Anemia is independently associated with NT-proBNP levels in asymptomatic predialysis patients with chronic kidney disease.

BACKGROUND: Although anemia and renal dysfunction are related to increased natriuretic peptides levels in heart failure patients, less is known about this relationship in asymptomatic predialysis patients with chronic kidney disease (CKD). The aim of this study was to investigate relationship between hemoglobin (Hb) concentration, N-terminal proBNP (NT-proBNP) levels and echocardiographic findings in these patients. METHODS: The study included 61 patients with CKD stage IV-V (34 male, mean age 62.6 ± 13.6 years) and 22 age- and sex -matched healthy persons as control group. All participants underwent clinical, laboratory and echocardiographic examination, including Tissue Doppler Imaging and colour M-mode Doppler. RESULTS: Patients with CKD had lower Hb levels (p<0.001), and higher levels of NT-proBNP (p<0.001) than healthy controls. Patients were divided into two groups according to their mean Hb levels: group A, Hb<10.3 g/dL and group B, Hb≥10.3 g/dL. Patients from group A was significantly older (p<0.001), left ventricular mass index was significantly higher (LVMI, p<0.001), LV diastolic function was worse (septal and lateral E'/A' ratio: p<0.05 and p<0.01, respectively), and the level NT-proBNP was higher (p<0.001) compared to patients from group B. The natural logarithm of NT-proBNP (lnNT-proBNP) showed highly significant correlation with Hb (p<0.001) and significant correlation with estimated glomerular filtration rate (p=0.035) in CKD patients. Multiple regression analysis revealed Hb levels (p<0.01), cholesterol (p<0.001), LV ejection fraction (p<0.001) and septal E/E' ratio (p<0.01) as the independent variables predicting as much as 54% variability of lnNTpro-BNP. CONCLUSIONS: The increased NT-proBNP levels in asymptomatic patients with advanced CKD were independently associated with echocardiographic parameters of LV function, but anemia may represent one of the important confounder of the relationship between NT-proBNP and cardiovascular abnormalities.

Bilateral ureteral obstruction due to primary myelofibrosis caused hyperuricaemia.

In healthy population, uric acid comprises the major component of 10-20% of renal stones. Extreme hiperuricaemia is seen in cancer patients with tumour lysis syndrome (TLS) which is classically associated with haematological malignancies with rapid tumour growth rates such as acute lymphoid leukaemia and high grade lymphomas. Primary melofibrosis (Agnogenic myeloid metaplasia-AMM) is a chronic myeloproliferative disease characterized by splenomegaly, a leukoerythroblastic blood picture, teardrop poikilocytosis and varying degrees of marrow fibrosis. Due to the increased extramedullary haematopoiesis, hiperuricemia may occur. However, TLS in patients with AMM is, according to the available literature, described just in one patient. In this paper we present a case of a 47-year-old male patient who was admitted to the hospital with symptoms of fatigue and small amount of urine, and clinical signs of plethora and enlarged spleen. The laboratory findings showed leuko-and erythrocytosis, increased levels of urea-BUN (32 mmol/l) and creatinine (766 mmol/l) as well as uric acid (920 mmol/l). The immediate abdominal ultrasound confirmed extreme splenomegaly, but also showed bilateral hydronephrosis of grade II-III with two stones in proximal part of right ureter and one in proximal part of left ureter as well as empty bladder. Stones were not seen on plain film. Since the patient was in complete anuria, with further rapid elevation of BUN and creatinine levels, bilateral ureteral stents were applicated together with extensive hydration, urine alkalization and administration of allopurinol which resulted in the complete recovery of kidney function. The bone marrow biopsy was also performed and histopathological diagnosis was: Hypercellulary phase of AMM.

Paraneoplastic bleeding disorder due to isolated hypofibrinogenemia: a case report.

An 80 years old male patient was admitted in our hospital with massive haematomas in the left forearm, chest and abdominal wall accompanied by intense back pain symptoms. Laboratory evaluation showed anemia, mild thrombocytopenia and elevated lactate dehydrogenase and alkaline phosphatase levels and normal concentrations of all the other biochemical parameters. Study of the coagulation status demonstrated prolonged thrombin time (TT), low fibrinogen levels--0.98 g/l while plasminogen, antithrombin III (AT III) and protein C levels were found to be within normal range. Computed tomography scans of the head, chest and abdomen showed an enlarged infiltrative prostate, osteolytic bone lesions in vertebras L5-S1 and a large haematoma of the abdominal wall as the only pathologic findings. Very high levels of the prostate specific antigen indicated the possible existence of a prostate carcinoma with metastases to the vertebral column that resulted in elevated alkaline phosphate and lactate dehydrogenase levels. There were no signs of liver involvement and impaired hepatic synthetic function. Based on the results of the laboratory tests we concluded that the cause of the bleeding disorder in our patient was an acquired hypofibrinogenemia, which is a very rare paraneoplastic phenomenon. The patient was treated with daily transfusions of cryoprecipitate with no long-term improvement. Then the specific anti-tumor therapy (ciproteron acetate) was initiated, and two weeks later, fibrinogen concentration and TT returned to normal values.

The effect of recombinant human erythropoietin treatment on insulin resistance and inflammatory markers in non-diabetic patients on maintenance hemodialysis.

BACKGROUND AND AIM: Iron overload and inflammation might participate in the pathogenesis of insulin resistance in community. The improvement of insulin resistance in hemodialysis (HD) patients is frequently seen after correction of anemia. The aim of this study was to investigate the influence of recobinant humam erythropoietin (Epo) treatment on insulin resistance in non-diabetic HD patients. PATIENTS AND METHODS: We investigated the effects of 6 months-duration treatment with Epo on insulin resistance and inflammatory parameters in 16 (6 male/10 female) patients on maintenance HD with renal anemia (hemoglobin concentration

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.

[Clinical importance and pathogenic mechanisms of insulin resistance in chronic renal insufficiency (part I): insulin resistance in patients with chronic renal insufficiency]. / Klinicki znacaj i patogenetski mehanizmi insulinske rezistencije u hronicnoj bubreznoj insuficijenciji (I-deo): insulinska rezistencija kod bolesnika sa hronicnom bubreznom insuficijencijom.

INTRODUCTION: This paper presents new investigations of abnormal insulin action in patients with chronic renal failure. Reduced tissue sensitivity to insulin action and the effects of the impairments on carbohydrate, protein and lipid metabolism have important pathophysiological implications in the genesis of the uremic syndrome. We analyzed confounding factors of reduced insulin sensitivity and potential sites of insulin resistance. INSULIN RESISTANCE IN HUMANS: Insulin resistance is associated with a number of metabolic and vascular abnormalities known as "syndrome X" or metabolic syndrome. Other features include obesity, particularly truncal distribution, glucose intolerance and non-insulin-dependent diabetes mellitus (NIDDM), hypertension, a specific dyslipidemia with raised triglyceride concentrations and a high low-density lipoprotein: high-density lipoprotein ratio, and hyperuricemia. These features, are all associated with accelerated atherogenesis and cardiovascular disease, the main cause of premature mortality. Some genetic (mutations affecting postreceptor signalling pathways) and environmental factors that could contribute to insulin resistance are discussed. INSULIN RESISTANCE IN CHRONIC RENAL FAILURE: The most prominent metabolic disturbance in uremic patients is insulin resistance due to a post-receptor defect. Insulin secretion is also impared, because the pancreatic beta-cell response to hyperglycemia is blunted. Insulin clearance by renal and extrarenal mechanisms is reduced. POSSIBLE SITES OF INSULIN RESISTANCE IN TERMINAL RENAL FAILURE: Increase in hepatic glucose production or impaired hepatic glucose uptake were overestimated. Impaired glucose uptake by peripheral tissues, primarily muscle and adipose tissue, has been extensively studied, and there is abundant evidence in patients with chronic renal failure. Decrease in renal glucose production would lead to a decrease in glucose appearance in circulation and decrease of insulin sensitivity. CONCLUSION: Cellular basis for insulin resistance in uremic patients is, however, unknown. It is now recognized that insulin-stimulated glucose transport in skeletal muscles and in other peripheral tissues is reduced. Although the majority of uremic patients are insulin resistant and about half of them are glucose intolerant, they are rarely diabetics. But, there are clinical implications of abnormal insulin metabolism in uremia. Cardiovascular complications are the most important consequences and significant cause of mortality in these patients.

[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.