The Role of miRNA in Renal Fibrosis Leading to Chronic Kidney Disease.

Chronic kidney disease (CKD) is an important health concern that is expected to be the fifth most widespread cause of death worldwide by 2040. The presence of chronic inflammation, oxidative stress, ischemia, etc., stimulates the development and progression of CKD. Tubulointerstitial fibrosis is a common pathomechanism of renal dysfunction, irrespective of the primary origin of renal injury. With time, fibrosis leads to end-stage renal disease (ESRD). Many studies have demonstrated that microRNAs (miRNAs, miRs) are involved in the onset and development of fibrosis and CKD. miRNAs are vital regulators of some pathophysiological processes; therefore, their utility as therapeutic agents in various diseases has been suggested. Several miRNAs were demonstrated to participate in the development and progression of kidney disease. Since renal fibrosis is an important problem in chronic kidney disease, many scientists have focused on the determination of miRNAs associated with kidney fibrosis. In this review, we present the role of several miRNAs in renal fibrosis and the potential pathways involved. However, as well as those mentioned above, other miRs have also been suggested to play a role in this process in CKD. The reports concerning the impact of some miRNAs on fibrosis are conflicting, probably because the expression and regulation of miRNAs occur in a tissue- and even cell-dependent manner. Moreover, different assessment modes and populations have been used. There is a need for large studies and clinical trials to confirm the role of miRs in a clinical setting. miRNAs have great potential; thus, their analysis may improve diagnostic and therapeutic strategies.

The Role of Inflammation and Oxidative Stress in Rheumatic Heart Disease.

Rheumatic heart disease (RHD), an acquired valvular disease, remains an important cause of morbidity and mortality in developing countries. This chronic illness starts from untreated streptococcal throat infection, resulting in acute rheumatic fever (ARF) in susceptible individuals. Repeated infections lead to a chronic phase characterized by the damage of heart valves. Inflammation has been found to play important role in the development of this disease. All the studies presented in this review clearly show the involvement of the inflammatory state in the progression of this disease. However, the exact role of cytokines in inflammation sites remains to be examined, since most studies have so far focused on peripheral blood. Such analysis would provide information on inflammatory mechanisms in situ.

Are Alterations in DNA Methylation Related to CKD Development?

The modifications in genomic DNA methylation are involved in the regulation of normal and pathological cellular processes. The epigenetic regulation stimulates biological plasticity as an adaptive response to variations in environmental factors. The role of epigenetic changes is vital for the development of some diseases, including atherogenesis, cancers, and chronic kidney disease (CKD). The results of studies presented in this review have suggested that altered DNA methylation can modulate the expression of pro-inflammatory and pro-fibrotic genes, as well those essential for kidney development and function, thus stimulating renal disease progression. Abnormally increased homocysteine, hypoxia, and inflammation have been suggested to alter epigenetic regulation of gene expression in CKD. Studies of renal samples have demonstrated the relationship between variations in DNA methylation and fibrosis and variations in estimated glomerular filtration rate (eGFR) in human CKD. The unravelling of the genetic-epigenetic profile would enhance our understanding of processes underlying the development of CKD. The understanding of multifaceted relationship between DNA methylation, genes expression, and disease development and progression could improve the ability to identify individuals at risk of CKD and enable the choice of appropriate disease management.

Will the Use of Pharmacogenetics Improve Treatment Efficiency in COVID-19?

The COVID-19 pandemic is associated with a global health crisis and the greatest challenge for scientists and doctors. The virus causes severe acute respiratory syndrome with an outcome that is fatal in more vulnerable populations. Due to the need to find an efficient treatment in a short time, there were several drugs that were repurposed or repositioned for COVID-19. There are many types of available COVID-19 therapies, including antiviral agents (remdesivir, lopinavir/ritonavir, oseltamivir), antibiotics (azithromycin), antiparasitics (chloroquine, hydroxychloroquine, ivermectin), and corticosteroids (dexamethasone). A combination of antivirals with various mechanisms of action may be more efficient. However, the use of some of these medicines can be related to the occurrence of adverse effects. Some promising drug candidates have been found to be ineffective in clinical trials. The knowledge of pharmacogenetic issues, which translate into variability in drug conversion from prodrug into drug, metabolism as well as transport, could help to predict treatment efficiency and the occurrence of adverse effects in patients. However, many drugs used for the treatment of COVID-19 have not undergone pharmacogenetic studies, perhaps as a result of the lack of time.

miRNA biomarkers in renal disease.

Chronic kidney disease (CKD), which is characterized by the gradual loss of kidney function, is a growing worldwide problem due to CKD-related morbidity and mortality. There are no reliable and early biomarkers enabling the monitoring, the stratification of CKD progression and the estimation of the risk of CKD-related complications, and therefore, the search for such molecules is still going on. Numerous studies have provided evidence that miRNAs are potentially important particles in the CKD field. Studies indicate that some miRNA levels can be increased in patients with CKD stages III-V and hemodialysis and decreased in renal transplant recipients (miR-143, miR-145 and miR-223) as well as elevated in patients with CKD stages III-V, decreased in hemodialysis patients and even more markedly decreased in renal transplant recipients (miR-126 and miR-155). miRNA have great potential of being sensitive and specific biomarkers in kidney diseases as they are tissue specific and stable in various biological materials. Some promising non-invasive miRNA biomarkers have already been recognized in renal disease with the potential to enhance diagnostic accuracy, predict prognosis and monitor the course of disease. However, large-scale clinical trials enrolling heterogeneous patients are required to evaluate the clinical value of miRNAs.

Emerging Anti-Atherosclerotic Therapies.

Cardiovascular disease (CAD) is the main cause of morbidity and deaths in the western world. The development of atherosclerosis underlying CAD development begins early in human life. There are numerous genetic and environmental risk factors accelerating its progression which then leads to the occurrence of acute events. Despite considerable progress in determining risk factors, there is still a lot of work ahead since identified determinants are responsible only for a part of overall CAD risk. Current therapies are insufficient to successfully reduce the risk of atherosclerosis development. Therefore, there is a need for effective preventive measures of clinical manifestations of atherosclerosis since the currently available drugs cannot prevent the occurrence of even 70% of clinical events. The shift of the target from lipid metabolism has opened the door to many new therapeutic targets. Currently, the majority of known targets for anti-atherosclerotic drugs focus also on inflammation (a common mediator of many risk factors), mechanisms of innate and adaptive immunity in atherosclerosis, molecule scavengers, etc. The therapeutic potential of cyclodextrins, protein kinase inhibitors, colchicine, inhibitors of p38 mitogen-activated protein kinase (MAPK), lipid dicarbonyl scavengers, a monoclonal antibody targeting interleukin-1ß, and P-selectin inhibitors is still not fully confirmed and requires confirmation in large clinical trials. The preliminary results look promising.

Pathomechanisms of Immunological Disturbances in ß-Thalassemia.

Thalassemia, a chronic disease with chronic anemia, is caused by mutations in the ß-globin gene, leading to reduced levels or complete deficiency of ß-globin chain synthesis. Patients with ß-thalassemia display variable clinical severity which ranges from asymptomatic features to severe transfusion-dependent anemia and complications in multiple organs. They not only are at increased risk of blood-borne infections resulting from multiple transfusions, but they also show enhanced susceptibility to infections as a consequence of coexistent immune deficiency. Enhanced susceptibility to infections in ß-thalassemia patients is associated with the interplay of several complex biological processes. ß-thalassemia-related abnormalities of the innate immune system include decreased levels of complement, properdin, and lysozyme, reduced absorption and phagocytic ability of polymorphonuclear neutrophils, disturbed chemotaxis, and altered intracellular metabolism processes. According to available literature data, immunological abnormalities observed in patients with thalassemia can be caused by both the disease itself as well as therapies. The most important factors promoting such alterations involve iron overload, phenotypical and functional abnormalities of immune system cells resulting from chronic inflammation oxidative stress, multiple blood transfusion, iron chelation therapy, and splenectomy. Unravelling the mechanisms underlying immune deficiency in ß-thalassemia patients may enable the designing of appropriate therapies for this group of patients.

Is a High HDL-Cholesterol Level Always Beneficial?

The specific interest concerning HDL cholesterol (HDL-C) is related to its ability to uptake and return surplus cholesterol from peripheral tissues back to the liver and, therefore, to its role in the prevention of cardiovascular diseases, such as atherosclerosis and myocardial infarction, but also transient ischemic attack and stroke. Previous epidemiological studies have indicated that HDL-C concentration is inversely associated with the risk of cardiovascular disease and that it can be used for risk prediction. Some genetic disorders are characterized by markedly elevated levels of HDL-C; however, they do not translate into diminished cardiovascular risk. The search of the potential causative relationship between HDL-C and adverse events has shifted the attention of researchers towards the composition and function of the HDL molecule/subfractions. HDL possesses various cardioprotective properties. However, currently, it appears that higher HDL-C is not necessarily protective against cardiovascular disease, but it can even be harmful in extremely high quantities.

Metabolomic Profile in Venous Thromboembolism (VTE).

Venous thromboembolism (VTE) is a condition comprising deep venous thrombosis (DVT) and pulmonary embolism (PE). The prevalence of this disease is constantly increasing and it is also a chief reason for morbidity. Therefore, the primary prevention of VTE remains a highly important public health issue. At present, its diagnosis generally relies on subjective clinical examination and ultrasound imaging. D-dimer is also used as a biomarker, but it is considered to be poorly specific and only moderately sensitive. There are also no reliable methods that could accurately guide the type of treatment and potentially identify patients who may benefit from more aggressive therapies without the risk of bleeding. The application of metabolomics profiling in the area of vascular diseases may become a turning point in early diagnosis and patient management. Among the most described metabolites possibly related to VTE are carnitine species, glucose, phenylalanine, 3-hydroxybutarate, lactic acid, tryptophan and some monounsaturated and polyunsaturated fatty acids. The cell response to acute PE was suggested to involve the uncoupling between glycolysis and oxidative phosphorylation. Despite technological advancement in the identification of metabolites and their alteration in thrombosis, we still do not understand the mechanisms and pathways responsible for the occurrence of observed alterations.

Ageing, Age-Related Cardiovascular Risk and the Beneficial Role of Natural Components Intake.

Ageing, in a natural way, leads to the gradual worsening of the functional capacity of all systems and, eventually, to death. This process is strongly associated with higher metabolic and oxidative stress, low-grade inflammation, accumulation of DNA mutations and increased levels of related damage. Detrimental changes that accumulate in body cells and tissues with time raise the vulnerability to environmental challenges and enhance the risk of major chronic diseases and mortality. There are several theses concerning the mechanisms of ageing: genetic, free radical telomerase, mitochondrial decline, metabolic damage, cellular senescence, neuroendocrine theory, Hay-flick limit and membrane theories, cellular death as well as the accumulation of toxic and non-toxic garbage. Moreover, ageing is associated with structural changes within the myocardium, cardiac conduction system, the endocardium as well as the vasculature. With time, the cardiac structures lose elasticity, and fibrotic changes occur in the heart valves. Ageing is also associated with a higher risk of atherosclerosis. The results of studies suggest that some natural compounds may slow down this process and protect against age-related diseases. Animal studies imply that some of them may prolong the lifespan; however, this trend is not so obvious in humans.

Pharmacogenomics of Hypertension Treatment.

Hypertension is one of the strongest modifiable cardiovascular risk factors, affecting an increasing number of people worldwide. Apart from poor medication adherence, the low efficacy of some therapies could also be related to inter-individual genetic variability. Genetic studies of families revealed that heritability accounts for 30% to 50% of inter-individual variation in blood pressure (BP). Genetic factors not only affect blood pressure (BP) elevation but also contribute to inter-individual variability in response to antihypertensive treatment. This article reviews the recent pharmacogenomics literature concerning the key classes of antihypertensive drugs currently in use (i.e., diuretics, ß-blockers, ACE inhibitors, ARB, and CCB). Due to the numerous studies on this topic and the sometimes-contradictory results within them, the presented data are limited to several selected SNPs that alter drug response. Genetic polymorphisms can influence drug responses through genes engaged in the pathogenesis of hypertension that are able to modify the effects of drugs, modifications in drug-gene mechanistic interactions, polymorphisms within drug-metabolizing enzymes, genes related to drug transporters, and genes participating in complex cascades and metabolic reactions. The results of numerous studies confirm that genotype-based antihypertension therapies are the most effective and may help to avoid the occurrence of major adverse events, as well as decrease the costs of treatment. However, the genetic heritability of drug response phenotypes seems to remain hidden in multigenic and multifactorial complex traits. Therefore, further studies are required to analyze all associations and formulate final genome-based treatment recommendations.

The Role and Function of HDL in Patients with Chronic Kidney Disease and the Risk of Cardiovascular Disease.

Chronic kidney disease (CKD) is a worldwide health problem with steadily increasing occurrence. Significantly elevated cardiovascular morbidity and mortality have been observed in CKD. Cardiovascular diseases are the most important and frequent cause of death of CKD patients globally. The presence of CKD is related to disturbances in lipoprotein metabolism whose consequences are dyslipidemia and the accumulation of atherogenic particles. CKD not only fuels the reduction of high-density lipoprotein (HDL) cholesterol concentration, but also it modifies the composition of this lipoprotein. The key role of HDL is the participation in reverse cholesterol transport from peripheral tissues to the liver. Moreover, HDL prevents the oxidation of low-density lipoprotein (LDL) cholesterol by reactive oxygen species (ROS) and protects against the adverse effects of oxidized LDL (ox-LDL) on the endothelium. Numerous studies have demonstrated the ability of HDL to promote the production of nitric oxide (NO) by endothelial cells (ECs) and to exert antiapoptotic and anti-inflammatory effects. Increasing evidence suggests that in patients with chronic inflammatory disorders, HDLs may lose important antiatherosclerotic properties and become dysfunctional. So far, no therapeutic strategy to raise HDL, or alter the ratio of HDL subfractions, has been successful in slowing the progression of CKD or reducing cardiovascular disease in patients either with or without CKD.

Do HDL and LDL subfractions play a role in atherosclerosis in end-stage renal disease (ESRD) patients?

BACKGROUND: Significantly increased cardiovascular mortality in patients with chronic kidney (CKD) disease cannot be explained by traditional risk factors. Recent studies revealed that the quality of HDL and LDL cholesterol may be more important than their serum levels. The aim of this study was to assess which LDL and HDL subfractions were more abundant in end-stage renal disease (ESRD) patients and to analyse whether subfraction distribution could be associated with accelerated atherosclerotic processes. METHODS: This study included 50 ESRD patients undergoing dialysis and 20 healthy volunteers. LDL and HDL subfractions were analysed in serum with the use of Lipoprint system. All patients had intima-media thickness (IMT) measured. RESULTS: Statistically significant differences in subfractions between control and study group were observed in case of: HDL1 (p < 0.0001), HDL2 (p = 0.009), HDL3 (p < 0.0001), HDL4 (p = 0.003), HDL5 (p = 0.01), HDL7 (p < 0.0001), HDL8 (p < 0.0001), HDL9 (p < 0.0001), HDL10 (p < 0.0001), large HDL (p < 0.0001), HDL Small (p < 0.0001) as well as IDL-B (p = 0.014), IDLA (p = 0.011), LDL2 (p = 0.007). Significant differences were also observed in HDL and LDL subfraction distribution between haemodialysis patients with normal and increased IMT: HDL6 (p = 0.020), HDL Large (HDL1-3) (p = 0.017), HDL Intermediate (HDL4-7) (p = 0.017). CONCLUSIONS: This study revealed that ESRD influenced HDL subfractions. In HD patients, large HDL subfractions are more abundant while small HDL fraction is more frequent in healthy persons. It failed to show the influence of end-stage disease on LDL subfraction levels. Shift in HDL subfractions might be responsible for the increased risk of atherosclerosis in CKD patients.

High-Density Lipoprotein and Low-Density Lipoprotein Subfractions in Patients with Chronic Kidney Disease.

BACKGROUND: Chronic Kidney Disease (CKD) is an independent risk factor for cardiovascular disease (CVD). CKD is accompanied by high cardiovascular mortality due to many factors, but atherosclerosis is thought to be a major cause at every CKD stage. It has been suggested that measuring and estimating changes in high density lipoprotein (HDL) and low density lipoprotein (LDL) subfractions may be important for predicting CVD in CKD patients. OBJECTIVE: The aim of this study was to determine and compare levels of HDL and LDL subfractions in patients with different CKD stages. METHODS: The study included 115 patients with CKD (CKD stage 2-25 patients, CKD stage 3-25; CKD stage 4-25 and CKD 5 undergoing dialysis - 40 patients) and 25 volunteers without CKD (control group). The Lipoprint System (Quantimetrix®) was used to analyse HDL and LDL subfractions. RESULTS: There were significant differences in the distribution of HDL1-HDL5 subfractions levels, which were significantly higher in patients with impaired renal function than in the control group (p≤.0.013 for all comparisons). HDL7-HDL10 subfractions were significantly more prevalent in healthy volunteers compared with CKD patients (p≤.0.001 for all comparisons). The analysis of LDL subfractions revealed significant differences only in IDL-B (p<0.05), IDL-A (p<0.05) and LDL2 (p<0.001) between patients with CKD stage 5 and controls. CONCLUSION: CKD influenced HDL and LDL subfractions. In CKD patients, large HDL subpopulations were more prevalent in contrast to small HDL subfractions in healthy subjects. Identification of patients with increased level of large HDL subfractions could be useful to identify CKD subjects at increased CV risk. Further studies with larger populations and with the application of a several methods of subfraction measurement are necessary to confirm these results.

Subfractions of high-density lipoprotein (HDL) and dysfunctional HDL in chronic kidney disease patients.

A number of studies have shown that chronic kidney disease (CKD) is associated with increased risk for cardiovascular disease (CVD). Chronic kidney disease is characterized by significant disturbances in lipoprotein metabolism, including differences in quantitative and qualitative content of high-density lipoprotein (HDL) particles. Recent studies have revealed that serum HDL cholesterol levels do not predict CVD in CKD patients; thus CKD-induced modifications in high-density lipoprotein (HDL) may be responsible for the increase in CV risk in CKD patients. Various methods are available to separate several subclasses of HDL and confirm their atheroprotective properties. However, under pathological conditions associated with inflammation and oxidation, HDL can progressively lose normal biological activities and be converted into dysfunctional HDL. In this review, we highlight the current state of knowledge on subfractions of HDL and HDL dysfunction in CKD.

Efficacy of Statin Therapy in Pulmonary Arterial Hypertension: A Systematic Review and Meta-Analysis.

Since the evidence regarding statin therapy in PAH has not been conclusive, we assessed the impact of statin therapy in PAH through a systematic review and meta-analysis of available studies. We searched selected databases up to August 1, 2015 to identify the studies investigating the effect of statin administration on PAH. Meta-analysis was performed using either a fixed-effects or random-effect model according to I(2) statistic. Meta-analysis of 8 studies with 665 patients did not suggest any significant improvement in 6-min walking distance (6MWD) by statin therapy (weighed mean difference [WMD]: -6.08 m, 95% confidence interval [CI]: -25.66, 13.50, p = 0.543; Q = 8.41, I(2) = 28.64%). Likewise, none of the other indices including pulmonary arterial pressure (WMD: -0.97 mmHg, 95%CI: -4.39, 2.44, p = 0.577; Q = 14.64, I(2) = 79.51%), right atrial pressure (WMD: 1.01 mmHg, 95%CI: -0.93, 2.96, p = 0.307; Q = 44.88, I(2) = 95.54%), cardiac index (WMD: 0.05 L/min/m(2), 95%CI: -0.05, 0.15, p = 0.323; Q = 3.82, I(2) = 21.42%), and pulmonary vascular resistance (WMD: -1.42 dyn*s/cm(5), 95%CI: -72.11, 69.27, p = 0.969; Q = 0.69, I(2) = 0%) was significantly altered by statin therapy. In conclusion, the results of the meta-analysis did not show a statistically significant effect of statin therapy in the improvement of 6MWD, pulmonary arterial pressure, right atrial pressure, cardiac index and pulmonary vascular resistance.