogenetic pathways include central insulin resistance and hypoglycemia in diabetes, neuroinflammation and adipokine imbalance in obesity, as well as arteriolosclerosis and lipohyalinosis in arterial hypertension. A more detailed understanding of cognitive disorders based on the recognition of underlying molecular mechanisms will aid in the development of new methods for prevention and treatment of devastating cognitive problems in MS.
Topics: Animals; Cognition Disorders; Dementia; Humans; Metabolic Syndrome; Risk Factors; Signal Transduction
PubMed: 31606384
DOI: 10.1016/j.lfs.2019.116932 -
Kidney International Reports Jun 2022Arteriolar microangiopathic (MA) lesions are independent risk factors for IgA nephropathy (IgAN) patient prognosis, and the underlying mechanism remains to be...
INTRODUCTION
Arteriolar microangiopathic (MA) lesions are independent risk factors for IgA nephropathy (IgAN) patient prognosis, and the underlying mechanism remains to be elucidated. The complement plays an important role in IgAN and thrombotic microangiopathy; however, its role in MA lesions in IgAN remains unclear.
METHODS
Immunohistochemistry was performed to detect arteriolar complement deposition. Enzyme-linked immunosorbent assay (ELISA) and whole-exome sequencing were performed to explore possible mechanism.
RESULTS
In this study, we found that patients with IgAN with MA lesions have more complement deposition, especially C4d, on renal arterioles than those in patients with arteriolosclerosis (AS) and patients with no vascular lesions (100% vs. 53% vs 14%, < 0.05). Furthermore, our large prospective cohort demonstrated that patients with IgAN with MA lesions had higher levels of Gd-IgA1 (median: 326.98 U/ml, interquartile range 303.46-370.5 vs. 319.22, 292.01-347.3 vs. 321.95, 291.68-350.68, = 0.014) and C3a (122.57 ± 42.07 vs. 93.79 ± 29.49 vs. 93.51 ± 45.87 ng/ml, = 0.01) than those in patients with AS and those with no vascular lesions. However, serum IgA1 and C3 levels were not significantly different. Finally, through whole-exome sequencing, we found that nearly half of the patients with MA lesions had rare genetic variations in complement-related genes.
CONCLUSION
Our results indicate that the complement is involved in the development of MA lesions in IgAN, which might be associated with the circulating complex containing Gd-IgA1.
PubMed: 35685318
DOI: 10.1016/j.ekir.2022.03.028