Compliance with guidelines and predictors of mortality in hemodialysis. Learning from Serbia patients.

OBJECTIVES: The aims of the study were to determine the percentage of patients on regular hemodialysis (HD) in Serbia failing to meet KDOQI guidelines targets and find out factors associated with the risk of time to death and the association between guidelines adherence and patient outcome. METHODS: A cohort of 2153 patients on regular HD in 24 centers (55.7% of overall HD population) in Serbia were followed from January 2010 to December 2012. The percentage of patients failing to meet KDOQI guidelines targets of dialysis dose (Kt/V>1.2), hemoglobin (>110g/L), serum phosphorus (1.1-1.8mmol/L), calcium (2.1-2.4mmol/L) and iPTH (150-300pg/mL) was determined. Cox proportional hazards analysis was used to select variables significantly associated with the risk of time to death. RESULTS: The patients were on regular HD for 5.3±5.3 years, dialyzed 11.8±1.9h/week. Kt/V<1.2 had 42.4% of patients, hemoglobin <110g/L had 66.1%, s-phosphorus <1.1mmol/L had 21.7% and >1.8mmol/L 28.6%, s-calcium <2.1mmol/L had 11.7% and >2.4mmol/L 25.3%, iPTH <150pg/mL had 40% and >300pg/mL 39.7% of patients. Using Cox model (adjustment for patient age, gender, duration of HD treatment) age, duration of HD treatment, hemoglobin, iPTH and diabetic nephropathy were selected as significant independent predictors of time to death. When targets of five examined parameters were included in Cox model, target for KtV, hemoglobin and iPTH were found to be significant independent predictors of time to death. CONCLUSION: Substantial proportion of patients examined failed to meet KDOQI guidelines targets. The relative risk of time to death was associated with being outside the targets for Kt/V, hemoglobin and iPTH.

Associations of GSTM1*0 and GSTA1*A genotypes with the risk of cardiovascular death among hemodialyses patients.

BACKGROUND: The presence of glutathione transferase (GST) M1 null genotype (GSTM1-null) in end-stage renal disease (ESRD) patients is associated with lower overall survival rate in comparison to those with GSTM1-active variants. We examined association between GSTM1 and GSTT1 deletion polymorphisms as well as SNPs in GSTA1/rs3957357 and GSTP1/rs1695 genes with overall and cause-specific cardiovascular mortality in ESRD patients. METHODS: Total of 199 patients undergoing hemodialysis were included in the study. Median value of time elapsed from dialysis initiation until the death, or the end of follow-up was 8 ± 5 years. The effect of GSTM1, GSTT1, GSTP1 and GSTA1 gene polymorphisms on predicting overall and specific cardiovascular outcomes (myocardial infarction, MI or stroke) was analyzed using Cox regression model, and differences in survival were determined by Kaplan-Meier. RESULTS: GSTM1-null genotype in ESRD patients was found to be independent predictor of overall and cardiovascular mortality. However, after false discovery rate and Bonferroni corrections this effect was lost. The borderline effect modification by wild-type GSTA1*A/*A genotype on associations between GSTM1-null and analyzed outcomes was found only for death from stroke. Homozygous carriers of combined GSTM1*0/GSTA1*A genotype exhibited significantly shorter time to death of stroke or MI in comparison with carriers of either GSTM1-active or at least one GSTA1*B gene variant. The best survival rate regarding cardiovascular outcome was found for ESRD patients with combined GSTM1-active and mutant GSTA1*B/*B genotype. CONCLUSIONS: Combined GSTM1*0/GSTA1*A genotypes might be considered as genetic markers for cardiovascular death risk in ESRD patients, which may permit targeting of preventive and early intervention.

Glutathione S-transferase A1, M1, P1 and T1 null or low-activity genotypes are associated with enhanced oxidative damage among haemodialysis patients.

BACKGROUND: Increased oxidative stress is a hallmark of end-stage renal disease (ESRD). Glutathione S-transferases (GST) are involved in the detoxification of xenobiotics and protection of oxidative damage. We hypothesized that genetic polymorphism in antioxidant enzymes GSTA1, GSTM1, GSTP1 and GSTT1 is more frequent in ESRD and modulates the degree of oxidative stress in these patients. METHODS: GSTA1, GSTM1, GSTP1 and GSTT1 genotypes were determined in 199 ESRD patients and 199 age- and gender-matched controls. Markers of protein and lipid oxidative damage [thiol groups, carbonyl groups, advanced oxidative protein products, nitrotyrosine, malondialdehyde (MDA) and MDA adducts], together with total oxidant status and pro-oxidant-antioxidant balance were determined. RESULTS: Individual GST polymorphisms influence vulnerability to both protein and lipid oxidation, with GSTM1-null gene variant having the most pronounced effect. Furthermore, a strong combined effect of null/low-activity GSTM1, GSTT1, GSTA1 and GSTP1 genotypes in terms of susceptibility towards oxidative and carbonyl stress was found in ESRD patients. When patients were stratified according to GSTM1 and GSTT1, the highest oxidant damage was noted in those with the GSTM1-null/GSTT1-null genotype. The observed effect was even stronger in patients with the third low-activity GSTP1 or GSTA1 genotype. Finally, the level of oxidative and carbonyl stress was most pronounced in the subgroup of patients with all four null or low-activity GSTM1, GSTT1, GSTP1 and GSTA1 genotypes. CONCLUSIONS: According to the GST genotype, ESRD patients may be stratified in terms of the level of oxidative and carbonyl stress that might influence cardiovascular prognosis, but could also improve efforts towards individualization of antioxidant treatment.

Treatment of lupus nephritis by mycophenolate mofetil.

BACKGROUND/AIMS: Mycophenolate mofetil (MMF) has been increasingly used for the treatment of lupus nephritis (LN). The aim of this study was to examine the efficacy and safety of MMF used with low doses of corticosteroids as maintenance therapy in patients with LN. METHODS: The study covered 35 patients, most of them with proliferative types of LN (5 WHO class III, 26 class IV), while 1 had class V and 3 class VI nephritis. MMF was administered in the dose of 1.5-2 g/24 h and prednisone at 10-20 mg/day. The treatment effects were followed over a 12-month period. RESULTS: After 3 months of therapy significant reduction in proteinuria was achieved (2.1 +/- 2.4 g/24 h vs. 1.0 +/- 1.0 g/24 h, p < 0.01) and maintained to the end of the study. In parallel, a significant rise in serum albumin, a fall of cholesterol and a significant increase in mean glomerular filtration rate were noted. Complete remission was achieved in 16 patients (45.7%), including all patients in class III and V plus 10 patients in class IV. Not a single adverse effect was observed. CONCLUSION: MMF combined with low doses of steroids is an effective and safe treatment for the maintenance of stable remission of LN.

Therapeutic equivalence of epoetin zeta and alfa, administered subcutaneously, for maintenance treatment of renal anemia.

INTRODUCTION: The primary objective of the trial was to prove the therapeutic equivalence of epoetin zeta to epoetin alfa when administered subcutaneously for maintaining target hemoglobin (Hb) in patients with renal anemia on chronic hemodialysis. Additional information was provided on the safety and tolerability of epoetin zeta with particular focus on the formation of anti-erythropoietin antibodies. METHODS: A total of 462 patients were randomized to either epoetin zeta or alfa for 28 weeks after an open period of dose adjustment of 12-16 weeks with only epoetin zeta. The aim of treatment was to maintain Hb between 10.0-12.0 g/dL with constant epoetin dosage. Primary endpoints were the mean Hb level and the mean weekly epoetin dosage during the last 4 weeks of treatment. Safety endpoints were the occurrence of anti-erythropoietin antibodies, incidence of Hb levels above 13 g/dL, ratings of tolerability, and adverse events (AEs). RESULTS: The mean Hb level (+/-SD) during the last 4 weeks of treatment was 10.94+/-0.84 g/dL (epoetin zeta) and 11.02+/-0.94 g/dL (epoetin alfa). The 95% confidence interval (CI) (''C0.28 g/dL to 0.12 g/dL) was entirely within the predefined equivalence range (+/-0.5 g/dL). The mean weekly epoetin dosage per body weight over the last 4 weeks of treatment was 97.0+/-94.3 IU/kg/week (epoetin zeta) and 86.0+/-78.0 IU/kg/week (epoetin alfa). The 95% CI (''C8.06 IU/kg/week to 29.96 IU/kg/week) was also within the predefined equivalence range of +/-45 IU/kg/week. The most common AEs were infections and infestations (15.1% of patients on epoetin zeta and 14.8% of patients on epoetin alfa). None of the patients developed anti-erythropoietin antibodies. CONCLUSIONS: Epoetin zeta, administered subcutaneously, is equivalent to epoetin alfa in respect of its clinical efficacy. The safety profile of both products is similar: no unexpected AEs were observed, no patients developed anti-erythropoietin antibodies, and both epoetin preparations were well tolerated.

Mycophenolate mofetil in high-risk patients with primary glomerulonephritis: results of a 1-year prospective study.

BACKGROUND/AIMS: Glucocorticoids and classic immunosuppressive drugs can improve disease activity in primary glomerulonephritis (GN). However, these drugs have serious toxicity and patients frequently experience inadequate response or relapse, so there is a need for alternative agents. This multicenter uncontrolled study analyzed the efficacy and safety of mycophenolate mofetil (MMF) in high-risk patients with primary GN. METHODS: A total of 51 patients with biopsy-proven membranous (n = 12), membranoproliferative (n = 15), mesangioproliferative (n = 10), focal segmental glomerulosclerosis (n = 13) and minimal change disease (n = 1) received MMF with low-dose corticosteroids for 1 year. The primary outcome included the number of patients with complete/partial remission. RESULTS: Proteinuria significantly decreased, from its median value of 4.9 g/day (IQR 2.9-8.4) to 1.28 g/day (IQR 0.5-2.9), p < 0.001. The urine protein/creatinine ratio significantly improved, from a median of 3.72 (IQR 2.13-6.48) to 0.84 (IQR 0.42-2.01), p < 0.001. The mean area under the curve for proteinuria significantly decreased, from 4.99 +/- 3.46 to 2.16 +/- 2.46, between the first (visits 1-2) and last (vists 4-5) treatment periods (p < 0.001). The change was similar for every type of GN, without difference between groups. eGFR slightly increased (62.1 +/- 31.8 to 65.3 +/- 31.8 ml/min, p = n.s.) and ESR, total proteins, albumins, total- and HDL-cholesterol parameters improved significantly. Systolic, diastolic and mean blood pressure decreased (p < 0.02 for systolic blood pressure). The age of patients was the only independent predictor of complete or partial remission. CONCLUSION: MMF proved to be efficient in 70% of high-risk patients with primary GN, who reached either complete or partial remission without safety concern after 12 months of treatment. Favorable effects of MMF therapy have to be confirmed in the long term and particularly after discontinuation of the drug.

Altered antioxidant capacity in human renal cell carcinoma: role of glutathione associated enzymes.

PURPOSE: We aimed to discern the role of glutathione (GSH) associated enzymes in maintaining high GSH levels in renal cell carcinoma (RCC) of the clear cell type and analyze RCC enzyme antioxidant capacity. Since changes in cellular redox balance in RCC might also be related to alterations of glutathione S-transferase (GST) phenotype, GST class alpha and pi expression was also explored. METHODS AND MATERIALS: Human kidney specimens of tumor and distant nontumor regions were obtained from 15 patients with RCC at the time of surgery. The activities of GSH-replenishing enzymes, gamma-glutamylcysteine synthetase (gamma-GCS), gamma-glutamyl transferase (gamma-GT), and glutathione reductase (GR), as well as the activities of antioxidant enzymes glutathione peroxidase (GPX) and catalase (CAT) were determined spectrophotometrically. GST alpha and pi class expression was determined by immunoblot. RESULTS: In the course of renal cancerization, significant changes appear in the activities of GSH-replenishing and antioxidant enzymes. The activity of the key enzyme of GSH synthesis, gamma-GCS, is up-regulated (P < 0.001), while the activities of gamma-GT and GR are down-regulated in renal tumors compared to nontumor tissue (P < 0.001 and P < 0.05, respectively). Activities of GPX and CAT were also down-regulated (P < 0.001 and P < 0.05, respectively) in RCC. Changes in enzyme antioxidant capacity in RCC were associated with decreased GST class alpha (P < 0.001) and unchanged GST pi expression at the protein level. CONCLUSIONS: Changes in redox status in RCC as a consequence of decreased enzyme antioxidant capacity, together with altered GST alpha expression, may be important factors in development and tumor growth. The up-regulation of gamma-GCS and high levels of GSH in RCC may be an attempt to limit injury caused by oxidative stress.

[The use of erythropoietin beta, two to three times per week, once per week and once every other week: meta-analysis of two clinical trials].

INTRODUCTION: Renal anemia is a very common finding in patients with chronic kidney disease (CKD), both in patients not yet requiring dialysis and in patients on hemodialysis. Erythropoietin therapy is a gold standard in the treatment of renal anemia for more than 15 years. The aim of this meta-analysis was to assess the efficacy of different regimes of Recormon (erythropoietin beta, F. Hoffmann-La Roche) in maintaining stable levels of hemoglobin (Hb) and hematocrit (HCT) in patients receiving hemodialysis. MATERIAL AND METHODS: Two multicenter open comparative three arm trials lasting for 24 weeks were conducted in Serbia and Montenegro, between 2004-2006, with a total of 216 patients from 23 hemodialysis centers (22 from Serbia and 1 from Montenegro). The inclusion criteria were as follows: stable Hb level (>100 g/l), ferritin level > 200 microg/l and transferrin saturation >20%. The patients also had to be on stable doses of Recormon, before starting the trial. A total of 203 patients finished the study according to the protocol, and their results were used for this meta-analysis. During the first 8 weeks all patients received the usual 2-3 times weekly dose of epo. 8 weeks later, 147 patients started receiveing epo once weekly, while 56 patients (group 1) continued on the 2-3 times dose during the entire study period. After another 8 weeks, 20 of those 147 patients receiving epo once weekly were transferred to once every week dose of epo (group 3), while 127 patients were on once weekly dose until the end of the trial (group 2). Primary efficacy parameter was the percentage of patients who maintained their target Hb and HCT level (>100 g/l and >30% for HB and HCT respectively). RESULTS AND DISCUSSION: The efficacy analysis included the per-protocol population (203 patients). Hb levels remained stable (>100 g/l) in all three groups. There were no statistically signifant differences in Hb levels between the groups, with mean Hb level > 11 g/dL in all three groups throughout the study. HCT levels also remained stable (>30%) in all three groups throughout the study, without statistical significance between visits and between groups. The average epo doses were not statistically different between groups, although group 3 had-slightly higher mean Hb level than groups 1 and 2. The main tolerability parameters. sitting systolic (SSBP) and diastolic (SDBP) blood pressures were monitored at all visits. Statistical analysis showed no difference in SSBP or SDBP between the visits or groups of patients throughtout the study, although one patient had to be excluded due to uncontrolled hypertension. Only one patient (0.5%) received one blood transfusion during both studies. CONCLUSION: All three dose regimens of subcutaneous epo beta were statistically equivalent in maintaining the target Hb and HCT levels. The use of epo once weekly or once every other week was not associated with dose increase, proving that optimization of treatment for every patient is possible in everyday clinical practice. The possibility of using 3 different dose regimes of epo beta, without compromising efficacy or increasing costs of treatment may be beneficial in the quest for better patient compliance.

Effect of n-3 fatty acids on nutritional status and inflammatory markers in haemodialysis patients.

AIMS: Nutrition as an aetiological factor participates a great deal in premature atherosclerosis in haemodialysis (HD) patients. The basic mechanisms of end-stage renal disease and premature atherosclerosis are connected with changes in cell functions at the membrane level. We investigated the red cell membrane fatty acids and the effects of fish oil supplements on nutritional status and inflammatory markers in HD patients. METHODS: We examined 42 HD patients (mean age 55 +/- 8 years). The control group consisted of 16 healthy subjects of similar age and sex to the tested group. HD patients were administered supplements with 2.4 g of n-3 polyunsaturated fatty acids per day for 2 months. Before and after supplementation, we examined plasma lipids, cell membrane erythrocyte phospholipids content, serum albumin, haemoglobin, interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-alpha). RESULTS: Baseline values in the tested group confirmed the presence of essential fatty acids deficiency. A statistically significant negative correlation between TNF-alpha and eicosapentaenoic acid (EPA) (r = -0.497; P < 0.05) and IL-6 and EPA (r = -468; P = 0.03) was found in HD patients before supplementation. There was a significant increase in docosahexaenoic acids, high density lipoprotein cholesterol, plasma albumin, haemoglobin levels in HD patients after supplementation (P = 0.0001). There was a significant increase in EPA (P = 0.01) after treatment, and there was a significant decrease in inflammatory markers (IL-6 and TNF-alpha, P = 0.0001) after supplementation in the tested group. CONCLUSION: A dietary regime with fish oil could be used in dialysis patients to slow down the development of atherosclerosis and improve nutritional parameters.

Metabolic syndrome in HD patients: association with body composition, nutritional status, inflammation and serum iron.

OBJECTIVE: Insulin resistance and metabolic syndrome (MeS) are common in end-stage renal disease (ESRD) patients on maintenance hemodialysis (HD). Such metabolic and clinical abnormalities may lead to an increased risk for cardiovascular disease. METHODS: The study group included 22 well-nourished and 20 middle- to moderate-malnourished, stable ESRD patients, with median dialysis duration of 48 months (IQR 24.5-82.0). To determine nutritional status, body composition, inflammatory biomarkers and the presence of MeS subjective global assessment (SGA), anthropometrical measurements (BMI and waist circumference), bioelectrical impedance analysis (BIA), and biochemical parameters [the levels of serum albumin, cholesterol, HDL-cholesterol, triglyceride, hematocrit, hemoglobin, iron, TIBC, transferrin saturation (TSAT), ferritin, calcium, phosphorus, intact parathormone (i-PTH), TNF-alpha, IL-6 and high sensitivity C-reactive protein (hs-CRP)] were used. All parameters were evaluated by comparisons between two groups, with MeS (Group 2) and without it (Group 1). Logistical regression analysis was used to evaluate the correlation between measured variables and the presence of MeS in HD patients. Independent variables for MeS were identified by backward multivariate regression analysis. To identify the independent predictors for insulin resistance index (HOMA-IR) multivariate regression analysis was conducted, after linear regression analysis. RESULTS: After adjustment for confounding variables, a model consisting of serum levels of iron, transferrin saturation (TSAT), and BMI which accounted for 62% of the variance in MeS, determined only BMI as an independent marker (according to ATP-III criteria). But, serum glucose level, iron, waist and total fat mass accounted for 68% of the variance in MeS, according to IDF criteria. Glucose level was an independent predictor. BMI and iron, as independent variables, contributed to 29% of the variance in IR HOMA, the sensitive marker of MeS. CONCLUSION: The present study demonstrated that serum iron participated together with independent predictors, glucose and BMI, in the pathogenesis of IR and MeS of ESRD patients on maintenance HD.

The effect of nutritional status, body composition, inflammation and serum iron on the developement of insulin resistance among patients on long-term hemodialysis.

We investigated the effect of body composition, nutrition, inflammation and iron status on insulin resistance in patients with long-term hemodialysis. We selected 43 stable end-stage chronic renal failure patients, on maintenance hemodialysis. We evaluated the nutritional status, body composition by subjective global assessment (SGA), anthropometric measurements (BMI and waist circumference), bioelectrical impedance analysis and biochemical parameters measurements [serum albumin, cholesterol, HDL-cholesterol, triglyceride, hematocrit, hemoglobin, iron, ferritin, calcium, phosphorus, intact parathormone (i-PTH), TNF-alpha, IL-6 and high sensitivity C-reactive protein]. All parameters were evaluated by comparisons between HOMA-IR tertiles, and after simple regression analysis, by backward multivariate regression analysis we identified independent variables for IR. As the tertile of HOMA-IR increased, serum level of glucose, insulin, and waist increascd, whereas HDL-cholesterol level decreased, or the prevalence of the metabolic syndrome increased across the tertiles of HOMA-IR. After adjustment for gender, age, hemodialysis duration, ferritin, phosphorus, waist and total fat percentages, multivariate regression analysis was performed and the association with HOMA-IR was still strong only for serum levels of iron and TNF-alpha. That explains 16% of the total variation in HOMA-IR. Our results suggest that the increase of IR in end-stage chronic renal failure patients on hemodialysis could be related to anemia and particularly to iron overload. Moreover, chronic inflammatory status with over-production of adipokine TNF-alpha participate in the pathogenesis of IR too. The present study demonstrated that adipokine TNF-alpha and serum iron participated as independent predictors in the pathogenesis of insulin resistance on long-term hemodialysis patients.

[Inflammatory markers, nutritional parameters and polyunsaturated fatty acids in hemodialysis patients].

INTRODUCTION: Malnutrition and inflammation are associated with end-stage renal disease. Inflammation leads to reduced synthesis of albumin, transferin, and other negative acute-phase proteins and increases their catabolic rates. The causes of inflammation are multifactorial, including oxidative modification of plasma proteins, interaction of blood with nonbiocompatible membranes, and other infectious processes. Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) powerfully predict death from cardiovascular disease in dialysis patients as well as progression of vascular injury. The aim of our study was to establish a correlation between markers of inflammation and parameters of malnutrition in hemodialysis patients. MATERIAL AND METHODS: We examined 42 hemodialysis patients at the mean age of 55+/-8 with dialysis duration 52.6+/-42. For nutritional assessment subjective global assessment (SGA), anthropometric parameters, bio-electric impedance (BIA), and biochemical nutritional parameters were used. We measured their plasma levels of inflammatory markers: C-reactive protein, IL-6 and TNF-alpha. Patients with severe malnutrition had higher level of IL-6 and TNF-alpha. RESULTS AND DISCUSSION: The following correlations between measured parameters emerged. There was a negative correlations between serum albumin concentration and inflammatory markers (r=-0.31; p=0.05). Anthropometric parameters in hemodialysis patients were lower when inflammatory markers were higher and correlation was significant (p=0.05). A statistically significant negative correlation between TNF-alpha and EPA (r=-0.497; p<0.05) and IL-6 and EPA (r=-468; p=0.03) was found in hemodialysis patients. CONCLUSION: The main findings of this study were that the decrease of nutritional parameters in hemodialysis patients were related to the degree of inflammation. Nutritional factors, as essential fatty acids, could lead to permanent changes in the inflammatory process.

"Watermelon stomach" in patients on chronic hemodialysis.

"Watermelon stomach" is a common name for gastric antral vascular ectasia (GAVE syndrome). This endoscopic finding is characterized by the appearance of parallel longitudinal red columns along mucosal folds, along with capillars dilatation and hemorrhagy. Finding reliable method for its recognition is of paramount importance. Patient B.D., a 54-year-old woman, developed renal failure, which led to hemodialysis treatment, on the basis of pyelonephritis chronica. As a consequence of the gastrointestinal bleeding, the patient had black stools and developed severe anemia. The endoscopic finding showed the existence of visible columns of vessels transversing the antrum in longitudinal folds and converging in the pylorus, with clear red spots and surrounding hyperemy covered by drops of fresh blood. The diagnosis of "watermelon stomach" was confirmed after the pathohistological examination of the tissue taken at the biopsy, followed by total gastrectomy. Postoperative status was normal, without gastrointestinal hemorrhagia, and she went on with hemodialysis. Before the surgery she received 105 blood transfusions, and after surgical treatment she has received only 18 so far. At the moment she is in good health condition, and on hemodialysis. The reason we have reported this case of "watermelon stomach" syndrome in patient with chronic renal failure is to indicate that this rare anomaly of gastric blood vessels can lead to gastrointestinal blood loss in these patients. Since it is often the reason for many wrong diagnoses, it should be also taken into consideration in cases like these.

[Possible complications of erythropoietin therapy in patients with chronic renal failure]. / Moguce komplikacije terapije eritropoetinom kod bolesnika sa hronicnom bubreznon insuficijencijom.

INTRODUCTION: There have been many publications in the past 20 years about positive effects of human recombinant erythropoietin, which is used in treatment of anemia, especially in patients on dialysis. COMPLICATIONS: The most important complications in patients treated with erythropoietin include: hypertensive reactions; thrombosis of AV fistula in patients on hemodialysis and appearance of severe anemia as a part of Pure Red Cell Aplasia (PRCA). The first two complications were managed quite easily with adequate erythropoietin dosage, and slower establishment of normal hemoglobin kevel, hematocrit level and red blood cell count, (our "target" Hb varied between 100 and 110 g/dl). PURE RED CELL APLASIA (PRCA): Pure Red Cell Aplasia is a progressive, marked anemia with sudden appearance of significant loss or complete absence of erythrocyte precursor cells in normal bone marrow. In patients with end stage renal disease treated with erythropoietin PRCA appears in acute form as a consequence of production of neutralizing antibodies to erythropoietin. Time period between the beginning of erythropoietin therapy and appearance of PRCA is from 3 weeks to approximately 9 months. SYMPTOMS AND SIGNS: PRCA is characterized by sudden appearance of anemia in patients who had a satisfactory response to erythropoietin therapy till that moment. In PRCA, anemia is normocytic, normochromic with normal survival of red blood cells, without deficit in components such as iron, folic acid or vitamin B12, low reticulocyte count, decrease in Hg and normal platelet count. DIAGNOSIS: Diagnosis is based on clinical data (marked anemia), bone marrow biopsy, which shows a lower number of precursor red blood cells and presence of antibodies against erythropoietin. Before PRCA is diagnosed, all other causes for erythropoietin resistance must be excluded. THERAPY: Therapy of PRCA is based on cessation of erythropoietin therapy (all kinds), and correction of anemia with blood transfusions. INCIDENCE: PRCA is very rare and occurs in less than 1:10.000 patient-years in patients treated with erythropoietin, not lethal by itself and generally reversible. Till December 31, 2002. PRCA has been diagnosed in 142 patients world wide. In Serbia and Montenegro till this moment there hasn't been a single case of this syndrome. PREVENTIVE MEASURES: Continuous follow-up of reticulocyte count is the first step. Although this is a very rare disease, most of European Societies of Nephrology made protocols that recommend only intravenous application of -epoetin. Considering this new situation, Nephrology Society of Serbia and Montenegro recommends that -epoetin should be given to patients on hemodialysis only intravenously, while subcutaneous application of -epoetin is recommended in patients before beginning the dialysis treatment and in patients on hemodialysis, or who had undergone kidney transplantation.

[Predictors of mortality in dialysis patients--association between malnutrition, inflammation and atherosclerosis (MIA syndrome)]. / Prediktori mortaliteta kod bolesnika na dijalizi--povezanost malnutricije, inflamacije i ateroskleroze (mia syndrome).

INTRODUCTION: Numerous recent studies have shown increased comorbidity and mortality in dialysis patients with malnutrition. Protein-energy malnutrition with muscle wasting occurs in a large proportion of patients with chronic renal failure and is, in addition to atherosclerosis, a strong risk factor for mortality in patients undergoing dialysis. Malnutrition is also associated with increased cardiovascular mortality in dialysis patients. PATHOGENIC FACTORS OF MALNUTRITION IN DIALYSIS PATIENTS: Malnutrition is associated with a number of metabolic and vascular abnormalities. These factors include hypoalbuminemia, dyslipidemia with raised triglyceride concentrations, low-density lipoprotein and very low-density lipoprotein concentrations, insulin resistance and high concentrations of acute-phase proteins. Low serum albumin concentration, usually used as an index of malnutrition, is highly associated with increased mortality risk in dialysis patients. However, serum albumin is affected by factors other than malnutrition and high concentrations of acute-phase proteins, such as C-reactive protein (CRP), which correlate with low serum albumin in malnourished patients on dialysis. Oxidative stress has emerged as an important cofactor for development of endothelial dysfunction as premature atherosclerosis. In this context, malnutrition, inflammation and markers of oxidative stress are associated with vascular diseases. ETIOLOGY OF MALNUTRITION IN DIALYSIS PATIENTS: In recent studies several reports have suggested that inflammation, alone or in combination with low protein intake, plays a significant role in etiology of malnutrition in uremic patients. Lipid abnormalities may not only be a consequence of renal disease, but also contribute to its progression. Lipoprotein (a) is also associated with various atherosclerotic diseases. THERAPY OPTIONS: New treatment strategies, such as high protein/energy vs. standard protein/energy nutritional regimens, are necessary as well as food intake and dietary supplements. Intensive supplementation of (1.5 g protein/kg/d and 45 kcal/kg/d) is necessary to improve nutritional status of dialysis patients. CONCLUSION: Cellular basis of pathogenetic factors in malnutrition is unclear. It is, however, now recognized that oxidative stress and inflammatory cytokine aggravates the nutritional status of these patients.