Roxadustat for the treatment of anaemia in chronic kidney disease patients not on dialysis: a Phase 3, randomized, open-label, active-controlled study (DOLOMITES).

BACKGROUND: Roxadustat, an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated for treatment of anaemia of chronic kidney disease (CKD). METHODS: This randomized, open-label, active-controlled Phase 3 study compared roxadustat versus darbepoetin alfa (DA) in non-dialysis-dependent (NDD) CKD patients with anaemia for ≤104 weeks. Doses were titrated to correct and maintain haemoglobin (Hb) within 10.0-12.0 g/dL. The primary endpoint was Hb response in the full analysis set, defined as Hb ≥11.0 g/dL and Hb change from baseline (BL; CFB) ≥1.0 g/dL in patients with BL Hb >8.0 g/dL or CFB ≥2.0 g/dL in patients with BL Hb ≤8.0 g/dL during the first 24 weeks of treatment without rescue therapy (non-inferiority margin, -15%). Key secondary endpoints included change in low-density lipoprotein (LDL), time to first intravenous (IV) iron use, change in mean arterial pressure (MAP) and time to hypertension occurrence. Adverse events were assessed. RESULTS: Of 616 randomized patients (roxadustat, 323; DA, 293), 424 completed treatment (roxadustat, 215; DA, 209). Hb response with roxadustat was non-inferior to DA (roxadustat: 256/286, 89.5% versus DA: 213/273, 78.0%, difference 11.51%, 95% confidence interval 5.66-17.36%). Roxadustat maintained Hb for up to 2 years. Roxadustat was non-inferior to DA for change in MAP and time to occurrence of hypertension and superior for change in LDL and time to first IV iron use. Safety profiles were comparable between groups. Findings suggest that there was no difference between groups regarding the composite endpoints major adverse cardiovascular events (MACEs) and MACE+ [MACE: 0.81 (0.52-1.25), P = 0.339; MACE+: 0.90 (0.61-1.32), P = 0.583]. CONCLUSIONS: Roxadustat is a viable option to treat anaemia in NDD CKD patients maintaining Hb levels for up to 104 weeks.

Roxadustat for the treatment of anemia in chronic kidney disease patients not on dialysis: a Phase 3, randomized, double-blind, placebo-controlled study (ALPS).

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 < 0.001]. Superiority of roxadustat was demonstrated for low-density lipoprotein cholesterol change from BL, and time to first use of rescue medication (both P < 0.001). The incidences of treatment-emergent adverse events were comparable between groups (roxadustat: 87.7%, placebo: 86.7%). CONCLUSIONS: Roxadustat demonstrated superior efficacy versus placebo in terms of both Hb response rate and change in Hb from BL. The safety profiles of roxadustat and placebo were comparable.

Population Pharmacokinetics of Bisoprolol in Hemodialysis Patients with Hypertension.

The aim of our study was to estimate clearance of bisoprolol and reveal the factors that could influence its pharmacokinetic (PK) variability in hypertensive patients on hemodialysis, using the population PK analysis. Parameters associated with plasma concentration of bisoprolol at steady state were analyzed in 63 patients (mean age 62.12 years, mean total weight 69.63 kg) who were hypertensive and on hemodialysis due to severe renal failure using non-linear mixed-effect modeling with ADVAN1 subroutine. The final regression model for the clearance of the drug included only creatinine clearance (CLcr) out of 12 tested covariates. The equation that describes CL of bisoprolol is the following: CL (l/h) = 0.12 + 6.33 * CLcr. These findings suggest that the routine measuring of serum creatinine level may be used to facilitate administration of bisoprolol in patients on hemodialysis.

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.

Dialysis headache in patients undergoing peritoneal dialysis and hemodialysis.

OBJECTIVES: Headache is among most frequently encountered neurological symptom during hemodialysis (HD), but still under investigated in peritoneal dialysis (PD) patients. The aim of this study was to assess the incidence and clinical characteristics of dialysis headache (DH) in HD and PD patients. MATERIAL AND METHODS: A total of 409 patients (91 on PD and 318 on HD) were interviewed using a structured questionnaire, designed according to the diagnostic criteria of the International Headache Classification of Headache Disorders from 2004. Patients with DH underwent a thorough neurological examination. RESULTS: DH was reported by 21 (6.6%) HD patients and 0 PD patients. PD patients had significantly lower serum sodium, potassium, calcium, phosphate, urea and creatinine, calcium-phosphate product, and diastolic blood pressure than HD patients. HD patients had significantly lower hemoglobin compared to PD patients. Primary renal disease was mostly parenchymal in HD patients, and vascular in PD patients. DH appeared more frequently in men, mostly during the third hour of HD. It lasted less than four hours, was bilateral, non-pulsating and without associated symptoms. CONCLUSION: Biochemical alterations may be implicated in the pathophysiology of DH. Specific features of DH might contribute to better understanding of this secondary headache disorder.

COMPLETE CORRECTION OF ANEMIA WITH RECORMON® (ERYTHROPOIETIN ß) IN PATIENTS ON CHRONIC HEMODIALYSIS.

INTRODUCTION: Suboptimal correction of anemia is associated with increased prevalence of cardiovascular diseases and increased morbidity and mortality of pre-dialysis and dialysis patients. The aim of the study was to compare the effect of optimal vs. suboptimal correction of anemia in hemodialysis patients with left ventricular hypertrophy. MATERIAL AND METHODS: The study included 50 patients, 32 males and 18 females, their mean age being 49.4±11.8 years, from five hemodialysis centers (Clinical Hospital Center Zvezdara, Beograd, Clinical Center Novi Sad, hospitals in Krusevac, Pirot and Zrenjanin). The patients had suboptimal hemoglobin level in spite of therapy (7.8±3.8 g/dl). In addition, the most important inclusion criteria was the left ventricular mass index above 160 g/m2 and the primary efficacy parameter was a decrease in the left ventricular mass index during 12 month study period. RESULTS: During the study, the number of patients who reached their hemoglobin >12 g/dl increased and the target hemoglobin (12-13 g/dl) was achieved in 24 (52%) of patients at the end of the study. At the same time, the left ventricular mass index significantly decreased as compared with the initial values (p=0.014). The left ventricular mass index was not significantly decreased in the patients who did not achieve the target hemoglobin level (207±65 vs. 217±38 g, p=ns) as compared with the patients who achieved the target hemoglobin (179±32 g/ m2 vs. 197±38 g/m2, p=0.007). The left ventricular ejection fraction did not change significantly during the study period. CONCLUSION: Anemia correction with erythropoietin ß resulted in the significantly corrected left ventricular hypertrophy in hemodialysis patients who had had a suboptimal hemoglobin level. Our results have shown that correction of left ventricular hypertrophy

Depression and quality of sleep in maintenance hemodialysis patients.

INTRODUCTION: Sleep disorders and psychological disturbances are common in end-stage renal disease (ESRD) patients. However, despite their frequency and importance, such conditions often go unnoticed, since all patients do not clearly manifest fully expressed symptoms. OBJECTIVE: This study aimed to determine the prevalence of depression and poor sleep quality and to examine the association between these disorders and demographic, clinical and treatment-related characteristics of ESRD patients on hemodialysis (HD). METHODS: The study included 222 patients (132 men and 90 women), mean age 57.3 +/- 11.9 years, from 3 HD centers in Central Serbia, which provided us with biochemical parameters and demographic data. Sleep quality and depression were assessed using the Pittsburgh Sleep Quality Index (PSQI) and Beck Depression Inventory (BDI), respectively. RESULTS: The average BDI was 16.1 +/- 11.3. Depressed patients were significantly older (p=0.041), had a significantly lower dialysis adequacy (p=0.027) and a significantly worse quality of sleep (p < 0.001), while they did not show significant difference as regarding sex, employment, marital status, comorbidities, dialysis type, dialysis vintage, shift and laboratory parameters.The average PSQI was 7.8 +/- 4.5 and 64.2% of patients were poor sleepers. Poor sleepers were significantly older (p = 0.002), they were more often females (p = 0.027) and had a significantly higher BDI (p < 0.001), while other investigated variables were. not correlated with sleep quality. A statistically significant positive correlation was found between BDI and PSQI (r = 0.604; p < 0.001). CONCLUSION: Depression and poor sleep quality are frequent and interrelated among HD patients.

Habitual coffee consumption enhances attention and vigilance in hemodialysis patients.

OBJECTIVE: Coffee drinking is the main source of caffeine intake among adult population in the western world. It has been reported that low to moderate caffeine intake has beneficial effect on alertness and cognitive functions in healthy subjects. The aim of this study is to evaluate the impact of habitual coffee consumption on cognitive function in hemodialysis patients. METHODS: In a cross-sectional study, 86 patients from a single-dialysis centre underwent assessment by the Montreal Cognitive Assessment tool and evaluation for symptoms of fatigue, mood, and sleep disorders by well-validated questionnaires. The habitual coffee use and the average daily caffeine intake were estimated by participants' response to a dietary questionnaire. RESULTS: Sixty-seven subjects (78%) consumed black coffee daily, mostly in low to moderate dose. Cognitive impairment was found in three-quarters of tested patients. Normal mental performance was more often in habitual coffee users (25% versus 16%). Regular coffee drinkers achieved higher mean scores on all tested cognitive domains, but a significant positive correlation was found only for items that measure attention and concentration (P = 0.024). CONCLUSIONS: Moderate caffeine intake by habitual coffee consumption could have beneficial impact on cognitive function in hemodialysis patients due to selective enhancement of attention and vigilance.

[Headache associated with haemodialysis].

INTRODUCTION: Haemodialysis (HD) is one of the most accessible methods for the treatment of the growing number of patients suffering from terminal-stage renal insufficiency. Although headache is the most frequently encountered neurological symptom during HD, there are few studies reporting its prevalence and clinical features. OBJECTIVE: The objective of this study was to examine the frequency, demographic and clinical features of headache during HD, and to compare these parameters among patients with and without headache. METHOD: The study involved 126 patients (48 female and 78 male) with chronic renal failure on regular HD for at least six months, at the Dialysis Unit of Nephrology Department, Krusevac. All patients were inquired about their possible problems with headache using the standardized questionnaire designed according to the diagnostic criteria of the International Headache Classification of Headache Disorders, second edition, published in 2004 (ICHD-II). Subsequently, the patients were clinically evaluated and patients with headaches were further subclassified by a neurologist with special interest in headache disorders. Patients with headache were compared to the patients without headache regarding age, sex, duration of HD, causes of end-stage renal disease, arterial diastolic and systolic blood pressure, and serum values of the most important blood parameters such as sodium, potassium, urea and creatinine. In the group of patients with headache we analyzed the characteristics of specific headache type according to ICHD-II classification. We also analyzed the most important clinical features of haemodialysis headache (HDH). RESULTS: In the group of 126 evaluated patients, 41 (32.5%) patients had headaches. There were no statistically significant differences between the patients with headaches and those without headaches regarding sex, age, BMI, duration of HD, causes of end-stage renal disease, arterial blood pressure, red blood cell count, serum concentration of haemoglobin, blood urea nitrogen, creatinine, glucose, MCHC, total protein, sodium and potassium. Fourteen patients (34% of those with headaches) experienced headache during the HD session and were subclassifled as HDH using diagnostic criteria of the International Headache Society. Tension type headache (41% of those with headaches) and migraine without aura (10%) were most common in the primary headache group and headache due to arterial hypertension (7%) was the most prevalent among the secondary headaches. Although there were some common clinical characteristics, we could not find a unifying clinical pattern in the patients with HDH. CONCLUSION: Haemodialysis headache is the most common headache in patients undergoing haemodialysis, and despite some common symptoms, it does not appear to be uniform in its clinical characteristics.

[Restless legs syndrome prevalence in patients on chronic hemodialysis in central Serbia].

BACKGROUND/AIM: Restless legs syndrome (RLS) is a sensorymotor disorder and the core feature of this syndrome is a distressing, irresistible need or urge to move the legs. RLS is one of the most troublesome conditions experienced by endstage renal disease patients treated with regular hemodialysis, and is significantly associated with their increased mortality. The aim of this study was to assess the prevalence of RLS in the patients with end-stage renal failure in the three dialysis centers in central Serbia, and to investigate the association of the syndrome with clinical characteristics and biochemical variables. METHODS: A cross-sectional multicentric study in which 166 consecutive hemodialysis patients were evaluated using a standard questionnaire based on diagnostic criteria elaborated by the International Restless Legs Syndrome Study Group was performed. All patients were reinterviewed and clinically examined by a qualified neurologist. The data on the patients with and without RLS were compared. RESULTS: The prevalence of RLS was 22.96% (95% CI, 16.57% to 29.35%). There was no significant difference in duration of hemodialysis and clinical characteristics when we compared the patients with RLS with those without RLS. We found significantly higher levels of blood urea nitrogen and creatinine and lower level of Kt/V index in the patients with RLS, which might point to inadequate dialysis in these patients. CONCLUSION: In our study the prevalence of RLS in the patients on the regular hemodialysis was 22.96%. The obtained results are similar to those of other studies using the same methodology in the white population on the regular hemodialysis.