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Background Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of chronic kidney disease (CKD) anemia. Methods This Phase 3, multicenter, randomized, double-blind, placebo-controlled study examined patients with Stages 3–5 CKD, not on dialysis (NCT01887600). Patients were randomized (2:1) to oral roxadustat or placebo three times weekly for 52–104 weeks. This study examined two primary efficacy endpoints: European Union (European Medicines Agency)—hemoglobin (Hb) response, defined as Hb ≥11.0 g/dL that increased from baseline (BL) by ≥1.0 g/dL in patients with Hb >8.0 g/dL or ≥2.0 g/dL in patients with BL Hb ≤8.0 g/dL, without rescue therapy, during the first 24 weeks of treatment; US Food and Drug Administration—change in Hb from BL to the average Hb level during Weeks 28–52, regardless of rescue therapy. Secondary efficacy endpoints and safety were examined. Results A total of 594 patients were analyzed (roxadustat: 391; placebo: 203). Superiority of roxadustat versus placebo was demonstrated for both primary efficacy endpoints: Hb response [odds ratio = 34.74, 95% confidence interval (CI) 20.48–58.93] and change in Hb from BL [roxadustat – placebo: +1.692 (95% CI 1.52–1.86); both P, Graphical Abstract

BACKGROUND AND AIMS Hypervolemia is one of the important risk factors for mortality in haemodialysis (HD) patients. The aim of this study is to determine the prognostic significance of volemia determined by bioimpedance spectroscopy (BIS), as well as cardiac biomarkers and echocardiographic (ECHO) measurements. METHOD A prospective single-centre observational study included 73 (42 m) chronic HD patients. The BIS and cardiac biomarkers were measured before the second weekly HD procedure. In addition, to overcome the problem of possible different pre-HD and post-HD fluid volume levels (`overhydration’, OH and post-HD or `dehydration’, DH, respectively) on different HD sessions of the week, the concept of Average Weekly hypervolemia (AVOH) or hypovolemia (AVDH) was implemented—the remaining two OH and DH values were calculated from pre-HD and post-HD weights and normal weight as suggested by BIS measurement. ECHO was performed 1 day after aforementioned measurements (i.e. 1 day after HD). RESULTS During observation period 11 subjects died (15%): seven (64%) directly due to cardiovascular (CV), two due to infective and due to malignant causes. Three-year cumulative survival was significantly lower (by Kaplan–Meier analysis) in those who had: 1) AVOH >13% extracellular fluid (ECV) (survival rate 73% versus 92% (P -3% ECV (survival 69% versus 94%; P 7350 pg/mL (survival 76% versus 93%; P 0.067 ng/mL, (survival rate 68% versus 94%; P CONCLUSION Determination of volemia by BIS, cardiac biomarkers and echocardiography has prognostic significance in HD patients. Further studies will show how much correction of dysvolemia affects their better survival.

BACKGROUND AND AIMS Many studies have shown that home haemodialysis (HOHD) provides fewer complications and better outcomes as compared with hospital haemodialysis (HHD). The aim of this study was to compare morbidity and survival in patients on HOHD and HHD. METHOD We analysed 26 prevalent HOHD patients who were matched with 52 HHD patients according to sex, age and Davies Comorbidity Index (DCI). DCI is based on seven groups of comorbidities: ischaemic heart disease (IHD), left ventricular dysfunction (LVD), peripheral vascular disease (PVD), malignancy, diabetes mellitus (DM), systemic collagen vascular disease and other significant pathology. Grade 0 had patients without any of these comorbidities, grade 1 those with 1–2 and those with 3 or more comorbidities had grade 2. Patients were followed from January 2011 to January 2020. We analysed an overall number of hospitalizations during the study period, a number of hospitalizations per year (annual hospital admission rate) and longevity of in-hospital stay (days). We categorized each hospitalization into 1 of 4 causes: cardiovascular disease (CVD), infection, vascular access dysfunction, or other cause. RESULTS Median age for HOHD and HHD patients was 55.7 and 56 years respectively and 77% of patients in both groups were men. Majority of the patients in both groups had DCI 1 (65%), 31% had DCI 0 and only 4% had DCI 2. The most common comorbidity for both HOHD and HHD patients was IHD (35% and 29% respectively), followed by HCV infection (35% and 17% respectively) and PVD (11.5% and 15% respectively). There was no difference between HOHD and HHD patients in an overall number of hospitalization (3.7 ± 3.3 versus 3.9 ± 2.8; P = .47), nor in annual admission rate for all-cause morbidity (0.5 ± 0.4 versus 0.6 ± 0.4; P = .28), but HHD patients had longer in-hospital stay (7.4 ± 9.8 days versus 9.3 ± 8.7 days; P = .05). Cause-specific morbidity showed that HHD patients had a more frequent annual admission rate for CVD (0.2 ± 0.1 versus 0.4 ± 0.3; P = .05), while there were no differences for infections (0.3 ± 0.2 versus 0.3 ± 0.3; P = .9) nor vascular access complications (0.3 ± 0.3 versus 0.4 ± 0.3; P = .3). Also, annual in-hospital stays for CVD (3.0 ± 3.1 versus 4.0 ± 4.5 days; P = .5), infection (6.4 ± 7.5 versus 5.7 ± 7.6 days; P = .6) and vascular access complications (6.0 ± 7.0 versus 7.7 ± 7.8 days; P = .5) did not differ between HOHD and HHD group. Kaplan–Meier curve revealed that survival in HOHD and HHD patients were 92.3% versus 90.4% at 3 years, 84.6% versus 70.2% at 5 years and 55.7% versus 50% at 9 years (log-rank test P = .5). CONCLUSION Our study has shown that HOHD and HHD patients had similar hospitalization rates, but patients on HOHD had better rehabilitation and shorter hospitalizations for all-cause morbidity. Despite this, HHD and HOHD patients had similar survival rates.

BACKGROUND AND AIMS Patients with late-stage chronic kidney disease (CKD) who are non–dialysis-dependent (NDD) or incident to dialysis (ID) (e.g. initiated dialysis within the last 4 months) or dialysis-dependent (DD) represent a vulnerable population at increased risk for morbidity and mortality despite significant clinical advancements in recent years. The safety of roxadustat in patients with NDD or ID-DD CKD requires further elucidation. METHOD In this post-hoc exploratory analysis, safety results from eligible patients with anemia of CKD enrolled in four phase 3, randomized, open-label studies [NDD (DOLOMITES) or ID-DD (SIERRAS, HIMALAYAS, ROCKIES)] were pooled and compared roxadustat to an erythropoiesis-stimulating agent (ESA). Endpoints were time to major adverse cardiovascular event [MACE; myocardial infarction, stroke and all-cause mortality (ACM)] and MACE+ (MACE plus congestive heart failure or unstable angina requiring hospitalization), ACM, and treatment-emergent adverse events (TEAEs). MACE and MACE + were evaluated for non-inferiority using hazard ratios (HRs) at 1.8 and 1.3-upper margins, respectively, and 95% confidence intervals (CIs). TEAEs were descriptively summarized. RESULTS In total, 2142 patients were evaluated (1083 roxadustat; 1059 ESA; 616 NDD; 1526 ID-DD). Roxadustat was non-inferior to ESA for risk of MACE [HR 0.79 (95% CI 0.61–1.02)] and MACE+ [HR 0.78, (95% CI 0.62–0.98)] with a consistent finding for ACM [HR 0.78 (95% CI 0.57–1.05)]. TEAEs were generally comparable between roxadustat and ESA groups, including any TEAE [incidence rate per 100 patient-exposure years (IR/100 PEY) 56.1 versus 53.5], TEAEs leading to discontinuation of study drug (IR/100 PEY 6.7 versus 5.1) and TEAEs leading to death (IR/100 PEY 6.9 versus 7.4). The most frequent (IR/100 PEY) TEAEs were hypertension (roxadustat 12.8, ESA 12.3), end-stage kidney disease (roxadustat 6.6, ESA 6.1), diarrhea (roxadustat 7.1, ESA 4.8) and hyperkalemia (roxadustat 4.3, ESA 4.8). CONCLUSION There was no evidence of an increased risk of cardiovascular events or mortality with roxadustat compared with ESA in patients with anemia who have NDD or ID-DD CKD. Although TEAE development occurred commonly in both the roxadustat and ESA groups, patients infrequently discontinued a study drug because of an adverse event.

Background/Aim. Overhydration (OH) and shortcomings of clinical assessment of so called ?dry weight? in hemodialysis (HD) patients are well known risk factors for high cardiovascular morbidity and mortality in this population. The purpose of this prospective randomized study was to investigate possible benefits of the active fluid management (AFM) guided by bioimpedance spectroscopy (BIS) on cardiac morphology, mechanics and function in chronic hemodialysis patients. Methods. The study lasted 9 months and 83 BIS naive patients were enrolled. Cardiac structural and functional characteristics were obtained using two dimensional Doppler echocardiography and global strains by speckle tracking modality. In addition, cardiac markers were measured. Results. Seventy three patients completed the study (38 in the active ? AFM group and 35 in the control group). At the end of the study, the main structural change in the active group of patients was reduction of left ventricular mass index (from 62.81 ? 19.74 g/m2.7 to 57.74 ? 16.87g/m2..7; p = 0.007), while main functional improvements in this group were better left ventricular ejection fraction (LVEF; from 41.27 ? 9.26% to 43.95 ? 8.84%; p = 0.006) and fractional shortening (FS; 27.86 ? 5.94% to 29.86 ? 5.83%; p = 0.056) in accordance with improvement of radial left ventricular (LV) mechanics detected by higher global radial strain (GRS) (18.56 ? 10.24% to 21.79 ? 12.16%; p = 0.014). The diastolic function of patients in the control group worsened significantly, assessed as ratio of Doppler velocity of early diastolic filling of left ventricle ? E, and average velocity of tissue Doppler measured at lateral part of the mitral annulus (e? lateral; E/e? lateral ratio 10.59 ? 5.00 to 11.12 ? 4.06; p = 0.036) and consecutively the right ventricular systolic pressure (RVSP) estimated indirectly by echocardiography: from 34.84 ? 10.18 mmHg to 38.76 ? 8.34 mmHg; p = 0.028. These functional changes were in correlation with significantly higher levels of Nterminal prohormone brain natriuretic peptide (NTproBNP) in this group of patients [median and interquartile range (IQR): 5810.0 pg/mL (3339.0?15627.0 pg/mL) to 8024.0 pg/mL (4433.0?17467.0 pg/mL; p = 0.038)]. The improvement in the LV structure and function in the active group correlated with better relative overhydration (ROH) management in this group ? the proportion of ?critically? overhydrated patients decreased from 45% at the start to 24% at the end of study (p = 0.003). At the end of the study, there were 49% of post-dialysis ?critically? dehydrated patients in the control group. Proportion of anuric patients increased only in the control group (63% to 77%; p = 0.063). Conclusion. Active fluid management, guided by bioimpedance spectroscopy had positive impact on cardiac hemodynamics and mechanics in our study patients and could improve clinical decisions regarding their optimal weight and further clinical course. Further data from well designed studies are needed urgently.

Cardiovascular (CV) morbidity and mortality increase along with the progression of chronic kidney disease (CKD). The potential novel biomarkers of cardiotoxicity have been tested with the aim of the early detection of patients at high CV risk, and among them are markers of inflammation, oxidative stress, acute renal injury, and microRNAs. The study analyzed biomarkers in non-dialysis-dependent (NDD, stage 3a–4 CKD) and dialysis-dependent (DD) CKD patients. The prospective cohort study included 87 patients who were followed for 18 months, during which period newly occurred CV events were recorded. Cox regression analysis confirmed serum albumin, urea, interventricular septum thickness diameter (IVST), the use of calcium antagonist, and erythropoiesis-stimulating agent to be significant predictors of CV outcome. No significant difference was observed in biomarkers of inflammation, oxidative stress, acute kidney injury (IL-18, CRP, ferritin, IMA, SOD, NGAL, and KIM-1), and miR-133a, in regards to the presence/absence of CV event, CV death, and left ventricular hypertrophy. Serum albumin, urea, IVST, and the use of calcium antagonist and erythropoiesis-stimulating agents were confirmed to be factors associated with CV events in CKD patients. Apart from traditional risk factors, new research is needed to define novel and reliable biomarkers of cardiotoxicity in CKD patients.

Background Peripheral arterial disease (PAD) is common in patients with end-stage renal disease on hemodialysis, but is frequently underdiagnosed. The risk factors for PAD are well known within the general population, but they differ somewhat in hemodialysis patients. This study aimed to determine the prevalence of PAD and its risk factors in patients on hemodialysis. Methods This cross-sectional study included 156 hemodialysis patients. Comorbidities and laboratory parameters were analyzed. Following clinical examinations, the ankle-brachial index was measured in all patients. PAD was diagnosed based on the clinical findings, ankle-brachial index

Introduction/Objective. Thrombosis of hemodialysis catheters is one of the major complications, which leads to catheter dysfunction. Although tissue plasminogen activator has been proven to be effective in reestablishing blood flow rate through dysfunctional catheters, clinical data in Serbia are missing. The objective of the study was to analyze tissue plasminogen activator efficacy in reestablishing blood flow rate and the influence on catheter survival. Methods. The study included 53 tunneled catheters from 32 patients on hemodialysis. After catheter dysfunction was established, 580,000 units of tissue plasminogen activator was applied into each catheter lumen for about two hours before hemodialysis. The criteria for success was blood flow rate on the next hemodialysis ? over 200 mL/minute was considered to be complete success, 180?200 mL/minute partial success, and under 180 mL/minute was considered a failure. Results. Out of 53, 25 catheters (47%) had dysfunction with an incidence of 3.8/1,000 catheter days. Catheters placed in femoral veins, ?after-first? catheters, catheters with infection, and catheters in older patients had higher risk for dysfunction. Multivariate logistic regression analysis confirmed that only older age was significantly related to catheter dysfunction. Of the total of 50 applications of tissue plasminogen activator, 35 (70%) were successful, seven procedures (14%) were partially successful and eight (16%) dysfunctional catheters failed to respond to therapy. Six-, 12- and 24-month survival was 87%, 81%, and 20%, respectively, for catheters without dysfunction, and 71%, 47.5%, and 12%, respectively, for catheters with dysfunction. Conclusion. Tissue plasminogen activator dosing is noninvasive, efficient, and safe in reestablishing blood flow rate through dysfunctional catheters, thus prolonging catheters life and sparing patients from additional vascular procedures.

In recent years, academic publishing excited a considerable interest in gut microbiota and its role in human health maintenance. In patients with chronic renal failure, gut microbiota is altered due to increased blood urea nitrogen and metabolic acidosis, specific diet and therapy, as well as prolonged intestinal transit time. Protein-fermenting bacteria such as E. coli, Bacteroides and Ruminicoccus spp dominate gut microbiota in patients with chronic renal failure. Therefore, the key nephroand cardiovascular toxins, such as indoxyl-sulfate (IS) and p-cresyl-sulfate (PCS) are produced in the gut mucosa. The important impact of increased serum levels of IS and PCS on cardiovascular comorbidity and further deterioration of renal function has been witnessed by numerous observational and animal studies. There are several therapeutic strategies for lowering serum levels of IS and PCS as well as their toxic effect. The use of synbiotics, preand probiotics, in order to modulate gut microbiota is the most optimal solution currently used. Probiotic cultures of Bifidobacter and Lactobacillus have presented themselves as the ones with the greatest potential to limit the growth of protein-fermenting bacteria responsible for the production of uremic toxins. Nevertheless, there is still a need for more well-designed prospective interventional studies, as well as for controls with well-defined diet restrictions, in order to establish definitive value of this kind of therapy in patients with chronic renal failure.

Background and Aims The new coronavirus disease (COVID 19) has become a worldwide health emergency with a wide spectrum of clinical presentation, from common cold symptoms to multiorgan failure. A great number of medical centers have reported that patients with COVID-19 have developed acute kidney injury. The kidney is a target organ for SARS - COV2 because of ACE2 receptor, the binding site for this virus, is expressed in kidney tissue. The potential mechanisms for kidney injury are direct kidney injury, inflammation, activation of coagulation and complement cascades. Data from centers worldwide reported a wide range of AKI incidence, from 0,5% in China to 46% in USA. The aim of this study was to analyze incidence, risk factors and outcomes of AKI in hospitalized patients with COVID 19 who were treated from 01.04. to 01.06.2020. at Nephrology Department of University Clinical Center Zvezdara, which was at the time transformed into COVID hospital. Method This retrospective observational study included 51 patients who had normal kidney function before the infection with SARS COV2, and 7 of them developed dialysis non-dependent AKI. Analysis included data collection from the patients’ history including demographic, clinical and administrative data. Statistical analysis has been performed using SPSS software version 20 (IBM Corporation, New York, USA). Results Out of 51 patients 7 (13.7%) developed AKI, mean age was 59 + 16 years and 53% were male. Diabetes mellitus was present in 27 of patients with AKI, hypertension in 6/7, obesity in 3/7, coronary artery disease in 1/7 and 1 of 7 patients was smoker. These risk factors except obesity (p= 0.05) didn’t vary significantly between two groups (AKI and non AKI patients with COVID-19). Our results showed significant correlation between AKI development and obesity (p= 0.05, OR 4.75), Charlston index score (p=0.01), D dimer score (p=0.01), and CT COVID score (p=0.03). Regarding the outcome, COVID 19 patients with AKI showed 7-fold higher risk for fatal outcome (p= 0.046). Conclusion Obesity, higher D dimer values, worse CT findings and higher Charlston comorbidity score index were associated with acute kidney injury in patients with COVID 19. AKI proved to be significant risk factor for fatal outcome in patients with SARS COV2 infection.

Background and Aims Acute kidney injury (AKI) secondary to urinary obstruction is a common urological-nephrological problem. In this retrospective study, our goals were to describe the etiology, management and outcomes of patients with obstructive nephropathy who were hospitalized at Nephrology Department during 2019. Method AKI was defined by the RIFLE classification. Diagnosis of obstruction was defined by ultrasound imaging, intravenous pyelography and CT scan. Results During 2019 AKI secondary to urinary obstruction was diagnosed to 64 patients. 73% of them were male, average age 65 ± 16 years. About 60% of the patients had bilateral hydronephrosis, chronic kidney disease and anuria duration longer than 24h. The following desobstructive procedures were applied: urinary catheterization to 33 patients, percutaneous nephrostomy tube to 14 patients, double-J stent to 7 and other procedures to 10 patients. The most common causes of obstruction were malignancy and benign prostatic hyperplasia 60%, calculosis 17%, and other causes 20% such as neurogenic bladder and retroperitoneal fibrosis. As many as 30% of patients required acute hemodialysis treatment, of which 6% remained on a chronic program in period of three months. Out of all, 30% of patients had a partial recovery of kidney function, while 20% had complete recovery. The most common complication was infection and bleeding. The univariate logistic regression, adjusted for age and hemodialysis treatment, has shown that significant independent predictors for chronic kidney disease progression were anuria duration >24h (RR 2.21; 95% CI 0.014-1.03; p=0.05), polyuria duration (RR 2.11; 95% CI 1.112-3.98; p=0.02) and duration of hospital treatment (RR 9.16; 95% CI 2.102-39.94; p=0.03). The most significant predictor of death was duration of hospital treatment (RR 9.16; 95% CI 2.102-3.399; p=0.003). Multivariate logistic regression did not shown significance any of the above risk factors. Conclusion Given that third of patients with obstructive nephropathy require acute HD, 6% remain in chronic HD, and almost one third require rehospitalization, close cooperation between a nephrologist and urologist is required. Rapid desobstructive procedures and careful monitoring after desobstruction is warranted. Requirement of regular screening remains opened for obstruction in vulnerable populations.

Background and Aims Randomised clinical trials evaluating anaemia correction using erythropoietin-stimulating agents (ESAs) in chronic kidney disease (CKD) patients have demonstrated an association between ESA use and increased risk of cardiovascular (CV) complications and mortality. Although the mechanism for this increased risk remains unclear, possibilities include rapid rates of rise (ROR) in haemoglobin (Hb), exposure to high ESA dose and dose escalation, a high Hb target range, and off-target effects of ESAs. Thus, current recommendations generally state that Hb levels should be maintained between 10 and 12 g/dL. Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), is used for the treatment of anaemia of CKD; roxadustat stimulates endogenous production of erythropoietin and enhances iron availability, thereby supporting red blood cell production. In this pooled analysis, we explored the relationship between 1) achieved Hb levels and 2) preliminary data for ROR of Hb and subsequent incidence rates of CV events in non–dialysis-dependent (NDD) CKD patients who received roxadustat. Method We analysed pooled data from four phase 3 studies in NDD patients (placebo-controlled: ALPS, ANDES, OLYMPUS; ESA-controlled: DOLOMITES) with anaemia of CKD who received any dose of roxadustat. The reported events occurred during the treatment period and within 7 days of the last dose of roxadustat. Incidence rates of adjudicated major adverse CV events (MACE: all-cause mortality [ACM], myocardial infarction, and stroke), MACE+ (MACE plus heart failure and unstable angina requiring hospitalisation), and ACM were examined relative to 1) most recent Hb level before the event and 2) the preliminary data for ROR of Hb within the 4 weeks of treatment immediately prior to the event. Results Overall, 2709 patients were randomised and received roxadustat. Incidence rates of MACE, MACE+, and ACM were 3- or 4-fold higher in patients with lower reported Hb levels (Hb 2 g/dL in Hb within the 4-week period prior to the event compared to those with a change of ≤2 g/dL within the same period (Table). However, it should be noted that patient-exposure years (PEY) were low for the subgroup of patients with ROR >2 g/dL (∼3.3% of overall PEY), and patients with a decreasing Hb were included in the ≤2 g/dL/4 weeks subgroup. Conclusion In this analysis of roxadustat-treated patients with NDD CKD, incidence rates of MACE, MACE+, and ACM were lower in patients who achieved target Hb levels of 10-12 g/dL compared with patients who achieved Hb

Background and Aims It is well-known that interstitial changes in patients with focal-segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) are linked with disease chronicity and progression. The aim of this study was to analyze is there any connection between interstitial changes and outcome after “first line” therapy in patients with FSGS/MCD. Method From 2014 till 2019, biopsy proven diagnosis of FSGS/MCD was established in 40 patients. Interstitial changes were classified in three groups as following: 0-w/o changes; 1-mild changes; 2-severe changes. Patients with nephrotic syndrome (No=29) were treated with prednisolone (1mg/kg) and after six months we have registered therapy outcome as: CR-complete remission; PR-partial remission; EX-death; NO-no effect. Results Among treated patients (age 50.4±15.3 years, 15 men), CR was achieved in 10 patients (34.5%) and 6 out of these 10 (60%) had no interstitial changes. Partial remission was observed in 11 patients (37.9%), in 4 patients (13.8%) therapy did not have any effect, and 4 patients (13.8%) deceased (table 1). All patients in EX and NO group had interstitial changes. There were no significant difference in age, gender, proteinuria, albuminaemia, creatinine and glycaemia levels between groups except for hemoglobin levels that were significantly lower in EX group than in others (∑ 15.144; p=0.002) and urea levels that were significantly higher in EX group (∑ 138.057; p=0.024). Conclusion Patients with FSGS/MCD respond well on standard immunosuppressive protocol, particularly in absence of interstitial changes what may increase the chance for achieving complete remission.

Background and Aims Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, induces a coordinated erythropoietic response by increasing endogenous erythropoietin levels and improving iron metabolism. This analysis was performed to examine the consistency of efficacy and cardiovascular safety results for roxadustat vs placebo or darbepoetin alfa (DA) in patients with non-dialysis-dependent (NDD) chronic kidney disease (CKD). Method Results from three phase 3, double-blind studies comparing roxadustat with placebo (ALPS, ANDES, OLYMPUS) with anaemia and stage 3-5 NDD CKD were pooled and assessed for consistency with results of an open-label study comparing roxadustat with DA (DOLOMITES) in predominantly European patients. The primary efficacy endpoint was haemoglobin (Hb) response, defined as (a) Hb ≥11.0 g/dL that changed from baseline (CFB) by ≥1.0 g/dL in patients with Hb >8.0 g/dL or (b) Hb CFB by ≥2.0 g/dL in patients with Hb ≤8.0 g/dL irrespective of and without rescue therapy for placebo-controlled (assessed for superiority) and DA-controlled (assessed for non-inferiority) studies, respectively. The secondary efficacy endpoint was Hb CFB to Weeks 28-36 using least squares mean difference (LSMD) without rescue therapy. The key safety endpoints of major adverse cardiovascular event (MACE, comprising death, myocardial infarction, and stroke) and MACE+ (MACE plus hospitalization with heart failure or unstable angina) were adjudicated in all studies. MACE and MACE+ for roxadustat vs placebo or DA were compared in the intention-to-treat sample using a Cox proportional hazards model. Results In total, 4886 patients were randomised in placebo-controlled (2386 roxadustat, 1884 placebo) and DA-controlled (323 roxadustat, 293 DA) studies. Baseline characteristics of patients treated with roxadustat vs placebo and roxadustat vs DA were similar: baseline Hb (placebo, 9.10 vs 9.10 g/dL; DA, 9.55 vs 9.55 g/dL) and iron repletion (placebo, 59.9% vs 59.8%; DA, 56.3% vs 51.9%). Roxadustat was superior to placebo for Hb response without rescue therapy (80.2% vs 8.7%; difference of proportion [DOP], 71.50%; 95% CI, 69.40-73.51) and noninferior to DA (89.5% vs 78.0%; DOP, 11.51%; 95% CI, 5.66-17.36). Mean Hb CFB (Weeks 28-36) achieved superiority in pooled analysis vs placebo (LS mean, 1.91 vs 0.14; LSMD, 1.77; 95% CI, 1.69-1.84; P Conclusion Roxadustat corrected Hb more effectively than placebo and comparably to DA in patients with anaemia and stage 3-5 NDD CKD. Cardiovascular safety was comparable between roxadustat and DA and placebo.

Background and Aims Heparin-induced thrombocytopenia (HIT) is a potentially fatal adverse reaction after administration of unfractionated or fractionated heparin, which underlies the generation of antibodies to the heparin complex and platelet factor 4 (PF4). It occurs in 5% of patients treated with unfractionated heparin and 0.5 - 1.5% fractionated heparin. The aim of the study is to determine the incidence and outcome of hemodialysis patients with HIT over 4-years period. Method This retrospective study analyzed patients who were tested for evidence of positive anti-heparin antibody in the period from 2015 to 2020 in Zvezdara University Medical Center. The diagnosis was confirmed by the 4T clinical scoring system, a positive antiheparin-PF4 ELISA test and a positive platelet aggregation test with heparin. Results During observation period, total of 64 tests were performed, out of which 23 patients were positive. Out of them, 14 patients were on HD, 7 patients (geriatric, surgery and cardiology departments) received therapy due to peripheral thrombosis, AIM or arrhythmia and 2 patients during 2020 due to SARS-CoV-2 bilateral pneumonia. All patients treated at nephrology, started hemodialysis (HD) with unfractionated heparin, while others were treated with LMWH. 4T scoring showed that 64% of patients had a moderate risk of developing HIT, while high risk was assessed in 36% of patients. Thrombotic complications in the form of deep venous thrombosis had 53% of patients and pulmonary thromboembolism had 17,5 % of patients. The greatest decrease in Tr was the most commonly observed between 10th and 14th day (61% of patients) and 39% from 4th to 10th day from start of heparin administration. In addition to heparin withdrawal and treatment with alternative non-heparin anticoagulation (fondaparinoux), 7 patients needed plasma treatment. 11 patients on HD were transferred to peritoneal dialysis (PD), and 3 patients recovered renal function. Overall mortality was 52%, and it was below 30% in hemodialysis patients. Conclusion HIT should be considered in patients at risk. It is necessary to abolish heparin treatment and use alternative method (PD) or alternative anticoagulation. Hemodialysis patients have better prognosis than other comparable patients

Background and Aims Since the outbreak of COVID 19 there have been 88.1 million confirmed cases and 1,9 million deaths in 218 countries, while in Serbia we have had 39.867 cases of COVID 19 and 3479 deaths with approximate death rate of 1%. Fatality rate worldwide vary widely, from 0% in Singapore to 8,8% in Mexico with the average value of 3%. Although there are many published studies about COVID 19, influence of chronic kidney disease and chronic dialysis on outcome of patients with the coronavirus infection is still not clear. The aim of this study was to explore whether the presence of CKD including ESRD and chronic dialysis treatment increases COVID 19 patients’ risk for adverse clinical outcome. Method This retrospective study included 88 patients who were hospitalized at the Nephrology department in Zvezdara University Clinical Center which was transformed into a COVID hospital at the time. These patients were treated from 01.04.2020. to 01.06.2020. and 37 (42%) of them had CKD, while 51 (58%) had no signs of kidney disease. We analysed data collection from the patients’ history, including age, sex, comorbidities, symptoms, blood and radiology findings, therapy and outcome. We compared outcome (fatal and need for mechanical ventilation) between CKD and non CKD group and also analized dialysis as a risk factor for adverse outcome. Statistical analysis has been performed using SPSS software version 20 and OR was calculated using Logistic Regression. Results We analysed 88 patients, a mean age of 62+15 years, 59.1% males. Out of 88 patients, 37 had CKD, while 27 of them were on hemodialysis and 2 on peritoneal dialysis (CAPD). At the end of follow-up, 46 patients (52.3%) was discharged home, 27 (30.7%) was transferred to another hospital and 14 (15.9%) died. Regarding influence of CKD on COVID-19 patients’ outcome it was shown that patients with CKD had 3-fold higher chances for discharge than for the fatal outcome (p=0.05) and 4-fold less risk for use of the mechanical ventilation (ns) as compared to non CKD patients. We also found that ESRD and chronic dialysis affect outcome with statistical significance (p=0.01) in a way that it doubles the risk for the adverse outcome. Conclusion Patients with CKD, especially those with ESRD had significantly higher risk for the lethal outcome and higher chances to require the mechanical ventilation.

Background and Aims Roxadustat regulates erythropoiesis and iron metabolism through hypoxia-inducible factor prolyl hydroxylase inhibition. This regional analysis evaluated efficacy and safety for roxadustat versus placebo/darbepoetin alfa (DA) in NDD CKD patients with anaemia. Method Results from three, double-blind phase 3 studies comparing roxadustat to placebo (ALPS, ANDES, OLYMPUS) in patients with anaemia and stage 3-5 NDD CKD were pooled and evaluated alongside results of an open-label study comparing roxadustat to DA (DOLOMITES) in the same population. Efficacy outcomes were compared in three regions (Europe, US, and other) in placebo-controlled studies (PCS) and two regions (Western Europe/Israel and Central/Eastern Europe) in the DA-controlled study (DCS). The primary efficacy endpoint in Europe was haemoglobin (Hb) response, defined as Hb ≥11.0 g/dL that changed from baseline (CFB) by ≥1.0 g/dL in patients with Hb >8.0 g/dL or as CFB ≥2.0 g/dL in patients with Hb ≤8.0 g/dL. The secondary efficacy endpoint was Hb CFB to Weeks 28-36 without rescue therapy (intravenous iron, red blood cell [RBC] transfusion, or erythropoiesis-stimulating agent [ESA] for PCS; RBC transfusion or ESA [roxadustat only] for DCS). Incidence of treatment-emergent adverse events (TEAEs) was summarised descriptively in two regions in PCS (Europe and non-Europe) and two regions in DCS (Western Europe/Israel and Central/Eastern Europe). Results A total of 4886 patients were randomised (2709 roxadustat; 1884 placebo; 293 DA). A significantly greater proportion of patients in all regions who received roxadustat had a Hb response without rescue therapy vs placebo (Europe: 77.9% vs 16.5%, difference of proportion [DOP] 61.4%, 95% CI: 56.5-66.2; US: 75.4% vs 8.3%, DOP 67.2%, 95% CI: 62.7-71.6; and other: 83.4% vs 5.5%, DOP 78.0%, 95% CI: 75.4-80.5) and a numerically greater proportion in both regions vs DA (Western Europe/Israel: 93.9% vs 83.5%, DOP 10.4%, 95% CI: 1.2-19.6; Central/Eastern Europe: 86.5% vs 75.4%, DOP 10.9%, 95% CI: 3.6-18.3). Mean Hb CFB was significantly greater with roxadustat vs placebo in Europe (2.01 vs 0.37 g/dL, LSMD 1.70, 95% CI: 1.55-1.84), US (1.80 vs 0.21 g/dL, LSMD 1.67, 95% CI: 1.53-1.82), and other (1.80 vs 0.06 g/dL, LSMD 1.77, 95% CI: 1.64-1.89) (all P Conclusion In patients with anaemia and stage 3-5 NDD CKD, roxadustat was more effective than placebo for correcting Hb and generating Hb response without rescue therapy in Europe, the US, and other countries. It was similarly effective as DA for correcting Hb and generating a Hb response without rescue therapy in Western Europe/Israel and Central/Eastern Europe. The incidence of select TEAEs was comparable and relatively low in all regions.

Background and Aims In recent years, obesity has reached epidemic proportions, and it's a great challenge to choose an adequate treatment for obese ESRD patients. The aim of the study was to analyze the outcome in patients with peritoneal dialysis with different degrees of nutrition expressed through body mass index at the beginning of treatment. Method The prospective clinical study included 53 incidental patients, who started peritoneal dialysis between June 2006 and August 2015. According to BMI on the beginning of treatment, patients were divided into three groups: normal weight: BMI of 18.5 - 24.9 kg/m2, n=17, overweight: BMI of 25 - 29.9 kg/m2, n=25, obese: BMI> 30.0 kg/m2. n=11. Mechanical and infective complications, technique survival and patients survival were analyzed over 48 - months period. Results In terms of mechanical complications, there was no difference between the groups- malposition of the catheter (p = 0.769), leakage of dialysate (p = 0.462), hernia (p = 0.381). Exit sitе infection were most prevalent in group 3 - 1 episode/22 patient months vs 1 episode/30 patient months in groups 1 and 2, but without statistical significance (p = 0.272). However, the lowest incidence of peritonitis was in the group 3 - 1 episode/40 patient months vs 1 episode/30 patient months in group 2, and 1 episode/33 patient months in group 1, but even here the difference did not reach statistical significance (p = 0.624). Cardiovascular events – myocardial infarction, stroke and peripheral vascular disease were rare in all groups, with no statistical significance between groups. The incidence of hospitalizations was highest in the obese group – 1 episode/22 patient months vs 1 episode/27 patient months in group 2, and 1 episode/25 patient months in group 1 (p = 0.735). Kaplan Meier's analysis showed the worst, but not significant, survival of the technique in a group of obese patients (group 1 vs. group 2; p = 0.536; group 1 vs. group 3 - p= 0.662; group 2 vs. group 3 - p = 0.357). Also, overall patient survival was not differed between the groups (group 1 vs group 2 - p = 0.387; group 1 vs group 3 - p= 0.885; group 2 vs group 3 - p = 0.375). According to Cox's analysis, only values of total cholesterol at the end of the follow-up period (p = 0.027) and diastolic blood pressure (p = 0.013) were significantly associated with overall survival obese patients. Conclusion In the present study the degree of nutrition at the beginning of treatment had no significant effect on the outcome of peritoneal dialysis treatment. Therefore, patients should not be discouraged for peritoneal dialysis on the basis of BMI.

Deletion polymorphism of glutathione S-transferase M1 (GSTM1), a phase II detoxification and antioxidant enzyme, increases susceptibility to end-stage renal disease (ESRD) as well as the development of cardiovascular diseases (CVD) among ESRD patients and leads to their shorter cardiovascular survival. The mechanisms by which GSTM1 downregulation contributes to oxidative stress and inflammation in endothelial cells in uremic conditions have not been investigated so far. Therefore, the aim of the present study was to elucidate the effects of GSTM1 knockdown on oxidative stress and expression of a panel of inflammatory markers in human umbilical vein endothelial cells (HUVECs) exposed to uremic serum. Additionally, we aimed to discern whether GSTM1-null genotype is associated with serum levels of adhesion molecules in ESRD patients. HUVECs treated with uremic serum exhibited impaired redox balance characterized by enhanced lipid peroxidation and decreased antioxidant enzyme activities, independently of the GSTM1 knockdown. In response to uremic injury, HUVECs exhibited alteration in the expression of a series of inflammatory cytokines including retinol-binding protein 4 (RBP4), regulated on activation, normal T cell expressed and secreted (RANTES), C-reactive protein (CRP), angiogenin, dickkopf-1 (Dkk-1), and platelet factor 4 (PF4). GSTM1 knockdown in HUVECs showed upregulation of monocyte chemoattractant protein-1 (MCP-1), a cytokine involved in the regulation of monocyte migration and adhesion. These cells also have shown upregulated intracellular and vascular cell adhesion molecules (ICAM-1 and VCAM-1). In accordance with these findings, the levels of serum ICAM-1 and VCAM-1 (sICAM-1 and sVCAM-1) were increased in ESRD patients lacking GSTM1, in comparison with patients with the GSTM1-active genotype. Based on these results, it may be concluded that incubation of endothelial cells in uremic serum induces redox imbalance accompanied with altered expression of a series of cytokines involved in arteriosclerosis and atherosclerosis. The association of GSTM1 downregulation with the altered expression of adhesion molecules might be at least partly responsible for the increased susceptibility of ESRD patients to CVD.

Membranoproliferative glomerulonephritis (MPGN) is characterized by mesangial cell proliferation and structural changes in glomerular capillary walls and double-contoured glomerular basement membrane (GBM). Usually, it is connected with cryoglobulinemia which is defined by the presence of a circulating, a cold-precipitating immunoglobulin. The chemical and immunological features of the cryoglobulins are used to define three types of cryoglobulinemia. In this report we describe the third case of MPGN type II with essential cryoglobulinemia without HCV infection, which is usually defined in the literature as MPGN type II. Here, we present 61-years old woman previously diagnosed with MPGN in 2012 at another institution. At that time, she was not examined in terms of cryoglobulinemia. Initially she was treated with pulses of methylprednisolone, then oral corticosteroids until cessation when complete remission was achieved. Meanwhile, she had two relapses of the disease. In October 2020 we re-evaluated her and found out positive cryoglobulins in repeating testing. Serological studies for anti-neutrophil cytoplasmic antibodies (ANCA), myeloperoxidase and proteinase 3, anti-double stranded DNA antibodies, anti-hepatitis C antibodies, anti-HIV antibodies and anti-hepatitis B surface antibodies were all negative. Serum M protein or monoclonal IgM were not detected. Percutaneous renal biopsy was compatible with the diagnosis of MPGN. Based on clinical, laboratory and histological evaluation, it was concluded that the patient had a MPGN with essential cryoglobulinemia. Therapy with mycophenolate mofetil had a beneficial effect on the course of disease and the patient achieved partial remission and stabile renal function for the last 3 months of follow-up. Since the therapy for MPGN with essential cryoglobulinemia is not standardized, further research in the field is needed.

Background and Aims Outcome of dialysis patients differ considerably across the globe and many studies confirmed that home-based treatments offer some advantages, not only in regard of quality of life but also regarding of patients’ outcome. History of home hemodialysis (HOHD) in our country dates from 1971. and since that time many patients were treated with this dialysis modality. HOHD changed over the time together with general improving of dialysis techniques and we aimed to analyze the results of treatment of our population treated by HOHD during different time points. Method We analyzed patients characteristics, dialysis and uremia-related complications and survival of patients on HOHD during three different time points: 2001. (No=70), 2011. (No=29) and 2019. (No=22). Results The most frequent reason for ESRD in 2001, 2011 and 2019. was glomerulonephritis (48%, 45%, 36% respectively), followed by polycystic kidney disease 24% in 2011. and 36% in 2019. Diabetes mellitus (DM) was rarely cause of ESRD: in 2001. 2.1%; 4.5% in 2019. and none in 2011. In 2001. the patients were more frequently treated using high flux membranes (HF) as compared to HDF (87.1% vs.12.9%), and through years this changed in favor of HDF (48% vs. 52% in 2011, and 13.6% vs. 86.4% in 2019). Anti HCV prevalence was 27.4%, 38%, 27%, in 2001, 2011. and 2019. respectively. Anemia status was better controlled in recent years revealed by Hb level: 10.5±2.0 g/dl in 2001, 12.1±1.6 in 2011. and 11.9±2.3 in 2019. with almost similar percentage of patients treated with ESA (31%, 28% and 36% respectively). In 2001, parathyroid hormone level (iPTH) was 379±236 pmol/l and only 20% of patients underwent parathyroidectomy while in 2011. and in 2019. parathyroidectomy was performed in 69% and 59% of patients respectively. Therefore, in 2011. and in 2019. mean iPTH level was 33.8±48.5 and 40±46.2pmol/l respectively. Kaplan-Mayer analysis confirmed ten-year survival of 42% for period 1982-2001, and the most frequent reasons for death were infection and cardiovascular diseases. During the period 2011. to 2019., ten-year survival was 88% and cardiovascular diseases led to death in most of the cases. Conclusion our results have shown that HOHD treatment improved through the years considering patients’ survival, anemia status and secondary hyperparathyroidism treatment. Apart from HDF, the other factors have to be taken into consideration.

Background and Aims Home hemodialysis (HOHD) has been available as a modality of renal replacement therapy since the 1960s, in our center since 1972. Despite better patients’ outcome provided by HOHD comparing to hospital hemodialysis (HHD), its adoption has been limited worldwide. The aim of this study was to compare anemia, nutrition, mineral metabolism and morbidity in patients on HOHD and HHD. Method we analyzed dialysis and uremia related complications and morbidity in 19 HOHD patients in comparison with patients on HHD (N= 57). Each HOHD patient was previously matched with three patients on HHD by sex, age and reason for end stage renal disease (ESRD). Patients on HHD were on dialysis 3x4 h per week while patients on HOHD had dialysis on consecutive days in duration of 5-6 hours. Also, patients on HOHD were more frequent on hemodiafiltration (HDF), 89.5% of them, as compared to HHD patients (only 21.4%). Results All patients on HOHD were using AVF as vascular access for HD, and most of the analyzed HHD patients (only 5.3% used AVG). As revealed by hemoglobin level (Hgb) patients on HOHD had significantly better anemia control than HHD patients (12±2.3 vs. 10.2±1g/dl, p=0.004), despite the lower ferritin level (94±117 vs. 256±175ng/ml, p=0,001) and less frequent use of erythropoietin-stimulating agents (ESA), (and only 31% on HOHD vs 80% patients on HHD, p=0,001). By analyzing patients that used ESA therapy, we revealed that HOHD patients had lower weekly dose of ESA (5333±3265 IU vs. 6068±4145 IU). The values of intact parathyroid hormone (iPTH), did not differ significantly between HOHD (311±419pg/ml ; min 5,25, max 1529) and HHD (233±212pg/ml; min 19,25, max 926), but higher percentage of patients in HOHD group underwent parathyroidectomy (63% vs. 3.5%). The average values of calcium, and phosphorus did not significantly differ between HOHD and HHD patients (2.4±0.3 vs. 2.3±0.2mmol/l; 1.5±0.5 vs. 1.6±0.5mmol/l, respectively). HOHD patients had significantly higher albumin level (43±4.5 vs. 40.6±4g/l, p=0,035). There was no difference in annual hospital admission rate (0.4±0.5 vs. 0.6±0.7, p=0.35) between groups, but HHD patients had longer in-hospital stay. (4.8±5.3 days for HOHD vs. 7.3±9.3 days for HHD; p=0.16). Vascular access complications were most frequent reason for hospitalization in both groups (37%), followed by cardiovascular complications 13.6%, in HOHD group and infectious complications in HHD group 24%. Conclusion Our study has shown that HOHD provides some advantages over HHD including better quality of life and better anemia and nutrition control, better control of parathyroid function and shorter in-hospital stay. More frequent and longer dialysis sessions may be possible reason including HDF.

Background and Aims Heparin-induced thrombocytopenia (HIT) is a potentially fatal adverse reaction after administration of unfractionated or fractionated heparin, which underlies the generation of antibodies to the heparin complex and platelet factor 4 (PF4). It occurs in 5% of patients treated with unfractionated heparin and 0.5 - 1.5% fractionated heparin. The aim of the study is to determine the incidence and outcome of hemodialysis patients with HIT over 4 years period. Method Our retrospective study analyzed patients who were tested for evidence of positive anti-heparin antibody in the period from 2015 to 2019 in Zvezdara University Medical Center. The diagnosis was confirmed by the 4T clinical scoring system, a positive antiheparin-PF4 ELISA test and a positive platelet aggregation test with heparin. Results During observation period, total of 54 tests were performed on HIT suspected patients, out of which 21 patients were positive. Out of them, 14 patients were on HD, and other 7 (geriatric, surgery and cardiology departments) received therapy due to peripheral thrombosis, AIM or arrhythmia. All patients treated at nephrology, started hemodialysis (HD) with unfractionated heparin, while others were treated with LMWH. 4T scoring showed that 64% of patients had a moderate risk of developing HIT, while high risk was assessed in 36% of patients. Thrombotic complications in the form of deep venous thrombosis had 50% of patients, pulmonary thromboembolism had 11% of patients. The greatest decrease in Tr was most commonly observed between 10th and 14th day (61% of patients) and 39% from 4th to 10th day from start of heparin administration. In addition to heparin withdrawal and treatment with alternative nonheparin anticoagulation (fondaparinoux), 5 patients needed plasma treatment. 11 patients on HD were transferred to peritoneal dialysis (PD), and 2 patients recovered renal function. Overall mortality was 52%, while in nephrology patients was below 30%. Conclusion HIT should be considered in patients at risk. It is necessary to abolish heparin treatment and use alternative method (PD) or alternative anticoagulation. Hemodialysis patients have better prognosis than other comparable patients.

Background and Aims Peritoneal dialysis is an important form of treatment for patients with end stage chronic kidney failure requiring renal replacement therapy but its use may be limitted by growing number of elderly and disabled patients. Often, they choose an assisted peritoneal dialysis (assCAPD) as first option, that can be performed by relative or a nurs. The aim of this research was to analyse differences between two groups of patients (CAPD vs. assCAPD) in order to establish if two variants are comparable in regard of patients outcome. Method We analysed 61 patient divided into two groups (ass CAPD, N= 16 and CAPD, N= 45) who were dialysed in Zvezdara University hospital for more than 3 months and correlated number of peritonitis, exit site infections and overall mortality rates between two groups during the period of 60 months. Assistance was provided on the volontary basis by family member. Results Patients in assCAPD group were unsignificantly older (68+11vs. 60 + 12 years) and had higher comorbidity score. The groups were homogeneous according the presence of diabetes mellitus, CRP and PTH levels. There were no significant difference between the two of groups in the number of peritonitis (p=0,77), exit site infections (p=0,37) and overall survival (p= 0,74, Figure 1.). Conclusion Family member provides very good assistance in peritoneal dialysis giving the results that are comparable to that of self-performing CAPD patients. This is therefore very successful treatmen option for a special population of ESRD patients who can not performe CAPD on their own.

Background and Aims Increased free radicals production and down-regulated antioxidant enzymes activities contribute to protein, lipid and DNA oxidative damage particularly in HD patients lacking for GSTM1 enzyme activity. At the same time, those patients exhibit higher mortality rate than those with active GSTM1 genotype. It has been shown that vitamin E-coated membranes (VitEM) may decrease oxidative stress and inflammatory status in overall HD patients. Therefore, for the first time we analyzed VitEM dialyzers in patients who are homozygote for GSTM1 gene deletion and in whom anti-oxidative and anti-inflammatory benefit could be the greatest. Method GSTM1 genotypes were determined by PCR in 170 chronic HD patients. Those with GSTM1-null genotype were randomized and 80 were included in the study. Forty of them were dialyzed for three months with VitEM, while other forty were dialyzed with high-flux polysufone membranes of the same surface. Markers of protein and lipid oxidative damage, inflammation (thiol groups, malondialdehyde (MDA), Interleukin-6 (IL-6)), together with plasma antioxidant activity (glutathione peroxidase (GPX), superoxide dismutase (SOD)) were determined at the start and at the end of the study. Results Seventy-five patients’ finished the study. There were no significant differences in baseline characteristics between the two groups (age, sex, body weight, dialysis vintage, vascular access, presence of diabetes, dialyzers surface, Kt/V and CRP). Also, there were no significant differences at baseline markers of protein and lipid oxidative damage, inflammation and plasma antioxidant activity. After three months of therapy, GPX, MDA, thiol groups increased significantly in both groups, but without statistical significance between groups (Table 1). SOD did not change significantly during three month period. IL-6 increased in control group, at the same time decreased in VitEM group, but without statistical significance. Conclusion Vitamin E-coated membranes did not influence markers of oxidative stress in HD patients with GSTM1-null genotype. Further studies in the field are required.

Background and Aims According to previous data, the prevalence of tunnelled cuffed vascular catheters (TCC) is more frequent in elderly as compared to younger HD patients. Still, it is not clear if elderly have decreased survival of TCC as compared with survival in younger. Method During the period from January 2010 to June 30, 2015, 110 permanent catheters were implanted in 64 patients (1.72 catheters per patient, 51.6% male mean age 67±12years, 20 diabetics). Out of all patients, 44 (68.7%) were older than 65 years, 12 (27.3%) were diabetic and 11 (25%) were previously treated with peritoneal dialysis. In the age-based subpopulations we compared the incidence of infections, thrombosis, chemical removal of thrombus by actilysis and TCC outcome. Results Reasons for TCC placement in elderly were inability of the second option and exhausted vascular approach and these reasons were found to be significantly more frequent compared to patients younger than 65 years (p = 0.020 ). Primary position of TCC was right jugular vein in both groups (39.1%, No = 25 vs 14.1% No = 9), more commonly in group of elderly patients, but there was no significant difference in the initial TCC position depending on the age structure of the patient (Hi square = 1.720, p = 0.886). The overall incidence of infections was 3.44 episodes per 1000 catheter days and patients' age did not affect TCC replacement, infection, thrombosis and inflammation. In the group of elderly, 27 patients had catheter infection (61.4%), 10 (22.7%) had catheter thrombosis and actilysis resolved thrombosis in 6 (13.6%) patients without significant difference as compared with younger patients. Catheter-induced bacteraemia were more common in TCC over 65 years (47 TCC vs. 12 TCC) but without statistical significance (p = 0.062). Similarly, exit site infection, was more common (14 TCC vs. 4 TCC) for those older than 65 years but also without statistical significance. Thrombosis of TCC occurred in 7 patients with TCC younger than 65 years and in 20 TCC in cohort of elderly (Hi square = 0.033, p = 0.535) (Table 1). Regarding treatment outcome, 19 (43.2%) elderly patients died while being treated with TCC, 12 patients (27.3%) changed treatment modality to peritoneal dialysis, 4 patients (9.1%) received arteriovenosus graft (AVG) and 9 patients had functional TCC at the end of follow up (20.5%) and no significant difference was found in the outcome compared to younger patients. Conclusion The reason for placement of TCC in elderly is the inability of other treatment options and exhaustion of vascular access. Concerning catheter related complication and outcome, there was no significant difference between the elderly and younger patient.

Background and Aims Serum levels of parathyreoid hormone is the main cause of mineral disorders in patients on chronic hemodialysis, and it well known that this hormone acts as an uremic toxine and contributes to oxidative stress and overall mortality rate. However, there are many observations which imply that the protean manifestations of renal bone disease cannot be explained simply by abnormalities of PTH or vitamin D metabolites. For example, levels of PTH correlate relatively poorly with various parameters of bone histology. It has been shown that uremia leads to cytokijne imbalance with overbalance of proinflammatory citokines such as TNF. Also, studies showed that calcimimetic therapy decreases not only PTH levels, but also levels of TNF. The aim was to analyse tumor necrosis factor (TNF) gene polymorphisms in group of hemodialysis patients and to correlate the findings with presence of secondary hyperparathyroidism. Method This cross sectional study included 202 patients on regular hemodialysis for more than six months in University Medical Centar Zvezdara. Venous blood for genotyping and for PTH analysis was collected on midweek dialysis session from each patient. Genetic analysis was performed by using polymerase chain reaction. Patients are diveded in two groups regarding the level of PTH, so that first group had normal PTH levels or mild SHPT, while patients in second group had sever SHPT. We analysed influence of genetic polymorphism for TNF on apperance of SHPT. Results The results have shown 3 fold lower risk for developing SHPT in GG homozygots for TNF gene with statistical significance (p=0,01)- Table 1. Conclusion Parathyreoid gland hyperfunction is multifactorial disorder and there are emerging evidence that cytokines as endogenous modulators have an important impact on its pathogenesis.

Background and Aims Relative hypervolemia or overhydration (ROH) above 15% of the normally hydrated body extracellular volume (ECV), assessed by bioimpedance spectroscopy (BIS), puts chronic hemodialysis (HD) patients at an increased risk of cardiovascular (CV) incidents and death, as numerous studies have shown. It has also been reported that the reduction of ROH to the value below 15% of ECV can positively affect hypertension and some aspects of the left ventricle (LV) function and morphology. The concept of Active Fluid Management (AFM) has been developed and it hypothesized that maintaining average (weekly) predialysis overhydration (AWOH) below 15% of ECV will preserve heart function and structure and thus lead to fewer CV complications. The purpose of this study was to investigate the effects of AFM concept guided by BIS on cardiac morphology, mechanics and function in chronic HD patients. Methods Randomized prospective single-center study lasted 9 months and included BIS naive HD patients from the Dialysis unit of Zvezdara University Medical Center in Belgrade with HD vintage greater of 3 months. BIS was performed by Body Composition Monitor (BCM). In accordance with the AFM concept, BIS was applied to patients in the Active group every time their average weekly ROH (AWOH) exceeded 15% of their normal ECV and their dry weight (DW) was time-adjusted according to the findings along with clinical assessment. In the Control group, patients were treated in accordance with the standard clinical practice. Cardiac structural and functional characteristics were obtained at the beginning and the end of the study by using 2-dimensional Doppler echocardiography and spackle tracking modality. Cardiac markers (high-sensitivity C-reactive protein, Troponin T and N-terminal pro-brain natriuretic peptide) were measured at the same time. Results The study included 42 patients (25 M) in the Active group and 41 patients (23 M) in the Control group. Patients from both groups were of similar age (56.1 ± 11.5 vs. 57.5 ± 13.2 years, p = 0.6) and HD vintage (79.9 ± 59.2 months vs. 95.3 ± 80.0 months, p = 0.6). 73 patients completed the 9 months study, 38 in the Active group and 35 in Control group. Within the Active group, recommended AWOH lower than 15% ECV has 55% at start and 76% of patients at the end of study (p< 0.01). In parallel, there were improvements in their LV ejection fraction (LVEF), from 41.3 ± 9.3% to 44.0 ± 8.8% (p < 0.01), LV end systolic volume index, from 40.2 ± 12.5 to 35.8 ± 13.5 ml/m2 (p < 0.05), LV mass indexed at height at 2.7 (LVMI2.7) from 62.8 ± 19.7 g / m2.7 to 57.7 ± 16.9 g/m2.7 (p Conclusion Active Fluid Management leads to the improvement of left ventricle systolic function and prevents worsening of diastolic function in the observed hemodialysis patients. This concept implemented could favourably affect the clinical course of hemodialysis patients in daily clinical practice.

Background: Increased oxidative stress is a hallmark of end-stage renal disease. Hemodialysis (HD) patients lacking glutathione transferase M1 (GSTM1) enzyme activity exhibit enhanced oxidative DNA damage and higher mortality rate than those with active GSTM1 enzyme. To our knowledge, this is the first study to use the vitamin E-bonded membranes (VEM) in patients with homozygous GSTM1 gene deletion, and we aimed to determine the effect of VEM on oxidative and inflammatory status in HD patients with homozygous GSTM1 gene deletion. Methods: GSTM1 genotypes were determined by polymerase chain reaction (PCR) in 170 chronic HD patients. Those with GSTM1-null genotype were randomized and 80 were included in the study. Forty of them were dialyzed for three months with VEM, while the other forty were dialyzed with high-flux same-surface polysulfone dialyzers. Markers of protein and lipid oxidative damage and inflammation (thiol groups, malondialdehyde (MDA), Interleukin-6 (IL-6)), together with plasma antioxidant activity (glutathione peroxidase (GPX), superoxide dismutase (SOD)) were determined. Results: Seventy-five patients finished the study. There were no differences at baseline in markers of protein and lipid oxidative damage, inflammation and plasma antioxidant activity. After three months of therapy, GPX, MDA, and thiol groups increased significantly in both groups, but without statistical significance between groups. SOD and C reactive protein (CRP) did not change significantly during the three-month period. IL-6 increased in the control group, and at the same time, decreased in the VEM group, but without statistical significance. Hemoglobin (Hb) value, red blood cells, erythropoiesis resistance index (ERI), serum ferritin and iron did not change significantly within or between groups. Regarding other laboratory parameters, proteins, albumins, triglycerides, serum phosphorus, serum bicarbonate and Kt/V showed significant improvements within groups but with no significant difference between groups. Conclusions: Our data shows that therapy with VEM over three months had no benefit over standard polysulfone membrane in decreasing by-products of oxidative stress and inflammation in dialysis patients lacking GSTM1 enzyme activity.

BackgroundSodium thiosulphate (NaTS) is mostly used in haemodialysis (HD) patients with calcific uraemic arteriolopathy. This double-blind, randomized, placebo-controlled study assessed the effect of NaTS on progression of cardiovascular calcifications in HD patients.MethodsFrom 65 screened patients, we recruited 60 patients with an abdominal aorta Agatston calcification score ≥100. Thirty patients were randomized to receive NaTS 25 g/1.73 m2 and 30 patients to receive 100 mL of 0.9% sodium chloride intravenously during the last 15 min of HD over a period of 6 months. The primary endpoint was the absolute change of the abdominal aortic calcification score.ResultsThe abdominal aortic calcification score and calcification volume of the abdominal aorta increased similarly in both treatment groups during the trial. As compared with the saline group, patients receiving NaTS exhibited a reduction of their iliac artery calcification score (−137 ± 641 versus 245 ± 755; P = 0.049), reduced pulse wave velocity (9.6 ± 2.7 versus 11.4 ± 3.6; P = 0.000) and a lower carotid intima-media thickness (0.77 ± 0.1 versus 0.83 ± 00.17; P = 0.033) and had better preservation of echocardiographic parameters of left ventricular hypertrophy. No patient of the NaTS group developed new cardiac valve calcifications during the trial as compared with 8 of 29 patients in the saline group. By univariate analysis, NaTS therapy was the only predictor of not developing new valvular calcifications. No adverse events possibly related to NaTS infusion were noted.ConclusionsWhile NaTS failed to retard abdominal aortic calcification progress, it positively affected calcification progress in iliac arteries and heart valves as well as several other cardiovascular functional parameters.

Cardiovascular calcifications (CVC) are present in up to 70% of non-diabetic dialysis patients. Sparse data are available on predictors of very long-term outcomes of such patients. The Belgrade Aachen Study on Calcification in Hemodialysis patients (BASCH study) aimed to study this using a comprehensive CVC assessment. We prospectively analyzed 220 hemodialysis patients followed for a mean of 76 months (median 73 months, range 6–160 months). We compared patients deceased from cardiovascular diseases (CVD) and survivors. Analyses included composite calcification scores (determined by combining ultrasound and X-ray analyses), demographic, clinical and laboratory data and pulse wave velocity (PWV). For survival analysis, patients were divided into group according to quartiles (Q). Compared to survivors, deceased patients from CVD were significantly older, more frequently hypertensive, had shorter dialysis times per week and lower Kt/V values, and they exhibited lower serum fetuin A, osteoprotegerin and hemoglobin as well as higher CRP levels. Composite calcification and Adragao scores were significantly higher in deceased patients from CVD as was PWV. Mean survival was 101 ± 47 months (Q1), 87 ± 51 month (Q2), 66 ± 48 (Q3) and 54 ± 45 months (Q4), p = 0.000. Cox multivariate regression analysis showed that independent predictors for cardiovascular mortality were composite calcification score in the range of third and fourth quartiles. Composite calcification score emerged as significant predictors of long-term survival in our group of largely non-diabetic dialysis patient population, finding that should be confirmed by intervention studies.

Background/Aim. Extremely Low Frequency Pulsed Electromagnetic Magnetic Field (ELF-PEMF) has a wide range of therapeutic applications which were expanding during the last decades. ELF-PEMF, as non-invasive, longterm safe method of physical therapy can influence a variety of aspects in chronic diseases including quality of life. Patients with chronic kidney disease (CKD), especially with end stage renal disease (ESRD), treated by dialysis, have lower health-related quality of life and changed normal way of living because of ESRD-related comorbid illnesses, associated conditions and complex dialysis procedures. The objective of this study was to assess the effectiveness of longterm ELF-PEMF in concordance with exercising on quality of life in ESRD patients on dialysis. Methods. A total of 124 patients (59 men and 65 women) with ESRD on dialysis program were divided into study group and control group. Patients included in the study group (n = 54) agreed to receive treatment with ELF-PEMF (18 Hz, 2 mT, applied during 40 minutes after ten consecutive dialysis procedures, four times through one year, 120 treatments in total) together with kinesitherapy over three years. The patients in the control group (n = 70) were subjected only to kinesitherapy as a physical therapy procedure. Quality of life was assessed through the Short Form Health Survey, version 2 (SF36v2) and the Functional Assessment of Chronic Illness Therapy, version 4 (FACIT Fatigue v4) questionnaires. Results. In the study group, treatment with ELF-PEMF significantly improved FACIT Fatigue v4 scale score as well as physical health, physical functioning, bodily pain and energy/ fatigue domains of SF=36v2 scale. There were no effects on mental health domain, limitations due to physical health problems, limitations due to personal or emotional problems, emotional well-being, social functioning, and general health perceptions. In the control group, no beneficial effects on FACIT Fatigue v4 scale and SF36v2 scale item were noticed. Conclusion. ELF-PEMF could be a additional and safe strategy for improving quality of life in patients with ESRD on dialysis.

Background/Aim. A variety of physical therapy options has been developed for the treatment of musculoskeletal disorders including those characterized with low bone mineral density (BMD). Extreme low frequency pulsed electromagnetic field (ELF-PEMF) can accelerate bone formation. Patients with end stage of renal disease (ESRD) are predisposed to high incidence of fractures due to bone disorder with multifactorial pathogenesis. Vitamin D, calcium supplements, antiresorptive and anabolic drugs in those patients have changed pharmacodynamics and pharmacokinetics and have minimal or limited effects. The aim of this study was to assess the effectiveness of long-term ELF-PEMF therapy applied in concordance with physical exercise on bone mass, incidence of new bone fractures and parathyroid hormone concentrations in ESRD patients on dialysis. Methods. In this 3-year prospective clinical trial, 151 patients with ESRD on dialysis program were subjected to treatment with ELF-PEMF (18 Hz, 2 mT) applied during 40 min after 10 consecutive dialysis procedures, 4 times through one year (120 treatments in total during three years) together with kinesitherapy (study group) or only with kinesitherapy (control group) on the voluntary basis. Results. Total of 124 patients have completed the study. In the study group (n = 54), regardless of sex, significant improvements of BMD, T-score and Z-score on both lumbar spine and femoral neck were achieved after 3-year treatment with ELF-PEMF. In the control group (n = 70), significant decreases of BMD, T-score and Z-score as well as the higher incidence of new bone fractures were recorded. Conclusion. ELF-PEMF could be a convenient and safe non-pharmacological therapeutic strategy for fracture prevention in nephrology practices.

For adequate hemodialysis, functional vascular access is obligatory. Neointimal hyperplasia (NIH) has a central role in stenosis and thrombosis development, which represent the most frequent causes of vascular access failure. Polymorphism of different genes that have a significant role in endothelial function may have an impact on NIH development. Therefore, the aim of our study is to determine the effect of angiotensin-converting enzyme (ACE) I/D and matrix metalloproteinase-3 (MMP3) 5A/6A polymorphism on risk for developing vascular access failure in hemodialysis patients. The study included 200 patients on regular hemodialysis at Nephrology Department, University Medical Center Zvezdara. Retrospective analysis included a collection of general and vascular access data from medical records. Genetic analysis was performed by using polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP). Patients were divided into two groups: Group 1-patients who have never experienced vascular access failure and Group 2-patients who have at least one spontaneous vascular access failure. There was no difference in age, gender, hemodialysis vintage, main diagnosis, presence of hypertension, and diabetes mellitus between the two groups. There were no statistically significant differences in the frequencies of ACE and MMP3 genotypes between the two groups. Without statistical significance, it was found that homozygotes for I allele had two times higher risk for developing vascular access failure than homozygotes for D allele (OR 2.00; 95%CI: 0.727-5.503; P = 0.180). In addition, patients with 5A allele have 1.7 times higher risk for developing vascular access failure compared with patients without this allele (OR 1.745; 95% CI: 0.868-3.507; P = 0.118). Patients with vascular access failure do not have different genotype distribution regarding ACE gene and MMP3 gene polymorphism as compared with patients without vascular access failure. Still, homozygotes for I allele and homozygotes for 5A allele have higher risk for developing vascular access failure compared with other patients.

The oxidative stress response via Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) interlinks inflammation- and metabolism-related pathways in chronic kidney disease. We assessed the association between polymorphisms in Nrf2, superoxide dismutase (SOD2), glutathione peroxidase (GPX1), and the risk of end-stage renal disease (ESRD). The modifying effect of these polymorphisms on both oxidative phenotype and ESRD prognosis, both independently and/or in combination with the glutathione S-transferase M1 (GSTM1) deletion polymorphism, was further analyzed. Polymorphisms in Nrf2 (rs6721961), SOD2 (rs4880), GPX1 (rs1050450), and GSTM1 were determined by PCR in 256 ESRD patients undergoing hemodialysis and 374 controls. Byproducts of oxidative stress were analyzed spectrophotometically or by ELISA. Time-to-event modeling was performed to evaluate overall survival and cardiovascular survival. The SOD2 Val/Val genotype increased ESRD risk (OR = 2.01, p = 0.002), which was even higher in combination with the GPX1 Leu/Leu genotype (OR = 3.27, p = 0.019). Polymorphism in SOD2 also showed an effect on oxidative phenotypes. Overall survival in ESRD patients was dependent on a combination of the Nrf2 (C/C) and GPX1 (Leu/Leu) genotypes in addition to a patients’ age and GSTM1 polymorphism. Similarly, the GPX1 (Leu/Leu) genotype contributed to longer cardiovascular survival. Conclusions: Our results show that SOD2, GPX1, and Nrf2 polymorphisms are associated with ESRD development and can predict survival.