Salusin-alpha - a New Factor in the Pathogenesis of Lipid Abnormalities in Hemodialysis Patients

Overview

Hyperlipidemia and atherosclerosis lead to cardiovascular diseases and are an indirect cause of increased death rate in the general population. This association is still more evident in specific subpopulations, like patients with advanced chronic kidney disease (CKD), especially hemodialysis (HD) patients, due to a higher prevalence of lipid disturbances and atherosclerosis compared to the general population. Cardiovascular events in CKD patients are frequently associated with traditional risk factors, including diabetes, male sex, hypertension, dyslipidemia and advanced age. However, these factors failed to fully account for the increased risk of cardiovascular events in CKD. The efforts are made to identify new risk factors that contribute to the development of atherosclerosis and participate in causes of cardiovascular death. In 2003, there were identified peptides designated salusin-alpha and salusin-beta. Development of atherosclerosis may be suppressed by salusin-alpha. Salusin-alpha may have a lipid lowering effect, similar to that of statins. The purpose of this study is to investigate whether 1) salusin-alpha is associated with lipid metabolism of HD patients (without or with metabolic syndrome or type 2 diabetes mellitus), similarly or not like in healthy or obese subjects; 2) treatment with atorvastatin and its effects are associated with changes in plasma salusin-alpha concentration, if so - whether it is dependent on the direct influence of atorvastatin on salusin-alpha or associated with a decrease in serum lipid level; 3) salusin-alpha may predict mortality in HD patients.

Purpose I, step 1. To investigate whether plasma salusin-alpha is associated with lipid and lipid-related abnormalities in hemodialysis (HD) patients, plasma salusin-alpha concentration, expression of receptor CD36 on macrophages, serum lipid parameters, anthropometric and laboratory indices of nutrition and biomarkers of inflammation will be cross-sectionally analyzed. In chronic kidney disease (CKD) patients there is a close association between atherosclerosis (A), malnutrition (M) and inflammation (I), known as MIA syndrome, so interactions between all these parameters will be obviously present and should be taken into account. In addition, homeostasis model assessment of insulin resistance (HOMA-IR) will be applied as insulin resistance is a metabolic abnormality occurring in advanced CKD, in metabolic syndrome shown in about 50% of HD patients and diabetic mellitus (DM), being a cause of CKD in approximately 40% of cases. Results of correlations and associations shown in HD patients will be compared with those of healthy controls and obese persons with normal renal function for evaluation of salusin-alpha relationships under different metabolic conditions, which may exert not uniform influence. Study populations: HD patients (n = 200) Obese persons (n = 50) Controls (n = 60) Data collection: Medical history (with special attention for demographics - age, gender, cause of CKD, renal replacement therapy vintage, changes in body weight, habits and data required for inclusion and exclusion criteria. Physical examination (with special attention for skin abnormalities related to lipid disturbances and blood pressure). Anthropometric indices: * directly measured: height, body weight, hip and waist circumferences, midarm circumference (MAC), triceps skin fold thickness (TSF) * calculated or estimated: hip to waist ratio (WHiR), height to waist ratio (WHeR), body mass index (BMI), in HD patients - dry body weight (DBW) Laboratory parameters * Apolipoprotein A1 (APOA1) * Apolipoprotein B (APO B) * Cholesterol - total * Cholesterol HDL * Cholesterol LDL directly measured * CD36 * Free fatty acids (FDA) * High sensitivity C-reactive protein (hsCRP) * HOMA-IR * Interleukin 6 (IL-6) * L-carnitine * Lipase * Lipoprotein(a) * Salusin-alpha * Triglycerides * Basic serum biochemistry Purpose I, step 2. HD patients suffering from type 2DM or having metabolic syndrome (MeS) are at risk of more severe lipid abnormalities than the remaining ones. Data collected in Step 1 will be helpful in diagnosis of MeS in the examined HD patients. The investigators expect that also in controls they will find persons with abnormal serum lipid profile. Differences inside these both groups may influence plasma salusin-alpha levels and the examined associations. Thereby, the following groups will be analyzed separately and compared to each other: For HD patients: * group with MeS and with type 2 DM * group only with MeS * group only with type 2 DM * group without MeS and without DM For controls: * group without detected serum lipid abnormalities * group with detected serum lipid abnormalities Validation of correlations/associations found in the cross-sectional study will be done in the prospective studies (Purpose II) and at the final analysis (Purpose III). Purpose II. The treatment with atorvastatin lowers serum LDL cholesterol in HD patients. Using this statin during the study, the investigators can observe dynamic changes in serum LDL cholesterol in HD patients with known plasma salusin-alpha concentration before atorvastatin medication. With repeated salusin-alpha measurements during continued atorvastatin treatment the investigators can follow concomitantly occurring (or not occurring) changes in plasma salusin-alpha concentrations, which can be related to atorvastatin directly or to its LDL cholesterol lowering effect. To elucidate this aspect, the investigators plan to examine hyperlipidemic HD patients treated with a prescribed diet and increased physical activity as well as obese persons (not taking lipid lowering medication) during weight lowering therapy, which usually decreases lipidemia. Results of these persons may give the answer whether a decrease in lipidemia without pharmaceutical medication leads (may be also leads) to changes in plasma salusin-alpha concentration. The prospective study is planned in two groups of persons: HD patients, participating in Step 1 (n = 200), Obese persons, participating in Step 1 (n = 50). Purpose III. Annual mortality rate in HD patients is 10 - 15%. LDL cholesterol and total cholesterol are predictors of mortality in end-stage renal disease patients. If salusin-alpha is associated with lipid abnormalities, it is a reasonable to check whether this peptide may be a predictor of mortality in HD patients. To investigate this aspect the investigators plan to perform the analysis of HD patients outcome after two years from the first salusin-alpha determination and to check whether there is any association between plasma salusin-alpha concentration and death from cardiovascular events and all cause death.