Anna Gluba

The role of Toll-like receptors in renal diseases

Toll-like receptors (TLRs) have a key role in innate immunity. These receptors recognize both pathogen-associated molecular patterns and molecules that are released from damaged tissue. TLRs mediate signal transduction pathways through the activation of transcription factors that regulate the expression of proinflammatory cytokines and chemokines and are required for the development of adaptive immune responses. TLRs might have an important role in the pathogenesis of renal diseases: their exaggerated activation is associated with ischemic kidney damage, acute kidney injury, end-stage renal failure, acute tubulointerstitial nephritis, acute renal transplant rejection and delayed allograft function. As the results of previous studies concerning the role of TLRs in renal diseases are conflicting, further work is needed to determine the exact role of these receptors and to evaluate strategies to prevent TLR-mediated local inflammation. This Review discusses the evidence supporting a role for TLRs in contrasting bacterial infections and in causing or aggravating renal conditions when TLR activation leads to a harmful inflammatory response.

Statin Therapy and New-onset Diabetes: Molecular Mechanisms and Clinical Relevance

Despite positive effects on the plasma lipid profile and vascular events, statin use is associated with various side effects. Among these, statins might cause a disruption of a number of regulatory pathways including insulin signaling. This may affect insulin sensitivity, pancreatic beta-cell function and adipokine secretion. The statin-associated risk of new-onset diabetes (NOD) appears to be a dose-dependent class effect. It still remains unclear whether statin treatment is associated with increased risk of NOD in the general population or if there are groups of individuals at particular risk. However, according to the available data it seems that cardiovascular (CV) benefits in high-risk individuals strongly favor statin therapy since it outweighs other risks. Whether statins should be used for primary prevention among patients with a relatively low baseline CV risk is still questionable, however the results of primary prevention trials have shown reductions in mortality in this population. Thus, there is a need for randomized, placebo-controlled statin studies with carefully selected groups of patients and NOD as a key end point in order to resolve queries concerning this issue.

Metabolic syndrome and renal disease

The metabolic syndrome (MetS) is a cluster of risk factors including insulin resistance, dyslipidemia and hypertension which are also relevant for the development of chronic kidney disease (CKD). It has proven difficult to elucidate whether the renal dysfunction in MetS is due to the MetS itself or the individual risk factors. For example, obesity - which is also part of the MetS - may enhance the risk of renal dysfunction development probably through mechanisms associated with renal hyperfiltration, hyperperfusion and focal glomerulosclerosis. Insulin resistance also promotes kidney disease by worsening renal hemodynamics. In patients with MetS, tubular atrophy, interstitial fibrosis, and arteriolar sclerosis indicating the presence of vascular damage, have also been described. As yet, there has been little evidence that preventing or treating symptoms of the MetS protects patients from renal impairment.

The role of polymorphisms within paraoxonases (192 Gln/Arg in PON1 and 311Ser/Cys in PON2) in the modulation of cardiovascular risk: a pilot study.

Paraoxonases (PONs) may exert anti-atherogenic action by reducing lipid peroxidation. We evaluated the influence of 2 polymorphisms within PON1 (192 Gln/ Arg) and PON2 (311 Ser/Cys) genes in 407 young Poles: 273 patients who experienced a first myocardial infarction (MI) under the age of 45 (study group) and 134 healthy volunteers (control group) with a HEART Score ≤2 (low risk). Paraoxonase 1 polymorphism 192Gln/Arg influenced the risk of premature MI (P = .0054). A positive family history of coronary artery disease (CAD) was associated with the 192Arg allele (P = .0107). The association between PON1 genotype (192 Gln/Arg) and low-density lipoprotein cholesterol (LDL-C) (P = .036) levels was also observed. However, we did not find any relationship between polymorphism 311Ser/Cys and CAD risk (P = .418). PON1 polymorphism 192Gln/Arg influenced the risk of premature MI. The association between PON1 genotype (192 Gln/Arg) and serum LDL-C levels may be explained by PON participation in reverse cholesterol transport.

An update on biomarkers of heart failure in hypertensive patients.

Biomarkers should have high sensitivity, specificity, reproducibility, be cost-effective, and provide incremental predictive or diagnostic utility over standard risk factors or tests. Despite numerous studies investigating biomarkers in heart failure (HF), there are only a few that predict HF in hypertensive patients. This article summarizes data from numerous studies concerning possible biomarkers of HF in hypertensive patients such as: serum uric acid (SUA), interleukins, monocyte chemoattractant protein one (MCP-1), cardiotrophin-1 (CT-1), carboxy-terminal propeptide of procollagen type I (PICP), type I collagen telopeptide (CITP) and N-terminal propeptide of type III procollagen (PIIINP), metalloproteinases (MMPs), B-type natriuretic peptide (BNP) and its derivatives, glycoprotein CA125 and cystatin C. Early detection of patients of increased risk of hypertensive heart disease may result in early implementation of effective preventive strategies. Therefore, there is need to identify newer biomarkers, if they can improve risk prediction, identifying patients, in which earlier or more aggressive intervention will improve clinical outcomes.

Role and significance of statins in the treatment of hypertensive patients

ABSTRACT Background: Statins are the first-line drug therapy in the treatment of hypercholesterolemia. The beneficial clinical impact of statins on the cardiovascular system results not only from their lipid-lowering action but also from other effects. Recently, it has been suggested that statins can reduce blood pressure, especially in hypertensive patients. Aim: The role of the hypotensive action of statins and other mechanisms which reduce cardiovascular risk in hypertensive patients are discussed in this review. Methods: Electronic databases searched were [MEDLINE (1966 – February 2009), EMBASE and SCOPUS (1965 – February 2009), DARE (1966 -- February 2009)]. Additionally, abstracts from national and international cardiovascular meetings were studied to identify unpublished studies. The main data search terms were: blood pressure, hypertension, hypercholesterolemia and statins. Findings: At present, it is difficult to unequivocally assess the impact of statins on blood pressure. However, according to most authors, the impact of statins on the decrease in BP is slight, but significant, especially among patients with hypertension.

Prevention of sudden cardiac death in patients with chronic kidney disease.

Cardiovascular deaths account for about 40% of all deaths of patients with chronic kidney disease (CKD), particularly those on dialysis, while sudden cardiac death (SCD) might be responsible for as many as 60% of SCD in patients undergoing dialysis. Studies have demonstrated a number of factors occurring in hemodialysis (HD) that could lead to cardiac arrhythmias. Patients with CKD undergoing HD are at high risk of ventricular arrhythmia and SCD since changes associated with renal failure and hemodialysis-related disorders overlap. Antiarrhythmic therapy is much more difficult in patients with CKD, but the general principles are similar to those in patients with normal renal function - at first, the cause of arrhythmias should be found and eliminated. Also the choice of therapy is narrowed due to the altered pharmacokinetics of many drugs resulting from renal failure, neurotoxicity of certain drugs and their complex interactions. Cardiac pacing in elderly patients is a common method of treatment. Assessment of patients’ prognosis is important when deciding whether to implant complex devices. There are reports concerning greater risk of surgical complications, which depends also on the extent of the surgical site. The decision concerning implantation of a pacing system in patients with CKD should be made on the basis of individual assessment of the patient.

Is polymorphism within eNOS gene associated with the late onset of myocardial infarction? A pilot study.

Introduction: Nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) is a potent vasodilator. Several polymorphisms in the eNOS gene have been described, some of them being linked with the increased risk of cardiovascular disease, coronary heart disease (CHD), and coronary spasm. Methods and Results: We studied 3 polymorphisms within the gene of eNOS (-786T/C, G10T, and 894 G/T) in patients with their first myocardial infarction (MI) younger than 45 years and in healthy volunteers. We found the relation between the occurrence of eNOS 894G allele and the Gensini score, which describes the severity of CHD (P = .020). Conclusions: The fact that first clinical manifestation of MI occurred in G carriers when the atherosclerotic plaque was much more advanced than in T carriers may suggest that wild-type genotype provided a better compensatory mechanisms due to NO synthesis and/or release. The polymorphisms within eNOS gene G10T, 894G/T, and -786T/C were not associated with the increased risk of MI.

Treatment of non-ST-elevation myocardial infarction and ST-elevation myocardial infarction in patients with chronic kidney disease

Renal dysfunction is frequent in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Chronic kidney disease (CKD) is associated with very poor prognosis and is an independent predictor of early and late mortality and major bleeding in patients with NSTE-ACS. Patients with NSTE-ACS and CKD are still rarely treated according to guidelines. Medical registers reveal that patients with CKD are usually treated with too high doses of antithrombotics, especially anticoagulants and inhibitors of platelet glycoprotein (GP) IIb/IIIa receptors, and therefore they are more prone to bleeding. Drugs which are excreted mainly or exclusively by the kidney should be administered in a reduced dose or discontinued in patients with CKD. These drugs include enoxaparin, fondaparinux, bivalirudin, and small molecule inhibitors of GP IIb/IIIa inhibitors. In long-term treatment of patients after myocardial infarction, anti-platelet therapy, lipid-lowering therapy and β-blockers are used. Chronic kidney disease patients before qualification for coronary interventions should be carefully selected in order to avoid their use in the group of patients who could not benefit from such procedures. This paper presents schemes of non-ST and ST-segment elevation myocardial infarction treatment in CKD patients in accordance with the current recommendations of the European Society of Cardiology (ESC).

Heart function disturbances in chronic kidney disease - echocardiographic indices

Introduction In chronic kidney disease (CKD) patients left ventricular (LV) diastolic dysfunction occurs frequently and is associated with heart failure (HF) and higher mortality. Left ventricular systolic dysfunction is associated with coronary artery disease (CAD) and is a major determinant of prognosis. The aim of this study was to assess indices of LV diastolic dysfunction in CKD patients. Material and methods Study included 118 CKD patients. All patients underwent transthoracic echocardiography. Diastolic function based on E and A, E/A ratio and pulmonary vein flow velocities as well as EF%, deceleration time, RA, LA volume were assessed. In dialysis patients examination was carried out before and after dialysis. Results In CKD patients the stage of renal failure was associated with the significant increase in LV mass (268.0 ±47.6 CKD I/II vs. 432.7 ±122.4 CKD V/dialysis, p < 0.0001), systolic LV (37.3 ±4.5 vs. 51.2 ±8.9, p < 0.0001) and diastolic LV (CKD I–II 44.7 ±4.1 vs. CKD III 48.5 ±6.7 vs. CKD IV 47.1 ±5.6; p = 0.004) dimensions and in the size of the LA (40.4 ±2.0 vs. 41.9 ±2.7 vs. 42.3 ±3.2 vs. 44.8 ±3.1; p < 0.0001). The increase the E/E’ ratio between groups of patients (6.7 ±1.5 vs. 8.9 ±2.4 vs. 11.5 ±4.0 vs. 13.5 ±5.0; p < 0.0001) was seen in this study. The reduction in deceleration time (247.2 ±34.5 in CKD I/II vs. 197.4 ±61.0 in CKD IV, p = 0.0005) along with the decrease in estimated glomerular filtration rate was also observed in this study. Conclusions Early identification of factors involved is necessary to prevent this devastating process. Many indexes of contractility are used and each of them has imperfections. It seems that TVI, E, E/A and E/E’ are good instruments for the early detection of left ventricular hypertrophy and diastolic dysfunction.