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Patients with end-stage kidney disease, treated with renal transplantation, are at increased risk of cardio-vascular disease (CVD) and cardio-vascular mortality. They are also characterized by an atherogenic dyslipidemia. Alterations of the fatty acids (FA) profile contribute to increased cardio-vascular risk in the general population. In the current study, we test the hypothesis that kidney transplantation is associated with ab-normalities in FA profile. The FA profile was analyzed by gas chromatography-mass spectrometry in 198 renal transplant recipients, and 48 control subjects. The most profound differences between renal transplant patients and controls were related to the content of branched chain FA, monounsaturated FA, and n-6 polyunsaturated FA, respectively. The FA profile significantly separated the patients from the controls in the principal component analysis (PCA). The abnormalities of FA profile showed a tendency for normalization in long-term kidney recipients, as compared to patients with recent transplants. The n-3 PUFA content demonstrated a strong inverse association with the presence of inflammation. Most profound alterations of the FA profile were observed in patients with impaired graft function (glomerular filtration rate < 45 mL/min). The study demonstrated significant disorders of the FA profile in kidney transplant recipients, which might contribute to cardio-vascular risk in this vulnerable patient population.

Purpose: In the general population, haemoglobin (Hb) concentration is higher in men than in women. However, target Hb levels in dialysis patients are set constant regardless of the patient's sex. The aim of this study was to evaluate Hb concentration and the use of erythropoiesis-stimulating agents (ESA) in peritoneal dialysis (PD) patients taking gender and dialysis adequacy into account., Methods: The study comprised two parts. The first was a cross-sectional analysis of Hb and ESA in 2180 prevalent PD patients. The second included 88 incident PD patients, followed for 36 months. During this time, the major parameters recorded at 12-month intervals included: Hb concentration, weekly ESA, total, renal, and peritoneal Kt/V. Erythropoietin resistance index (ERI) was calculated as the ratio between ESA dose and achieved Hb., Results: In prevalent PD patients, Hb concentration was significantly lower in women, (11.2 ± 1.4 vs. 11.5 ± 1.6 g/dl; p < 0.001), despite higher doses of ESA (2691 ± 1821 vs. 2344 ± 1422; p = 0.001). Hb concentrations were related to dialysis adequacy in both cohorts. However, despite significantly higher Kt/V, women were characterized by a lower Hb level. In incident patients, this association was present throughout the observation period, while the ESA dose in women was significantly higher at every time point. In multiple regression analysis, gender was an independent determinant of ERI (b = 0.34; p < 0.05)., Conclusions: Despite higher dialysis adequacy, Hb concentration in women treated with PD is significantly lower, and the ability to correct it impaired, as compared to men.

Unlabelled: ♦, Background: Biocompatible fluids for peritoneal dialysis (PD) have been introduced to improve dialysis and patient outcome in end-stage renal disease. However, their impact on hydration status (HS), residual renal function (RRF), and dialysis adequacy has been a matter of debate. The aim of the study was to evaluate the influence of a biocompatible dialysis fluid on the HS of prevalent PD patients. ♦, Methods: The study population consisted of 18 prevalent PD subjects, treated with standard dialysis fluids. At baseline, 9 patients were switched to a biocompatible solution, low in glucose degradation products (GDPs) (Balance; Fresenius Medical Care, Bad Homburg, Germany). Hydration status was assessed through clinical evaluation, laboratory parameters, echocardiography, and bioimpedance spectroscopy over a 24-month observation period. ♦, Results: During the study period, urine volume decreased similarly in both groups. At the end of the evaluation, there were also no differences in clinical (body weight, edema, blood pressure), laboratory (N-terminal pro-brain natriuretic peptide, NTproBNP), or echocardiography determinants of HS. However, dialysis ultrafiltration decreased in the low-GDP group and, at the end of the study, equaled 929 ± 404 mL, compared with 1,317 ± 363 mL in the standard-fluid subjects (p = 0.06). Hydration status assessed by bioimpedance spectroscopy was +3.64 ± 2.08 L in the low-GDP patients and +1.47 ± 1.61 L in the controls (p = 0.03). ♦, Conclusions: The use of a low-GDP biocompatible dialysis fluid was associated with a tendency to overhydration, probably due to diminished ultrafiltration in prevalent PD patients., (Copyright © 2016 International Society for Peritoneal Dialysis.)

Purpose: When choosing a dialysis option for ADPKD patients, peritoneal dialysis (PD) is often discouraged, due to its potential drawbacks: risk of abdominal hernias and dialysis fluid leaks, risk of peritonitis and insufficient dialysis adequacy. The present study was designed to compare the outcomes and dialysis efficacy in ADPKD patients treated with PD, in comparison with non-ADPKD subjects., Methods: This study was a retrospective analysis of the data from the national PD registry in which 106 ADPKD and 1606 non-ADPKD incident PD patients were evaluated. Data on dialysis adequacy, risk of dialysis-associated complications, as well as patient and technique survival were compared between the groups., Results: The ADPKD patients did not differ from the non-ADPKD controls in terms of dialysis adequacy. After a median observation time of 32 months, there were no differences in patient or technique survival. The risk of abdominal hernias and dialysis fluid leaks was twice as high in ADPKD subjects, compared to the non-ADPKD group. However, these complications did not result in a need for a permanent transfer to hemodialysis., Conclusions: Dialysis adequacy, and patient and technique survival are similar in the ADPKD and non-ADPKD patients treated with PD. PD seems a feasible treatment option for end-stage renal failure in the course of ADPKD.

Introduction: Since renal replacement therapy has started to be a routine procedure in chronic kidney disease (CKD), patients no longer die of end-stage renal disease (ESRD). Today, patients with CKD live longer and the most important causes of morbidity and mortality in this group are cardiovascular events. Lipid abnormalities, such as hypertriglyceridemia (HT), are an important factor of high cardiovascular risk in this group. It is known that HT is partially caused by inhibition of lipolysis, but it is also postulated that increased lipogenesis is another cause of HT. Previous studies performed in our center has provided evidence that lipogenesis is increased in the animal model of ESRD. , Objectives: The aim of this study was to investigate the activities of lipogenic enzymes in the subcutaneous white adipose tissue in patients with CKD., Patients and Methods: The study was performed on 36 patients (17 women and 19 men). Patients with ESRD were divided into 2 groups: patients on conservative treatment in the prehemodialysis period (pre‑HD group, n = 18) and patients on maintenance hemodialysis (HD group, n = 18). The control group consisted of 22 patients without ESRD. The activities of lipogenic enzymes in the subcutaneous white adipose tissue (fatty acid synthase, adenosine triphosphate citrate lyase, malic enzyme, glucose‑6‑phosphate dehydrogenase, and 6‑phosphogluconate dehydrogenase) were assessed by spectrophotometry. , Results: There were no statistically significant differences in the activities of lipogenic enzymes in a fat tissue sample between patients with ESRD and the control group., Conclusions: The results did not confirm increased lipogenesis in patients with ESRD.

Background: The association between cholesterol and mortality is reversed in end-stage renal disease (ESRD). This phenomenon has many potential explanations, one of them being 'time discrepancy of competing risks'. It states that hypercholesterolaemia is beneficial only in the short term, while it worsens survival over a long-term interval. It is also proposed that the reversed relationship between cholesterol and outcome is due to confounding protein-energy wasting. The aim of the study was to verify the hypothesis of time discrepancy of competing risks in 1191 incident dialysis patients (Netherlands Cooperative Study on the Adequacy of Dialysis)., Methods: Conditional Cox proportional hazards analysis was applied, where associations between cholesterol level and short-term versus long-term mortality were being compared. Furthermore, to evaluate associations between cholesterol and outcome free from confounding, Mendelian randomization was introduced, using apolipoprotein E (apoE) genotype., Results: Hypercholesterolaemia (>240 mg/dL) was associated with improved 5-year survival when compared to the low cholesterol group (<200 mg/dL), hazard ratio (HR) = 0.62 (0.47-0.82), P < 0.001. However, conditional Cox proportional hazards analysis revealed that the reverse association between high cholesterol and all-cause mortality was evident only during the first year of follow-up, HR = 0.43 (0.23-0.80), P < 0.01, and then, gradually, declined. The apoE genotype significantly affected cholesterol concentration. The ε2 carriers, associated with low cholesterol, had significantly increased risk of non-cardiovascular mortality., Conclusions: Reverse association between cholesterol concentration and mortality in dialysis patients is short-termed, consistent with the hypothesis of time discrepancy of competing risks. Low cholesterol appeared to affect non-cardiovascular mortality in ESRD patients free from confounders.

Background: In the general population, a high apoB/apoA-I ratio is a strong risk factor for cardiovascular disease and mortality. However, whether this is the case in chronic kidney disease (CKD) patients is currently unknown., Study Design: The apoB/apoA-I ratio was evaluated in 391 incident CKD stage 5 patients examined close to dialysis initiation, and again after 1 year of dialysis in a subgroup of 182 patients, subsequently followed for up to 3 years., Results: Baseline values of the apoB/apoA-I ratio as well as changes in the ratio during the first year of dialysis correlated with body mass index (BMI) and fat mass. The baseline apoB/apoA-I ratio showed no association with 4-year mortality. However, after adjustment for confounders, a high apoB/apoA-I ratio (>0.9) predicted short-term (first year) survival [hazard ratio (HR): 0.35; 95% confidence interval (CI): 0.13-0.85)] and long-term (next 3 years) mortality (HR: 1.72; 95% CI: 1.01-2.96). An increase in the apoB/apoA-I ratio during the first year of dialysis was linked to a survival advantage thereafter (HR: 0.48; 95% CI: 0.22-0.98). However, this association lost its significance (HR: 0.62; 95% CI: 0.26-1.36) after adjustment for indices of protein-energy wasting., Conclusions: A high apoB/apoA-I ratio and an increase in this ratio during the first year on dialysis were associated with short-term survival advantage in CKD patients. This paradoxical relationship represents an example of the so-called reverse epidemiology phenomenon in CKD patients and suggests that the apoB/apoA-I ratio should always be interpreted with caution in this patient population.

Objective: Expression of heat shock protein (Hsp) 72 is one of the major mechanisms acting against cellular injury. It displays a plethora of functions, including a considerable impact on inflammation. The aim of this study was to investigate Hsp72 expression in blood monocytes of patients with chronic kidney disease (CKD)., Material and Methods: Hsp72 protein level was assessed by flow cytometry in blood monocytes of predialysis, haemodialysis (HD) and continuous peritoneal dialysis patients, and controls. It was followed by evaluation of Hsp72 gene expression in the same cohorts by reverse transcription-polymerase chain reaction., Results: The level of Hsp72 protein was significantly lower in the predialysis (359+/-83 AU) and HD groups (293+/-62 AU) than in controls (405+/-51 AU) (p<0.01 and p<0.001, respectively). The amount of mRNA was significantly lower only in the HD group, compared with controls (0.39+/-0.10 vs 0.48+/-0.10, p<0.01). In the predialysis group, there were negative correlations between Hsp72 protein level and serum creatinine concentration, blood urea nitrogen and C-reactive protein., Conclusions: This study demonstrates that uraemic toxicity decreases expression of Hsp72. Attenuation of Hsp 72 expression in uraemia, found in the present study, could contribute to the inflammatory state, a common complication in CKD patients.

Objective: Enhanced liver cholesterol synthesis is present in experimental chronic renal failure (CRF), even though cholesterol concentrations in blood and liver are increased, suggesting that CRF results in disturbed cholesterolegenesis feedback regulation., Design: This study sought to elucidate whether dietary cholesterol exerts inhibitory effects on liver cholesterologenesis in CRF rats., Methods: Male Wistar rats were used. Experimental CRF was achieved by a 5/6 nephrectomy model. Cholesterologenesis was measured (1) in vivo by tritiated water incorporation into cholesterol, and (2) in vitro (using liver slices) by [(14)C]-acetate and [(3)H]-mevalonate incorporation into cholesterol. In addition, the mRNA abundance of 3-hydroxy-3-methylglutaryl-CoA reductase, a rate-limiting enzyme in cholesterologenesis pathway, as well as its activity, was determined. Finally, the mRNA level of liver sterol regulatory element-binding protein-2, a nuclear transcription factor engaged in intracellular cholesterol homeostasis, was measured., Results: Experimental CRF was associated with significantly increased concentrations of serum and liver cholesterol. In vitro and in vivo cholesterologenesis was enhanced in CRF rats. A cholesterol-enriched diet resulted in a significant decrease in (1) in vivo and in vitro cholesterol synthesis, (2) 3-hydroxy-3-methylglutaryl-CoA reductase gene expression, and (3) the level of liver sterol regulatory element-binding protein-2 mRNA in CRF rats., Conclusions: Despite elevated plasma and liver cholesterol concentrations, cholesterologenesis is increased in CRF rats. It is, however, inhibited by dietary cholesterol. These results suggest that a feedback inhibition of cholesterologenesis by dietary cholesterol is preserved in experimental CRF.

End-stage renal disease (ESRD) is associated with significantly increased morbidity and mortality resulting from cardiovascular disease (CVD) and infections, accounting for 50% and 20%, respectively, of the total mortality in ESRD patients. It is possible that these two complications are linked to alterations in the immune system in ESRD, as uremia is associated with a state of immune dysfunction characterized by immunodepression that contributes to the high prevalence of infections among these patients, as well as by immunoactivation resulting in inflammation that may contribute to CVD. This review describes disorders of the innate and adaptive immune systems in ESRD, underlining the specific role of ESRD-associated disturbances of Toll-like receptors. Finally, based on the emerging links between the alterations of immune system, CVD, and infections in ESRD patients, it emphasizes the potential role of the immune dysfunction in ESRD as an underlying cause for the high mortality in this patient population and the need for more studies in this area.

Background & Aims: Muscle wasting is considered the best marker of protein-energy wasting in end-stage renal disease (ESRD). We tested the usefulness of a simple observer subjective muscle atrophy (MA) grading in relation to morbidity and mortality in ESRD patients., Methods: In two different ESRD cohorts (265 incident patients starting dialysis and 221 prevalent hemodialysis patients), each patient's degree of MA was visually graded by a trained nurse on a scale from 1 to 4 as part of the subjective global assessment. This score was confronted with inflammatory and nutritional indexes as well as objective measurements of muscle atrophy. Patients were then prospectively followed for up to four or six years, depending on the cohort., Results: Thirty percent of the incident and 39% of the prevalent patients presented signs of MA. Across worsening MA scale, nutritional and anthropometric markers of muscle loss were incrementally poorer. Inflammation markers as well as the proportion of women became progressively higher. Female sex, presence of cardiovascular disease, inflammation and low insulin-like growth factor-1 levels were associated with increased significant odd ratios of MA in each cohort. After adjustment for age, sex, inflammation, diabetes, cardiovascular disease, glomerular filtration rate and/or time on hemodialysis, the hazard ratio of death for moderate/severe MA was 2.62 (95% CI: 1.34, 5.13; p=0.001) and 3.04 (95% CI: 1.61, 5.71; p=0.0001) in the incident and prevalent cohorts respectively., Conclusion: Increased MA is more common in female dialysis patients and associated with inflammation, poor nutritional and anthropometric status, as well as a 3-fold increased 4-6 year mortality. Our data support the use of frequent MA and/or nutritional assessments in the clinical practice.

Sterol regulatory element-binding protein-2 (SREBP-2) is a transcription factor regarded as the main regulator of cholesterol homeostasis. Therefore, increased level of SREBP-2 could be responsible for hypercholesterolemia, which is observed in experimental chronic renal failure (CRF). This study was designed primary to evaluate the impact of experimental CRF (5/6 nephrectomy model) on rat liver SREBP-2 gene expression. In CRF rats, a twofold increase in SREBP-2 mRNA level, as well as in mature SREBP-2 protein abundance was found, when compared to control animals. It was associated with enhanced activity and mRNA abundance of liver HMG-CoA reductase, a rate-limiting enzyme for cholesterol biosynthesis. A twofold increase in liver cholesterologenesis rate was also noted. We conclude that experimental CRF is associated with increased liver SREBP-2 gene expression. This is probably the cause for enhanced HMG-CoA reductase gene expression and, consequently, for increase in liver cholesterol synthesis in CRF rats. Despite increased SREBP-2 gene expression we found LDL-receptor mRNA level to be lower than in controls, suggesting SREBP-2 independent mechanisms of LDL-receptor transcriptional regulation in CRF rats. Enhanced cholesterol synthesis and decreased LDL-receptor mRNA level are probably responsible for an almost fourfold increase in serum cholesterol concentration in CRF rats.

Anorexia is possibly one of the most important causes of malnutrition in uremic patients. The cause of this abnormality is still unknown. Considering that: (a) NPY is one of the most important stimulants of food intake; (b) eating is a central nervous system regulated process and (c) NPY is expressed in hypothalamus, we hypothesized that the decrease of NPY gene expression in the hypothalamus could be an important factor contributing to anorexia associated with uremic state. In contrast to the prediction, the results presented in this paper indicate that the NPY gene expression in the hypothalamus of chronic renal failure (CRF) rats was significantly higher than in the hypothalamus of control (pair-fed) rats. Moreover, we found that serum NPY concentration in CRF rats was higher than in control (pair-fed) animals. The increase of plasma NPY concentration in CRF rats may be due to the greater synthesis of the neuropeptide in liver, since higher level of NPY mRNA was found in liver of CRF rats. The results obtained revealed that experimental chronic renal failure is associated with the increase of NPY gene expression in hypothalamus and liver of rats.

Endothelial dysfunction (ED) in peritoneal dialysis patients plays pivotal role in progression of atherosclerosis and hemostasis disturbances. Malnutrition is one of the most important complication of PD. Both ED and malnutrition cause higher rate of cardiovascular events in these patients. 32 PD patients were analyzed. Endothelial function was assessed by measurements of serum level of vWF:Ag; t-Pa:Ag; TM:Ag. Nutritional status assessment included: body mass index-BMI, MAMC measurements; and serum albumin, total protein, prealbumin, transferrin, cholesterol, insulin, insulin like growth factor-1 (IGF-1). There were higher levels of vWF:Ag but lower of t-PA:Ag and TM:Ag after 12 month of observation. Serum levels of prealbumin, insulin, cholesterol were stable, but there were lower levels of albumin, IGF-1, and higher of transferrin at the end of the follow up. There were no differences in anthropometric indices during the follow up. We found statistically significant linear correlations: t-Pa:Ag vs prealbumin; t-Pa:Ag vs cholesterol; TM:Ag vs albumin. In the course of 12 months observation of peritoneal dialysis patients we found deterioration of endothelial function, expressed by evaluated endothelial antigens. Some correlations found in our study might express close relationship between endothelial function markers and nutritional status.

Background: Patients with chronic renal failure (CRF) are at increased risk of atherosclerosis development. One of the major steps in pathogenesis of atherosclerosis is formation of foam cells. Scavenger receptor CD36 is among the major receptors for oxidized low density lipoproteins (oxLDL) and therefore it plays a crucial role in foam cell formation. The aim of the present study was to investigate the expression of CD36 on blood monocytes of CRF patients., Methods: Expression of CD36 on blood monocytes of CRF patients treated with hemodialysis (HD), peritoneal dialysis (PD), those not yet on dialysis (predialysis), and controls was assessed with the use of flow cytometry. Additionally, the major lipid peroxidation markers, malondialdehyde (MDA) and 4-hydroxyalkenals (HAE), were measured. Further, impact of treatment with HMG-CoA reductase inhibitors (statins) on CD36 expression in CRF patients was evaluated., Results: Expression of monocyte CD36, measured as mean fluorescence intensity (MFI) was significantly higher in HD and PD patients, when compared to controls without renal insufficiency (respectively: 1011 +/- 288 and 1000 +/- 309 vs. 710 +/- 313; P < 0.01 for both groups). This was not the case in predialysis group (828 +/- 363 vs. 710 +/- 313). Higher concentrations of lipid peroxidation indicators, MDA and HAE were observed in all three subgroups of CRF patients (2.1 +/- 0.51, 2.02 +/- 0.27, and 1.81 +/- 0.53 microm in HD, PD, and predialysis group, respectively, vs. 1.13 +/- 0.59 microm in controls; P < 0.01). Patients treated with statins showed significantly lower CD36 expression than patients without statin therapy., Conclusions: The present study, for the first time, demonstrates increased expression of CD36 scavenger receptor in CRF patients. This may be a possible risk factor for accelerated atherogenesis observed in this group of patients.

Lipid disturbances are a constant feature of chronic renal failure (CRF). They compose a significant risk factor for vascular complications, leading to increased morbidity and mortality in this patients group. The major lipid abnormality in the course of CRF is hypertriglyceridemia, but increased cholesterol level is also common. Numerous studies, including these from our Centre, point to the conclusion that hypertriglyceridemia is a consequence of both, increased TG production and impaired TG removal. In contrast hypercholesterolemia is mainly due to enhanced cholesterol biosynthesis. HMG-CoA reductase inhibitors (statins) compose the most promising group of drugs to treat lipid abnormalities in CRF. Apart from their lipid-lowering abilities they possess non-lipid, so called pleiotropic activities, which make them especially useful in proliferative and inflammatory kidney diseases.

Lipid disorders are one of the known metabolic changes associated with chronic renal failure (CRF) [1, 2]. They are present as: hypertriglyceridemia--existed in 60% of CRF patients and hypercholesterolemia observed in 20-30% of people with this syndrome. These disorders, what was shown also in our own studies, are existing in different intensity in patients treated with maintenance haemodialysis [3], peritoneal dialysis [4] and after renal transplantation as well [5]. Mechanism of hypertriglyceridemia, despite over thirty years of studies, is still not finally elucidated. The opinion that it is a result of impaired triglyceride removal (due to decreased activities of both lipoprotein and hepatic lipases) is well documented, however the role of lipogenesis in its development is obscure [6, 7]. The reports concerning this problem contain contradictory data. In our studies performed several years ago we have shown that lipogenesis rate in white adipose tissue of uremic rats is significantly augmented [8, 9, 10] due to activation of free fatty acid synthase. Therefore, recently we paid once again our attention on the activity of this lipogenesis rate limiting enzyme responsible for the long term regulation. We measured its activity, protein abundance and mRNA level in liver and epididymal white adipose tissue of rats with surgically induced renal failure (two-stage subtotal nephrectomy). The results support the thesis that lipogenesis takes a part in a hypertriglyceridemia found in renal failure. There have been observed a significant increase in plasma triglyceride and VLDL concentrations in uremic animals and it was associated with the increase of FAS activity, FAS protein abundance and FAS mRNA. The results were similar in both studied tissues. Moreover, there have been also observed the increased activities of malic enzyme, glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase. All these enzymes participate in NADPH production, which is a necessary substrate for fatty acid biosynthesis [11, 12, 13]. Concluding, it appears that the rise in plasma triglyceride and VLDL concentrations observed in CRF rats is not only the result of increased liver and white adipose tissue lipogenesis rate. One has to remember, that these date are strictly original and enabling to elucidation further pathogenesis of hyperlipidemia in CRF. In the second set of experiments performed also in rats with experimentally induced CRF we have found that hypercholesterolemia observed in those animals is dependent on the significant activation of cholesterol synthase, induced by increased production of this enzyme (increment of protein abundance and synthase mRNA [14, 15]. Simultaneously, we have performed original studies on the diurnal rhythm of cholesterologenesis, showing that activity of this process is significantly augmented during whole twenty four hours [15]. Summarizing, one have to underline that our observations have important impact to the elucidation of lipid disturbances pathomechanism. Nevertheless further studies are necessary to establish how experimental data are corresponding with human pathology.

The aim of the present study was to examine hypothesis that the enhanced cholesterologenesis, found in rats with experimental chronic renal failure (CRF) resulted from the increased gene expression of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase--the rate limiting enzyme in the cholesterologenesis pathway, responsible for mevalonate synthesis. Wistar rats were used and experimental CRF was achieved by 5/6 nephrectomy model. We examined: (a) the changes in the rat liver microsomal HMG-CoA reductase activity, (b) the rat liver HMG-CoA reductase mRNA abundance in various times of day. Obtained data indicates that the increased activity of HMG-CoA reductase in the liver of rats with experimental CRF parallel enhanced mRNA level and suggests that enhanced cholesterol biosynthesis, observed in experimental CRF is at least in part due to the increased HMG-CoA reductase gene expression. The results also indicate that the physiological diurnal rhythm of HMG-CoA reductase activity is preserved in the course of experimental CRF.

Hypercholesterolemia plays an important role in the lipid abnormalities in chronic renal failure (CRF). It is thought to contribute to both a progression of renal failure and atherosclerosis. Despite intensive research, the etiopathogenesis of hypercholesterolemia in CRF patients is still obscure. The present study was designed to evaluate the possible role of cholesterol overproduction in the development of hypercholesterolemia associated with experimental CRF. We found that plasma total cholesterol and cholesterol distributed in VLDL, LDL and HDL concentrations were significantly enhanced in CRF rats. Simultaneously, the rate of liver cholesterol biosynthesis in vivo (measured by determining the incorporation of tritium from tritiated water intraperitoneally injected into cholesterol ), liver microsomal 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity and liver HMG-CoA reductase mRNA presence were elevated. Significant increases in activity of liver malic enzyme, glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, NADPH-producing enzyme (required for cholesterol synthesis) have also been observed in CRF rats. In conclusion, the increased rate of liver cholesterol biosynthesis due to increase of HMG-CoA reductase and NADPH-producing enzyme gene expression could be one of the possible causes of hypercholesterolemia in CRF animals.

Changes in lipid metabolism are an important risk factor for vascular complications during chronic renal failure (CRF). In experimental CRF hypercholesterolemia has been found to be the main lipid disorder. It is probably due to enhanced cholesterologenesis. Mechanisms of these changes remain poorly understood. It is well known that activity of cholesterologenesis undergoes a significant diurnal rhythm. However, there was no evidence that this rhythm is still present in the course of experimental CRF. Results of our studies indicate that in contrast to puromycin induced nephrotic syndrome, diurnal rhythm of cholesterologenesis in CRF rats is preserved both in liver and in the intestine tissue. Significant higher incorporation of tritiated water into cholesterol fraction was found in vivo both in liver as well as in intestine of CRF rats, as compared to control animals. Increased (with comparison to the controls) incorporation of 14C-acetate, and 3H-mevalonate into CRF rat liver sterols indicate that mechanism of enhanced cholesterologenesis is more complex than simply due to the elevated level of mevalonate (potential substrate for cholesterologenesis) which has been reported in plasma of CRF animals.