Continuous Erythropoietin Receptor Activator for the Treatment of Chronic Dialysis Patients with Renal Anemia in Daily Clinical Practice in Poland: A Non-Interventional, Multi-Center, Pragmatic NAVIGO Trial.

BACKGROUND: Renal anemia is one of the most common complications of chronic kidney disease (CKD). This real-life study assessed the effectiveness of methoxy polyethylene glycol-epoetin beta, a continuous erythropoietin receptor activator (C.E.R.A.), for the treatment of CKD-associated anemia in patients receiving dialysis in daily clinical practice. METHODS: 247 patients receiving chronic intermitted dialysis in 26 centers in Poland with CKD-associated symptomatic anemia, ESA-naïve, and with balanced iron stores in the investigators' opinion were enrolled this real-life study. Over 12 months, the following data were collected: hemoglobin (Hb) concentration and dosage, route of administration and dosing scheme of C.E.R.A., dialysis adequacy, adverse events, iron therapy, and blood transfusions. RESULTS: During the treatment, a Hb concentration of ≥10 g/dL was noted in 90.9% of hemodialysis patients (n = 224) and 96.0% of peritoneal dialysis patients (n = 23). At baseline, 7.8% of patients had a Hb concentration of 10-12 g/dL, which increased to 63.3% after 12 months. The median time when Hb concentration was maintained within 10-12 g/dL was 115.2 (interquartile range 49.1-188.7) days. A Hb concentration ≥12 g/dL was observed after 7 months of treatment in a maximum of 24.1% of hemodialysis patients, and 31.8% of peritoneal dialysis patients. The median time elapsed between the start of treatment and the first Hb concentration >10 g/dL was 42.0 (21.0-78.2) days. C.E.R.A. was well tolerated. CONCLUSIONS: C.E.R.A. corrects CKD-associated anemia in dialysis patients, and maintains Hb levels within the recommended target range. The study also confirmed the acceptable safety profile of the drug.

Higher Serum-Soluble α-Klotho Level Does Not Predict Longer Survival after Stroke.

RESULTS: There were 5 recurrent strokes and 89 deaths during the 36-month follow-up. Even though no significant differences in OS and SFS between soluble α-Klotho level tertile groups were recorded, unexpectedly, OS and SFS were highest in patients with the lowest soluble α-Klotho concentrations. Moreover, the Cox proportional models adjusted for established risk factors, kidney function, and the severity of stroke revealed that each 100 pg/mL increase in soluble α-Klotho levels was associated with decreased OS (HR = 0.951 (0.908-0.995), p < 0.05) and SFS (HR = 0.949 (0.908-0.993), p < 0.05). In addition, the α-Klotho to iFGF23 index was predicting neither OS nor SFS. CONCLUSION: Soluble α-Klotho levels in serum were not related to the severity of neurological deficits and long-term outcomes in patients with IS. No neuroprotective effect of soluble α-Klotho levels in patients with IS was demonstrated.

Severity of Vitamin D Deficiency Predicts Mortality in Ischemic Stroke Patients.

BACKGROUND: Vitamin D (VD) deficiency is considered an independent risk factor for death due to cardiovascular events including ischemic stroke (IS). We assessed the hypothesis that decreased levels of 25-hydroxyvitamin D (25-OH-D) are associated with increased risk of mortality in patients with IS. METHODS: Serum 25-OH-D, intact parathyroid hormone (iPTH), and intact fibroblast growth factor 23 (iFGF23) levels were assessed in serum of 240 consecutive patients admitted within the 24 hours after the onset of IS. Mortality data was obtained from the local registry office. RESULTS: Only three subjects (1.3%) had an optimal 25-OH-D level (30-80 ng/mL), 25 (10.4%) had a mildly reduced (insufficient) level, 61 (25.4%) had moderate deficiency, and 151 (62.9%) had a severe VD deficiency. 20% subjects had secondary hyperparathyroidism. The serum 25-OH-D level was significantly lower than that in 480 matched subjects (9.9 ± 7.1 vs. 21.0 ± 8.7 ng/mL). Of all the patients, 79 (32.9%) died during follow-up observation (44.9 months). The mortality rates (per year) were 4.81 and 1.89 in a group with and without severe VD deficiency, respectively (incidence rate ratio: 2.52; 95% CI: 1.44-4.68). There was no effect of secondary hyperparathyroidism and iFGF23 levels on mortality rates. Age, 25 - OH - D < 10 ng/mL, and functional status (modified Rankin scale) were significant factors increasing the risk of death in multivariable Cox proportional hazard regression test. CONCLUSIONS: Severe VD deficiency is an emerging, strong negative predictor for survival after IS, independent of age and functional status. VD supplementation in IS survivals may be considered due to high prevalence of its deficiency. However, it is uncertain whether it will improve their survival.

Osteoprotegerin Assessment Improves Prediction of Mortality in Stroke Patients.

BACKGROUND: Elevated circulating osteoprotegerin (OPG) level is associated with an increased risk of hospitalization for ischemic stroke and coronary artery disease. The aim of the present study was to analyze whether OPG assessment may improve the prediction of mortality in patients with stroke. PATIENTS AND METHODS: Serum OPG, fetuin A, 25-OH-D3, intact parathyroid hormone levels were assessed in serum samples which were left over after routine tests in a hospital laboratory. This assessment was conducted in 240 consecutive patients with acute ischemic stroke, admitted within 24hours after the onset of symptoms to the Stroke Unit. Mortality data were obtained from the local registry office. RESULTS: The mean OPG serum level was 14.6 ± 6.0pmol/L (range: 3.7-43.4). There were no significant differences in the OPG values between men and women (13.9 ± 5.0 versus 15.1 ± 6.7 pmol/L; P = .12). Therefore, tertiles were calculated for the whole group. During the follow-up, 85 (35.4%) patients died and 92 (38.3%) died or had recurrent stroke. OPG level appeared a significant predictors of death and composite end-point (death/recurrent stroke), in addition to the well-established once (age, atrial fibrillation, diabetes RANKIN at admission and discharge, severity of stroke). In multivariable stepwise backward analyses, the OPG level persisted as a significant and independent predictor of death (hazard ratio [HR] = 1.084 (95% confidence intervals: 1.036-1.134)] and composite and point (HR = 1.082 [1.037-1.129]). CONCLUSIONS: OPG level may be considered as a predictor of mortality in stroke patients.

Nutrient intake assessed with Diet History Questionnaire II, in relation to long-term calcium-phosphate control in hemodialysis patients with end-stage renal failure.

BACKGROUND: Diet is a key factor that determines proper alignment of calcium-phosphate and nutritional status among hemodialysis (HD) patients. OBJECTIVES: To assess the nutrient intake in relation to long-term calcium-phosphate control in HD patients with end-stage renal failure. MATERIAL AND METHODS: The study included 107 patients (66 men, 41 women) from 10 dialysis centers in the Upper Silesia region of Poland. To analyze the diet composition during the previous year, a portion-sized version of the Diet History Questionnaire II (DHQ-II) from National Institutes of Health was used. The nutrient intake was assessed in accordance with the most complex recommendations on HD patients' nutrition - K/DOQI Clinical Practice Guidelines for nutrition in chronic renal failure. Poor long-term alignment of calcium-phosphate homeostasis was defined as the presence of over 50% monthly phosphorus concentrations exceeding 5 mg/dL, and for calcium 10.2 mg/dL, during the last 6-month period. RESULTS: Lower than recommended protein intake was found in 63% of HD patients (average consumption: 0.9 ±0.5 g/kg/day). Most of the patients consumed too much fat (33.5 ±6.7% of daily energy intake) and sodium (2912 ±1542 mg/day). In 42% of patients, dietary phosphorus intake was consistent with the recommendations (13.3 ±7.5 mg/kg/day). Protein intake over 1.2 g/kg/day resulted in an increased consumption of phosphorous, but did not increase the risk of misalignment of phosphorus concentrations (OR = 1.15 [0.40-3.27]); p = 0.8). Poor control of serum phosphorus concentrations was observed in 69% of patients (they were on average 8 years younger). The average intake of protein and phosphate in the groups with good or not satisfactory serum phosphorus alignment did not differ significantly. CONCLUSIONS: Adequate control of protein intake is not sufficient to obtain phosphorus alignment, especially in younger HD patients.

N-Terminal Prohormone of Brain Natriuretic Peptide but not C-Terminal Pre-Pro Vasopressin (Copeptin) Level is Associated with the Response to Antihypertensive Therapy in Haemodialysis Patients.

BACKGROUND/AIMS: Volume overload, frequently clinically asymptomatic is considered as a causative factor limiting the effectiveness of antihypertensive therapy in haemodialysis (HD) patients. Therefore, the aim of this study was to assess plasma levels of N-terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP) and a C-terminal portion of the precursor of vasopressin (CT-proAVP, copeptin), surrogate markers of volume overload in HD patients in relation to the number of antihypertensive drugs used in the hypertension treatment. METHODS: One hundred and fifty adult HD patients (92 males) were enrolled into this study. Clinical data concerning blood pressure (BP) measurements prior haemodialysis session and pharmacotherapy were collected from all patients. In addition to routine laboratory parameters, plasma levels of NT-proBNP and CT-proAVP were measured, and daily sodium and water consumption were estimated with a portion-size food frequency questionnaire. RESULTS: Among 145 (96.7%) hypertensive HD patients, 131 were receiving antihypertensive medication. Despite antihypertensive therapy, 31.0% had inadequate BP control. Plasma concentration of NT-proBNP was associated with systolic (R=0.19; p=0.02) but not diastolic BP values and with the number of received antihypertensive drugs (R=0.21; p=0.01). The highest NT-proBNP values were observed in patients receiving 3 or more antihypertensive drugs. In contrast, no significant correlation was found between plasma CT-proAVP concentrations and BP values as well as and the number of antihypertensive drugs. Receiver operator curve analysis showed that NT-proBNP values over 13,184 pg/mL predicted the use of at least 3 antihypertensive drugs in maximal doses in the therapy of hypertension, similar analyses performed for CT-proAVP showed much less specificity. CONCLUSIONS: 1. Increased levels of NT-proBNP seems to be a better biomarker of multidrug antihypertensive therapy requirement than CT-proAVP. 2. Whether estimation of NT-proBNP in these patients will be also better biomarker than copeptin in the prediction of cardiovascular complications related to hypertension needs further investigations.

Relationship between plasma levels of zonulin, bacterial lipopolysaccharides, D-lactate and markers of inflammation in haemodialysis patients.

BACKGROUND: Increased permeability of the intestinal wall and intestinal dysbiosis may contribute to chronic systemic inflammation, one of the causes of accelerated atherosclerosis and cardiovascular morbidity and mortality burden in patients with chronic kidney disease. The aim of this study was to evaluate the association between markers of intestinal permeability and inflammation in haemodialysis (HD) patients. METHODS: Plasma concentration of zonulin, haptoglobin, TNFα, IL6, D-lactates and bacterial lipopolysaccharides (LPS) was assessed in blood samples obtained after overnight fast before midweek morning HD session in 150 stable, prevalent HD patients. Daily intake of energy and macronutrients was assessed on the basis of a food frequency questionnaire. RESULTS: Serum hsCRP level was increased in over 70% of patients. Plasma levels of zonulin [11.6 (10.9-12.3) vs 6.8 (5.8-7.8) ng/mL], IL6 [6.2 (1.0-10.3) vs 1.3 (1.0-2.0) pg/mL] and TNFα [5.9 (2.9-11.8) vs 1.6 (1.3-1.8) pg/mL], but not LPS and D-lactates were significantly higher in HD than in healthy controls. D-lactates and LPS levels were weakly associated with IL6 (R = 0.175; p = 0.03, and R = 0.241; p = 0.003). There was a borderline correlation between plasma zonulin and serum hsCRP (R = 0.159; p = 0.07), but not with IL6, LPS and D-lactates. In multiple regression, both serum CRP and plasma IL6 variability were explained by LPS (ß = 0.143; p = 0.08 and ß = 0.171; p = 0.04, respectively), only. CONCLUSION: The weak association between plasma D-lactate, LPS and IL6 levels indicates that intestinal flora overgrowth or increased intestinal permeability contributes very slightly to the chronic inflammation development in HD patients.

Functional deficiency of vitamin K in hemodialysis patients in Upper Silesia in Poland.

PURPOSE: Functional vitamin K deficiency (both K1 and K2) is postulated to be one of the most relevant links between chronic kidney disease and vascular calcification in hemodialysis (HD) patients. Recommended dietary restrictions in HD patients superimposed on diversity of eating habits across the countries may affect the prevalence of functional vitamin K deficiency. The aim of this study was to determine the level of functional vitamin K deficiency and its relation to vitamin K1 intake in HD patients in Upper Silesia in Poland. METHODS: Protein-induced vitamin K absence or antagonist-II (PIVKA-II) and undercarboxylated matrix Gla protein (ucMGP) were assessed by ELISA in 153 stable, prevalent HD patients and 20 apparently healthy adults (to establish normal ranges for PIVKA-II and ucMGP). Daily phylloquinone intake was assessed using a food frequency questionnaire. RESULTS: PIVKA-II and ucMGP levels were increased in 27.5 and 77.1 % of HD patients in comparison with the reference ranges in apparently healthy controls, respectively. In 45 % of cases, the increased PIVKA-II level was explained by insufficient phylloquinone intake for Polish population (recommended intake: >55 µg for women and >65 µg for men). Applying ROC analysis, we showed that vitamin K1 intake below 40.2 µg/day was associated with increased PIVKA-II levels. There was no correlation between vitamin K1 intake and plasma concentration of ucMGP, or between PIVKA-II and ucMGP. CONCLUSIONS: (1) Functional vitamin K1 deficiency is explained by low vitamin K1 intake in less than half of HD patients. (2) Undercarboxylated matrix Gla protein level is a poor surrogate for functional vitamin K1 deficiency.

[Osteoprotegerin as a marker of atherosclerosis and a prognostic factor in stroke]. / Osteoprotegeryna jako wskaznik nasilenia miazdzycy i czynnik prognostyczny w udarze mózgu.

Stroke is one of the most common causes of disability and lack of independence in activities of daily living in adults. One of the most important factors predisposing to stroke, besides hypertension and atrial fibrillation, is carotid atherosclerosis. Rupture of unstable plaque with formation of a platelet plug is the cause of about 20-25% of ischemic strokes. Osteoprotegerin (OPG) is an important regulator of bone remodeling under physiological and disease conditions, as well as the regulator of osteoclast differentiation. Elevated plasma OPG level is associated with increased risk of ischemic stroke and heart diseases, including atrial fibrillation, and is observed in patients with symptomatic carotid artery stenosis and atherosclerotic vulnerable plaques. Furthermore, the occurrence of certain genotypes of OPG is 10 times more common in people with unstable atherosclerotic plaque, making them an independent risk predictor of plaque instability. This article summarizes the current state of knowledge on the potential role of OPG as a biomarker and prognostic indicator of stroke.