Relationship between inflammatory cytokines and cardiorenal anemia syndrome: treatment with recombinant human erythropoietin (rhepo).

BACKGROUND AND AIM: Hemodialysis (HD) patients are exposed to persistent inflammatory state. Erythropoietin resistance is known to be strongly associated with chronic inflammation. Aim of the study was to analyze the effect of elevated inflammatory markers on hemoglobin levels and rhEPO requirements in stable patients of our hemodialysis center. PATIENTS AND METHODS: The study population consisted of 42 patients, 19F/23M, mean age 54.5+/-12.0 years. C-reactive protein (CRP), interleukin-6 (IL-6), hemoglobin (Hb), ferritin and left ventricular mass index (LVMi) were recorded. Group 1 consisted of 10 patients with Hbor=10 g/dl, mean 12.6+/-1.91 g/dl. None of these 20 patients had been previously treated with rhEPO. Group 3 consisted of 22 patients with mean Hb 10.1+/-1.5 g/dl after treatment with rhEPO. RESULTS: Group 1 patients had significantly higher IL-6 concentrations than Group 2 (5.21+/-3.94 vs 3.03+/-3.64, p<0.03). Group 3, treated with rhEPO had IL-6 concentrations significantly lower compared to Group 1 (1.15+/-3.81 vs 3.03+/-3.64, p<0.05). HD pts in Group 1 presented significantly higher CRP concentrations compated to pts of Group 2 and 3 (23.1+/-9.1 vs 7.02+/-8.7 and 7.89+/-9.6 respectively, p<0.05). A negative correlation was demonstrated between IL-6 and Hb level (r: 0.33 p<0.05). CONCLUSIONS: A better management of anemia might improve inflammatory state and survival in this population.

Inflammatory cytokines and malnutrition as related to risk for cardiovascular disease in hemodialysis patients.

Malnutrition and inflammation are associated with end-stage renal disease (ESRD). Interleukin (IL)-6 and tumor necrosis factor alpha (TNF-alpha) powerfully predict death from cardiovascular disease. The aim of our study was to establish an association between markers of inflammation and parameters of malnutrition in patients on hemodialysis. The study population consisted of 42 hemodialysis patients with different parameters of malnutrition. Blood samples were taken after an overnight fast, and plasma lipid profiles (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides) were measured by using conventional enzymatic methods. Serum urea and creatinine levels were also measured by routine procedures. Plasma high-sensitivity C-reactive protein level (hs-CRP), TNF-alpha, and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA). Standard Doppler echo examinations were used to determine plaque on carotid arteries, and end-diastolic diameter (EDD) and ejection fraction (EF) were measured by echocardiography. Malnourished patients exhibited significantly greater evidence of cardiovascular disease and carotid plaques. Factor (principal component) analysis indicated 6 latent factors with 67.5% of the variance explained within all investigated parameters. Cluster analysis was used to distinguish the inflammatory markers and the nutritional markers from other parameters and to visualize similarities between variables. In summary, this cross-sectional study in hemodialysis patients found a high prevalence of malnutrition, inflammation, carotid plaques, and cardiovascular disease. Malnourished dialysis patients are more often found with cardiovascular disease and carotid plaques. In addition, these patients have higher levels of inflammatory cytokines, which may partly explain the elevated risk for atherosclerotic vascular disease.

Effects of N-3 PUFAs supplementation on insulin resistance and inflammatory biomarkers in hemodialysis patients.

AIMS/HYPOTHESIS: It was suggested that polyunsaturated n-3 fatty acids (n-3 PUFAs) could improve insulin sensitivity and have an anti-inflammatory effects in overall population. This study investigates a possible effect of n-3 PUFAs supplementation on the insulin sensitivity and some inflammatory markers; hence, patients with chronic renal failure (CRF) on maintenance hemodialysis (MHD) are presented with insulin resistance. METHODS: This study explored the ratio between red blood cells (RBC) phospholipid long chain fatty acids (LC FAs) and components of metabolic syndrome (MeS) in 35 patients (mean age 54.50 +/- 11.99 years) with CRF on MHD. Furthermore, the effects of omega-3 FA eight-week's supplementation (EPA+DHA, 2.4 g/d) on the MeS features and inflammatory markers TNF-alpha, IL 6, and hsCRP were examined. RESULTS: Supplementation increased EPA and DHA levels in RBCs (p = 0.009 for EPA and p = 0.002 for DHA). Total n-6 PUFAs: n-3 PUFAs ratio tended to be lower after supplementation (p = 0.31), but not significantly. Data revealed a significant decrease of saturated FAs (SFA) (p = 0.01) as well as total SFA: n-3 PUFAs ratio during the treatment (p = 0.04). The values of serum insulin and calculated IR index-IR HOMA were reduced after supplementation (p = 0.001 for both). There was a significant decrease in the levels of all inflammatory markers (p = 0.01 for TNF alpha, p = 0.001 for IL 6, p = 0.001 for hsCRP, and p = 0.01 for ferritin). In multivariate regression analysis, only the changes in n-6 PUFAs: n-3 PUFAs ratio independently contributed to 40% of the variance in IR HOMA. The impact of changes in PUFAs level in RBCs membrane phospholipid fatty acids on inflammation markers was also registered. The changes in n-6: n-3 PUFAs ratio independently contributed to 18% of the variance in TNF alpha. CONCLUSION: It was concluded that the EPA and DHA moderate dose administration in the patients with CRF on MHD had a beneficial effect on insulin resistance decrease. The anti-inflammatory effects of the supplemented PUFAs were also presented.

Epidemiology of end-stage renal disease and current status of hemodialysis in Yugoslavia.

Maintenance hemodialysis (HD) in Yugoslavia started in the sixties and followed the dialysis trends in the Western Europe. However, in the last decade the development of renal replacement therapy (RRT) slowed down. In this report the epidemiology of ESRD from 1997-1999 and the survey of the status of HD treatment in Yugoslavia in 1999 are presented. Epidemiological data are obtained by the annual center questionnaires (response rate: 92.6 -94.2%). The survey of HD status is based on a specific questionnaire and covered 2108 patients (65%). At the end of 1999 there were 56 RRT centers in Yugoslavia treating 3939 patients: 3232 (82%) patients by HD, 248 (6.3%) by peritoneal dialysis, and 459 (11.7%) living with transplanted kidney. In a three year period, incidence of ESRD ranged from 108-128 pmp, point prevalence from 435-463 pmp and mortality rate from 20.7-17.9. Numerous refugee patients were treated over the last 10 years. Main causes of ESRD were glomerulonephritis (30%); Balkan nephropathy represented 11% and diabetic nephropathy 7% of all primary renal diseases. Cardiovascular and cerebrovascular diseases were the most common causes of death of RRT patients. Most centers are overcrowded and HD machines are worn out. Mean Kt/V was 1.19+/-0.08, mean URR% 58.8+/-7.4. The shortage of drugs prevented adequate management: 83% of HD patients had hemoglobin level less than 100 g/L but only 10.3 -17.8% were treated with rHuEpo; 64.5% of patients had phosphate levels higher than 1.7 mmol/L but only 33.5% used phosphate binders; 47% of patients had hypertension despite the antihypertensive therapy. The prevalence of hepatitis B remained unchanged (about 14%) in HD population during the last three years, but the prevalence of anti-HCV positive patients decreased (31-23%). In conclusion, there is a well developed dialysis service in Yugoslavia but insufficient conditions for adequate treatment.

[Clinical significance and pathogenic mechanisms of insulin resistance in chronic renal insufficiency (part II): pathogenic factors of insulin resistance in chronic renal insufficiency]. / Klinicki znacaj i patogenetski mehanizmi insulinske rezistencije u hronicnoj bubreznoj insuficijenciji (II deo): patogenetski faktori insulinske rezistencije u hronicnoj bubreznoj insuficijenciji.

INTRODUCTION: Factors implicated in the pathogenesis of insulin resistance in chronic renal failure are: uremic toxins, exercise tolerance, metabolic acidosis, secondary hyperparathyroidism, vitamin D deficiency. Many of them may contribute, but are not the main cause of insulin resistance in uremia. The aim of this review is to debate about each, separately. UREMIC TOXINS: Hippurate and pseudouridine are specific for uremia and inhibit glucose utilization at concentrations found in sera of uremic subjects. Partially purified toxins from uremic sera, after hemodialysis therapy, ameliorate beta-cell response to hyperglycemia and increase tissue sensitivity to insulin. EXERCISE INTOLERANCE: Exercise intolerance is common among hemodialysis patients, and also it can be the cause of insulin resistance. Moderate endurance training program improved both the exercise tolerance and insulin sensitivity in patients on hemodialysis. METABOLIC ACIDOSIS: Metabolic acidosis is frequent in uremia, but not in hemodialysis patients. Treatment of metabolic acidosis increases insulin sensitivity and insulin secretion, but significant degree of insulin resistance still exists in uremic patients. SECONDARY HYPERPARATHYROIDISM: After surgical correction of hyperparathyroidism, in hemodialysis patients, glucose tolerance and insulin secretion increase without significant changes in insulin sensitivity. Defect in insulin release attributable to reduced ATP content in the pancreatic islets induced partially by high intracellular calcium, secondary to augmented PTH-induced calcium entry into cells. VITAMIN D DEFICIENCY: Acute and chronic intravenous 1,25-Dihydroxycholecalciferol therapy corrects insulin resistance in dialysis patients, in absence of PTH suppression. These results are consistent with the hypothesis that 1,25(OH)2 D3 deficiency is a primary factor of insulin resistance. ERYTHROPOIETIN THERAPY: Corrects insulin resistance beside anaemia. CONCLUSION: Now we know more about pathogenesis of insulin resistance in uremic patients, and we must begin with early treatment of every pathogenic factor. Insulin sensitivity improved after hemodialysis, although it was still lower than control values.

[Apolipoproteins as risk factors in patients on a regular hemodialysis program]. / Apolipoproteini kao faktori rizika kod bolesnika na hronicnom programu hemodijalize.

Apolipoprotein abnormalities in patients undergoing permanent hemodialysis programme appear to be risk factors for development of cardiovascular diseases. Our aim was to determine the presence of risk factors of lipidic origin in these patients. We examined a group of 45 patients on hemodialysis--26 males (average age of 52.4 years) and 19 females (average age of 51.3 years). The patients were divided into normolipemic (n = 23) and hyperlipemic group (n = 22). The control group consisted of nine men (average age of 55.7 years) and nine women (average age of 58.3 years). The values of triglycerides, total cholesterol, HDL-cholesterol, LDL-cholesterol (computatively), apolipoprotein AI and apolipoprotein B were determined. There was not statistically significant difference of atherosclerosis index (LDL-cholesterol/HDL-cholesterol) between normolipemic and hyperlipemic group of patients, as well as in relation to the control group. The relation between apo B/apo AI in both groups was significantly different in relation to the control group (p = 0.0001, p = 0.0001); difference found between normolipemic and hyperlipemc group was also important (p = 0.003). The obtained results show that examination of apolipoprotein AI and apolipoprotein B in case of patients on hemodialysis, both noromolipemic and hyperlipemic, indicates the presence of risk factors for coronary diseases and atherosclerosis.

[Hyperinsulinism in hyperlipoproteinemia in patients on a chronic hemodialysis program]. / Hiperinsulinizam u hiperlipoproteinemiji kod bolesnika na hronicnom programu hemodijalize.

The aim of this study was to establish possible hyperinsulinemia, as a consequence of insulin resistance in chronic hemodialysis patients. We examined 45 HD (hemodialysis) patients and 18 healthy subjects. On an empty stomach the following parameters were established: glucose, insulin, triglycerides, total cholesterol, HDL (high-density lipoprotein)-cholesterol and LDL (low-density lipoprotein)-cholesterol. Body mass index and waist-hip ratio were also examined. Hyperlipoproteinemia was established in 22 patients (21 with type IV and 1 with type II b), while 23 patients were normolipidemic. Insulinemia was significantly increased in the group of patients with hyperlipoproteinemia, both comparing normolipidemic patients and healthy subjects (x1 = 20.7; p = 0.0001; x2 = 13.2, p = 0.0001; x3 = 11.3, p = 0.0001). In the group with hyperlipoproteinemia there was a positive correlation between levels of insulinemia and triglyceridemia (r = 0.41, p = 0.05). It can be concluded that hyperinsulinemia in the group of patients with hyperlipoproteinemia, on hemodialysis, is an imperative for treating insulin resistance, and in that way causes of lipoprotein metabolism disorders.

[Visceral protein status and hyperlipoproteinemia in patients on hemodialysis]. / Visceralni proteinski status i hiperlipoproteinemije kod bolesnika na hemodijalizi.

Long-term therapy and inadequate diet regimens in terminal phase patients with renal insufficiency lead to loss of body weight which causes changes in anthropometric indexes. The occurrence of hypoalbuminemia in chronic hemodialysis patients without nephrotic syndrome, is a clear sign of malnutrition. The aim of this study was to establish the visceral protein status in these patients as well as to find if there is a difference in this status in regard to hyperlipemic and normolipemic patients. 45 chronic dialysis patients were examined: 26 males with a mean age of 52.4 years and 19 females with a mean age of 51.3 years. They were divided into two groups: the first group of 22 hyperlipemic patients and the second group of 23 normolipemic patients. The control group consisted of 18 healthy subjects (9 females with a mean age of 58.3 years and 9 males with a mean age of 55.7 years). In regard to lipid fractions we determined the total cholesterol, HDL (high density lipoprotein), LDL (low density lipoprotein) cholesterol and triglycerides. The following anthropometric indexes have been used: BMI (body mass index) and muscle mass index (triceps). Albuminemia was performed in all subjects as an indicator of undernutrition. There was a significant difference in albumin level in hyperlipemic and healthy subjects (p = 0.0001), as well as normolipemic and healthy subjects (p = 0.0001), whereas no significant difference was established between hyperlipemic and normolipemic subjects. Values for triceps as a muscle mass index significantly differed in the group of normolipemic subjects (p = 0.03). Body mass index did not significantly differ among groups. In the group of normolipemic subjects BMI was significantly in correlation with values for triceps (p = 0.001). Significant correlation between albumin level and anthropometric indexes was not established. Gathered results indicate that in the group of normolipemic hemodialysis patients malnutrition can be dangerous.

[Lipid status in patients on a chronic hemodialysis program]. / Lipidni status bolesnika na hronicnom programu hemodijalize.

Dyslipidemia causes development of atherosclerosis in chronic hemodialysis patients. The goal of this study was to determine values of serum lipids in hemodialysis patients. The study comprised 45 patients, whereas the control group consisted of 45 healthy persons of corresponding age and sex. We determined triacyglycerols, total cholesterol, HDL (high density lipoprotein) and LDL (low density lipoprotein) cholesterol in the serum of patients on an empty stomach. There were 51% of patients with normal findings, and 49% with hyperlipoproteinemia type IV. In regard to the control group triacyglycerol was increased both in patients with hyperlipoproteinemia type IV and in patients with normolipemia. Levels of total cholesterol were higher in patients with hyperlipoproteinemia type IV, while values of HDL cholesterol were decreased in both subgroups of patients in regard to the control group. Values of total cholesterol in relation to HDL cholesterol > 4.5 occurred in 38% of patients. Lipid profile of hemodialysis patients, including those with normolipidemia, points to high risk of cardiovascular diseases.

[Serum phospholipids in patients in a chronic hemodialysis program]. / Fosfolipidi seruma u bolesnika na hronicnom programu hemodijalize.

The aim of this investigation was to determine concentrations of total and single phospholipids and to examine distribution of phospholipid fractions in serum of chronic hemodialysis patients. The investigation included 21 patients, 10 with normal lipid level in serum and 11 with hyperlipoproteinemia type IV. The control group consisted of 17 healthy normolipidemic persons. The gathered results show that in hemodyalisis patients the level of phospholipids (3.10 +/- 0.66 mmol/L) is higher than the level of phospholipids in the control group (2.25 +/- 0.35 mmol/L). Dialysis patients with hyperlipoproteinemia type IV have an increased level of serum phospholipids (3.51 +/- 0.43 mmol/L) in regard to dialysis patients with normolipidemia (2.46 +/- 0.57 mmol/L). The distribution of phospholipid fractions, that is proportional occurrence of lysophosphatidylcholine, sphingophospholipids and phosphatidylcholine is disturbed in dialysis patients no matter what their lipid status is.

[Hepatitis C virus infection in patients on chronic hemodialysis]. / Infekcija virusom hepatitisa C kod bolesnika na hronicnoj hemodijalizi.

Frequency of HCV infection was examined in patients on chronical program of hemodialysis considering the high risk to which they had been exposed because of frequent blood transfusion. We determined anti-HCV antibodies in 57 patients (29 male and 28 female) average age 52.6 years with terminal chronic renal failure. Frequency of anti-HCV antibodies (determined by ELISA Ortho test of first generation) was in correlation with the number of received transfusions and with duration of dialysis treatment and it was compared with anti-HCV antibody findings in hemodialysis staff (the control group of healthy persons). Results of the examination showed that anti HCV antibodies were positive in 38.95% examined patients (n = 57), and it showed that the patients on hemodialysis were a critical group for HCV infection. There was no correlation with the blood groups. Level of transaminases, HBsAg and immunity test in anti-HCV positive patients were in the physiological range. In order to prevent HCV infection in the dialysis centres, it is necessary to conduct routine test in patients and staff, and undertake all measures of protection.

[Lupus nephritis: clinico-morphologic correlation]. / Lupusni nefritis: klinicko-morfoloska korelacija.

The aim of the study was to determine the correlation between some clinical parameters and histopathologic findings in patients with lupus nephropathy. Eighteen patients (17 female and one male) with the diagnosis of lupus nephritis were examined at the Nephrological Clinical of the Faculty of Medicine. Three to eight months passed between diagnosing systemic lupus erithematosus and kidney biopsy. At the time of biopsy the average age of patients was 33.3 +/- 2.9 years (18-52 years). In more than half of the 18 cases the disease was evidenced as nephrotic syndrome, but most of them had renal failure and increased blood pressure. In patients with diffuse proliferative glomerulonephritis proteinuria was significantly higher than in other histopathologic groups. Serum nitrogen was considerably higher while creatinine clearance was much lower in patients with diffuse proliferative glomerulonephritis than in other histopathologic groups. Circulating immune complexes were increased, and the complement (C3 and C4) concentration was slower in patients with lupus nephropathy, but the significant difference was present only when diffuse glomerulonephritis was compared to other histopathologic groups.