MAFLD and CKD: An Updated Narrative Review

Accumulating evidence now indicates that non-alcoholic fatty liver disease (NAFLD), which is the most common chronic liver disease observed in clinical practice worldwide, is independently associated with an increased risk of incident chronic kidney disease (CKD). Given that NAFLD is linked to insulin resistance, obesity and type 2 diabetes mellitus, an international panel of experts have recently proposed a name change from NAFLD to metabolic associated fatty liver disease (MAFLD). Since the diagnostic criteria for NAFLD and MAFLD are different, observational studies assessing the potential concordance (or even superiority) of MAFLD, compared with NAFLD, in detecting patients at increased risk of hepatic and extra-hepatic complications (including CKD) are required. Hence, in the last two years, some observational studies have investigated the potential relationship between MAFLD and CKD. The result is that, at present, evidence regarding the concordance or even superiority of MAFLD, compared with NAFLD, in detecting patients at higher risk of CKD is still preliminary, although some data indicate that MAFLD identifies patients with CKD as accurately as NAFLD. In this narrative review, we will discuss: (a) the epidemiological evidence assessing the association between NAFLD and risk of incident CKD, (b) the epidemiological data investigating the association between MAFLD and risk of CKD and (c) the biological mechanisms underlying the association between NAFLD/MAFLD and CKD.     

Vitamin D and Ocular Diseases: A Systematic Review

The contributory roles of vitamin D in ocular and visual health have long been discussed, with numerous studies pointing to the adverse effects of vitamin D deficiency. In this paper, we provide a systematic review of recent findings on the association between vitamin D and different ocular diseases, including myopia, age-related macular degeneration (AMD), glaucoma, diabetic retinopathy (DR), dry eye syndrome (DES), thyroid eye disease (TED), uveitis, retinoblastoma (RB), cataract, and others, from epidemiological, clinical and basic studies, and briefly discuss vitamin D metabolism in the eye. We searched two research databases for articles examining the association between vitamin D deficiency and different ocular diseases. One hundred and sixty-two studies were found. There is evidence on the association between vitamin D and myopia, AMD, DR, and DES. Overall, 17 out of 27 studies reported an association between vitamin D and AMD, while 48 out of 54 studies reported that vitamin D was associated with DR, and 25 out of 27 studies reported an association between vitamin D and DES. However, the available evidence for the association with other ocular diseases, such as glaucoma, TED, and RB, remains limited.     

Role of Vitamin K in Chronic Kidney Disease: A Focus on Bone and Cardiovascular Health

Chronic kidney disease (CKD) is commonly associated with vitamin K deficiency. Some of the serious complications of CKD are represented by cardiovascular disease (CVD) and skeletal fragility with an increased risk of morbidity and mortality. A complex pathogenetic link between hormonal and ionic disturbances, bone tissue and metabolism alterations, and vascular calcification (VC) exists and has been defined as chronic kidney disease–mineral and bone disorder (CKD-MBD). Poor vitamin K status seems to have a key role in the progression of CKD, but also in the onset and advance of both bone and cardiovascular complications. Three forms of vitamin K are currently known: vitamin K1 (phylloquinone), vitamin K2 (menaquinone), and vitamin K3 (menadione). Vitamin K plays different roles, including in activating vitamin K-dependent proteins (VKDPs) and in modulating bone metabolism and contributing to the inhibition of VC. This review focuses on the biochemical and functional characteristics of vitamin K vitamers, suggesting this nutrient as a possible marker of kidney, CV, and bone damage in the CKD population and exploring its potential use for promoting health in this clinical setting. Treatment strategies for CKD-associated osteoporosis and CV disease should include vitamin K supplementation. However, further randomized clinical studies are needed to assess the safety and the adequate dosage to prevent these CKD complications.     

The Role of Vitamin D and Vitamin D Binding Protein in Chronic Liver Diseases

Vitamin D (calciferol) is a fat-soluble vitamin that has a significant role in phospho-calcium metabolism, maintaining normal calcium levels and bone health development. The most important compounds of vitamin D are cholecalciferol (vitamin D3, or VD3) and ergocalciferol (vitamin D2, or VD2). Besides its major role in maintaining an adequate level of calcium and phosphate concentrations, vitamin D is involved in cell growth and differentiation and immune function. Recently, the association between vitamin D deficiency and the progression of fibrosis in chronic liver disease (CLD) was confirmed, given the hepatic activation process and high prevalence of vitamin D deficiency in these diseases. There are reports of vitamin D deficiency in CLD regardless of the etiology (chronic viral hepatitis, alcoholic cirrhosis, non-alcoholic fatty liver disease, primary biliary cirrhosis, or autoimmune hepatitis). Vitamin D binding protein (VDBP) is synthesized by the liver and has the role of binding and transporting vitamin D and its metabolites to the target organs. VDBP also plays an important role in inflammatory response secondary to tissue damage, being involved in the degradation of actin. As intense research during the last decades revealed the possible role of vitamin D in liver diseases, a deeper understanding of the vitamin D, vitamin D receptors (VDRs), and VDBP involvement in liver inflammation and fibrogenesis could represent the basis for the development of new strategies for diagnosis, prognosis, and treatment of liver diseases. This narrative review presents an overview of the evidence of the role of vitamin D and VDBP in CLD, both at the experimental and clinical levels.     

Label-Free Quantitative Proteomics Reveals Differences in Molecular Mechanism of Atherosclerosis Related and Non-Related to Chronic Kidney Disease

The major cause of mortality in patients with chronic kidney disease (CKD) is atherosclerosis related to traditional and non-traditional risk factors. However, the understanding of the molecular specificity that distinguishes the risk factors for classical cardiovascular disease (CVD) and CKD-related atherosclerosis (CKD-A) is far from complete. In this study we investigated the disease-related differences in the proteomes of patients with atherosclerosis related and non-related to CKD. Plasma collected from patients in various stages of CKD, CVD patients without symptoms of kidney dysfunction, and healthy volunteers (HVs), were analyzed by a coupled label-free and mass spectrometry approach. Dysregulated proteins were confirmed by an enzyme-linked immunosorbent assay (ELISA). All proteomic data were correlated with kidney disease development and were subjected to bioinformatics analysis. One hundred sixty-two differentially expressed proteins were identified. By directly comparing the plasma proteomes from HVs, CKD, and CVD patients in one study, we demonstrated that proteins involved in inflammation, blood coagulation, oxidative stress, vascular damage, and calcification process exhibited greater alterations in patients with atherosclerosis related with CKD. These data indicate that the above nontraditional risk factors are strongly specific for CKD-A and appear to be less essential for the development of “classical” CVD.     

HDL Cholesterol and Non-Cardiovascular Disease: A Narrative Review

High density lipoprotein (HDL) cholesterol has traditionally been considered the “good cholesterol”, and most of the research regarding HDL cholesterol has for decades revolved around the possible role of HDL in atherosclerosis and its therapeutic potential within atherosclerotic cardiovascular disease. Randomized trials aiming at increasing HDL cholesterol have, however, failed and left questions to what role HDL cholesterol plays in human health and disease. Recent observational studies involving non-cardiovascular diseases have shown that high levels of HDL cholesterol are not necessarily associated with beneficial outcomes as observed for age-related macular degeneration, type II diabetes, dementia, infection, and mortality. In this narrative review, we discuss these interesting associations between HDL cholesterol and non-cardiovascular diseases, covering observational studies, human genetics, and plausible mechanisms.     

Nature versus Number: Monocytes in Cardiovascular Disease

Monocytes play a key role in cardiovascular disease (CVD) as their influx into the vessel wall is necessary for the development of an atherosclerotic plaque. Monocytes are, however, heterogeneous differentiating from classical monocytes through the intermediate subset to the nonclassical subset. While it is recognized that the percentage of intermediate and nonclassical monocytes are higher in individuals with CVD, accompanying changes in inflammatory markers suggest a functional impact on disease development that goes beyond the increased proportion of these ‘inflammatory’ monocyte subsets. Furthermore, emerging evidence indicates that changes in monocyte proportion and function arise in dyslipidemia, with lipid lowering medication having some effect on reversing these changes. This review explores the nature and number of monocyte subsets in CVD addressing what they are, when they arise, the effect of lipid lowering treatment, and the possible implications for plaque development. Understanding these associations will deepen our understanding of the clinical significance of monocytes in CVD.     

From Diabetes to Atherosclerosis: Potential of Metformin for Management of Cardiovascular Disease

Atherosclerosis is a common cause of cardiovascular disease, which, in turn, is often fatal. Today, we know a lot about the pathogenesis of atherosclerosis. However, the main knowledge is that the disease is extremely complicated. The development of atherosclerosis is associated with more than one molecular mechanism, each making a significant contribution. These mechanisms include endothelial dysfunction, inflammation, mitochondrial dysfunction, oxidative stress, and lipid metabolism disorders. This complexity inevitably leads to difficulties in treatment and prevention. One of the possible therapeutic options for atherosclerosis and its consequences may be metformin, which has already proven itself in the treatment of diabetes. Both diabetes and atherosclerosis are complex metabolic diseases, the pathogenesis of which involves many different mechanisms, including those common to both diseases. This makes metformin a suitable candidate for investigating its efficacy in cardiovascular disease. In this review, we highlight aspects such as the mechanisms of action and targets of metformin, in addition to summarizing the available data from clinical trials on the effective reduction of cardiovascular risks.     

Fibrinogen and Atherosclerotic Cardiovascular Diseases—Review of the Literature and Clinical Studies

Atherosclerotic cardiovascular diseases (ASCVD), including coronary artery disease, cerebrovascular disease, and peripheral arterial disease, represent a significant cause of premature death worldwide. Biomarkers, the evaluation of which would allow the detection of ASCVD at the earliest stage of development, are intensively sought. Moreover, from a clinical point of view, a valuable biomarker should also enable the assessment of the patient’s prognosis. It has been known for many years that the concentration of fibrinogen in plasma increases, inter alia, in patients with ASCVD. On the one hand, an increased plasma fibrinogen concentration may be the cause of the development of atherosclerotic lesions (increased risk of atherothrombosis); on the other hand, it may be a biomarker of ASCVD, as it is an acute phase protein. In addition, a number of genetic polymorphisms and post-translational modifications of fibrinogen were demonstrated that may contribute to the risk of ASCVD. This review summarizes the current data on the importance of fibrinogen as a biomarker of ASCVD, and also presents the relationship between molecular modifications of this protein in the context of ASCVD.     

Vitamin D-Related Genes and Thyroid Cancer—A Systematic Review

Vitamin D, formerly known for its role in calcium-phosphorus homeostasis, was shown to exert a broad influence on immunity and on differentiation and proliferation processes in the last few years. In the field of endocrinology, there is proof of the potential role of vitamin D and vitamin D-related genes in the pathogenesis of thyroid cancer—the most prevalent endocrine malignancy. Therefore, the study aimed to systematically review the publications on the association between vitamin D-related gene variants (polymorphisms, mutations, etc.) and thyroid cancer. PubMed, EMBASE, Scopus, and Web of Science electronic databases were searched for relevant studies. A total of ten studies were found that met the inclusion criteria. Six vitamin D-related genes were analyzed (VDR—vitamin D receptor, CYP2R1—cytochrome P450 family 2 subfamily R member 1, CYP24A1—cytochrome P450 family 24 subfamily A member 1, CYP27B1—cytochrome P450 family 27 subfamily B member 1, DHCR7—7-dehydrocholesterol reductase and CUBN—cubilin). Moreover, a meta-analysis was conducted to summarize the data from the studies on VDR polymorphisms (rs2228570/FokI, rs1544410/BsmI, rs7975232/ApaI and rs731236/TaqI). Some associations between thyroid cancer risk (VDR, CYP24A1, DHCR7) or the clinical course of the disease (VDR) and vitamin D-related gene polymorphisms were described in the literature. However, these results seem inconclusive and need validation. A meta-analysis of the five studies of common VDR polymorphisms did not confirm their association with increased susceptibility to differentiated thyroid cancer. Further efforts are necessary to improve our understanding of thyroid cancer pathogenesis and implement targeted therapies for refractory cases.     

Vitamin D Deficiency and Gender Alter Vasoconstrictor and Vasodilator Reactivity in Rat Carotid Artery

The vitamin-D-sensitivity of the cardiovascular system may show gender differences. The prevalence of vitamin D (VD) deficiency (VDD) is high, and it alters cardiovascular function and increases the risk of stroke. Our aim was to investigate the vascular reactivity and histological changes of isolated carotid artery of female and male rats in response to different VD supplies. A total of 48 male and female Wistar rats were divided into four groups: female VD supplemented, female VDD, male VD supplemented, male VDD. The vascular function of isolated carotid artery segments was examined by wire myography. Both vitamin D deficiency and male gender resulted in increased phenylephrine-induced contraction. Acetylcholine-induced relaxation decreased in male rats independently from VD status. Inhibition of prostanoid signaling by indomethacin reduced contraction in females, but increased relaxation ability in male rats. Functional changes were accompanied by VDD and gender-specific histological alterations. Elastic fiber density was significantly decreased by VDD in female rats, but not in males. Smooth muscle actin and endothelial nitric oxide synthase levels were significantly lowered, but the thromboxane receptor was elevated in VDD males. Decreased nitrative stress was detected in both male groups independently from VD supply. The observed interactions between vitamin D deficiency and sex may play a role in the gender difference of cardiovascular risk.     

The Effects of Vitamin D Supplementation in COVID-19 Patients: A Systematic Review

Vitamin D has an immune-modulating effect on respiratory tract infections. For this reason, it has been proposed as part of the treatment in COVID-19. Furthermore, vitamin D deficiency has been associated with worse clinical outcomes of this disease. The aim of this systematic review was to determine whether vitamin D supplementation modifies the disease course. Therefore, eleven studies involving randomised clinical trials are analysed, in which groups of COVID-19 patients with or without vitamin D supplementation as part of the treatment are compared. A control group was treated with best available therapy, and in some of the clinical trials, also with a placebo. According to the outcomes, it seems that patients benefit from receiving a daily or maintained in time vitamin D dose regardless of vitamin D serum levels at the beginning of the trial. The administration of a single vitamin D dose does not seem to have any effect on the health status of these patients. However, the outcomes are heterogeneous and larger clinical trials are necessary.     

Chronic Hyperkaliemia in Chronic Kidney Disease: An Old Concern with New Answers

Increasing potassium intake ameliorates blood pressure (BP) and cardiovascular (CV) prognoses in the general population; therefore the World Health Organization recommends a high-potassium diet (90–120 mEq/day). Hyperkalaemia is a rare condition in healthy individuals due to the ability of the kidneys to effectively excrete dietary potassium load in urine, while an increase in serum K⁺ is prevalent in patients with chronic kidney disease (CKD). Hyperkalaemia prevalence increases in more advanced CKD stages, and is associated with a poor prognosis. This scenario generates controversy on the correct nutritional approach to hyperkalaemia in CKD patients, considering the unproven link between potassium intake and serum K⁺ levels. Another concern is that drug-induced hyperkalaemia leads to the down-titration or withdrawal of renin-angiotensin system inhibitors (RASI) and mineralocorticoids receptors antagonists (MRA) in patients with CKD, depriving these patients of central therapeutic interventions aimed at delaying CKD progression and decreasing CV mortality. The new K⁺-binder drugs (Patiromer and Sodium-Zirconium Cyclosilicate) have proven to be adequate and safe therapeutic options to control serum K⁺ in CKD patients, enabling RASI and MRA therapy, and possibly, a more liberal intake of fruit and vegetables.     

Molecular Biological and Clinical Understanding of the Pathophysiology and Treatments of Hyperuricemia and Its Association with Metabolic Syndrome,Cardiovascular Diseases and Chronic Kidney Disease

Uric acid (UA) is synthesized mainly in the liver, intestines, and vascular endothelium as the end product of an exogenous purine from food and endogenously from damaged, dying, and dead cells. The kidney plays a dominant role in UA excretion, and the kidney excretes approximately 70% of daily produced UA; the remaining 30% of UA is excreted from the intestine. When UA production exceeds UA excretion, hyperuricemia occurs. Hyperuricemia is significantly associated with the development and severity of the metabolic syndrome. The increased urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) expression, and glycolytic disturbances due to insulin resistance may be associated with the development of hyperuricemia in metabolic syndrome. Hyperuricemia was previously thought to be simply the cause of gout and gouty arthritis. Further, the hyperuricemia observed in patients with renal diseases was considered to be caused by UA underexcretion due to renal failure, and was not considered as an aggressive treatment target. The evidences obtained by basic science suggests a pathogenic role of hyperuricemia in the development of chronic kidney disease (CKD) and cardiovascular diseases (CVD), by inducing inflammation, endothelial dysfunction, proliferation of vascular smooth muscle cells, and activation of the renin-angiotensin system. Further, clinical evidences suggest that hyperuricemia is associated with the development of CVD and CKD. Further, accumulated data suggested that the UA-lowering treatments slower the progression of such diseases.     

Vitamin D-Related Single Nucleotide Polymorphisms as Risk Biomarker of Cardiovascular Disease

Cardiovascular diseases (CVDs) are a group of disorders of the heart and blood vessels. In addition to environmental risk factors, genetic predisposition increases the risk; this includes alterations in the vitamin D receptor gene (VDR). These alterations play a key role in modifying vitamin D uptake, being able to modify its function and increasing susceptibility to cardiovascular disorders. The aim of this study was to evaluate the association of polymorphisms in the VDR gene and risk of CVD in a Caucasian population. A retrospective case-control study was conducted comprising 246 CVD patients and 246 controls of Caucasian origin from Southern Spain. The genetic polymorphisms BsmI (rs1544410), TaqI (rs731236), ApaI (rs7975232), FokI (rs2228570) and Cdx2 (rs11568820) were determined by means of real-time polymerase chain reaction (PCR) for allelic discrimination using TaqMan^® probes. The logistic regression analysis adjusted for body mass index and diabetes revealed that the TT genotype was associated with a higher risk of CVD in both the genotypic model (p = 0.0430; OR = 2.30; 95% CI = 1.06–5.37; TT vs. CC) and the recessive model (p = 0.0099; OR = 2.71; 95% CI = 1.31–6.07; TT vs. C). Haplotype analysis revealed that the haplotype GAC (p = 0.047; OR = 0.34; 95% CI = 0.12–0.98) was associated with increased risk of CVD. The VDR polymorphisms FokI (rs2228570) was significantly associated with the development of CVD. No influence was observed of the VDR polymorphisms BsmI (rs1544410), TaqI (rs731236), ApaI (rs7975232) and Cdx2 (rs11568820) on the risk of developing CVD in the patients studied.     

Vitamin D Deficiency in Testicular Cancer Survivors: A Systematic Review

Testicular cancer (TC) is the most frequent tumor in young males. In the vast majority of cases, it is a curable disease; therefore, very often patients experience a long survival, also due to their young age at diagnosis. In the last decades, the role of the vitamin D deficiency related to orchiectomy has become an increasingly debated topic. Indeed, vitamin D is essential in bone metabolism and many other metabolic pathways, so its deficiency could lead to various metabolic disorders especially in long-term TC survivors. In our article, we report data from studies that evaluated the incidence of hypovitaminosis D in TC survivors compared with cohorts of healthy peers and we discuss molecular mechanisms and clinical implications.     

A Narrative Review of Current Understanding of the Pathophysiology of Polycystic Ovary Syndrome: Focus on Plausible Relevance of Vitamin D

Polycystic ovarian syndrome (PCOS) is the most prevalent endocrinopathy of reproductive years. Salient features in presentation of patients PCOS include menstrual dysfunction, hyperandrogenism and/or polycystic appearance of ovaries on ultrasound. While the diagnosis of PCOS depends on presence of specified criteria, misdiagnoses are common. Despite years of extensive research, the exact aetiology of PCOS remains largely unknown. In the past decade, apart from insulin resistance and hyperandrogenemia, anti-mullerian hormone (AMH), an important marker of ovarian reserve, and vascular endothelial growth factor (VEGF), a crucial factor in angiogenesis, have been examined as plausible players of causative relevance for PCOS. Vitamin D, a sex-steroid hormone that is universally known for its relevance for skeletal health, has received increasing attention due to growing evidence supporting its pivotal in reproductive physiology and in PCOS. In this review we summarize our current understanding of the mechanisms relevant to the pathophysiology of PCOS and examine the role of vitamin D signalling in this context.     

Diabetic Cardiovascular Disease Induced by Oxidative Stress

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among patients with diabetes mellitus (DM). DM can lead to multiple cardiovascular complications, including coronary artery disease (CAD), cardiac hypertrophy, and heart failure (HF). HF represents one of the most common causes of death in patients with DM and results from DM-induced CAD and diabetic cardiomyopathy. Oxidative stress is closely associated with the pathogenesis of DM and results from overproduction of reactive oxygen species (ROS). ROS overproduction is associated with hyperglycemia and metabolic disorders, such as impaired antioxidant function in conjunction with impaired antioxidant activity. Long-term exposure to oxidative stress in DM induces chronic inflammation and fibrosis in a range of tissues, leading to formation and progression of disease states in these tissues. Indeed, markers for oxidative stress are overexpressed in patients with DM, suggesting that increased ROS may be primarily responsible for the development of diabetic complications. Therefore, an understanding of the pathophysiological mechanisms mediated by oxidative stress is crucial to the prevention and treatment of diabetes-induced CVD. The current review focuses on the relationship between diabetes-induced CVD and oxidative stress, while highlighting the latest insights into this relationship from findings on diabetic heart and vascular disease.