Serum phosphate optimal timing and range associated with patients survival in haemodialysis: the COSMOS study.

BACKGROUND: Serum phosphate is a key parameter in the management of chronic kidney disease-mineral and bone disorder (CKD-MBD). The timing of phosphate measurement is not standardized in the current guidelines. Since the optimal range of these biomarkers may vary depending on the duration of the interdialytic interval, in this analysis of the Current management of secondary hyperparathyroidism: a multicentre observational study (COSMOS), we assessed the influence of a 2- (midweek) or 3-day (post-weekend) dialysis interval for blood withdrawal on serum levels of CKD-MBD biomarkers and their association with mortality risk. METHODS: The COSMOS cohort (6797 patients, CKD Stage 5D) was divided into two groups depending upon midweek or post-weekend blood collection. Univariate and multivariate Cox's models adjusted hazard ratios (HRs) by demographics and comorbidities, treatments and biochemical parameters from a patient/centre database collected at baseline and every 6 months for 3 years. RESULTS: There were no differences in serum calcium or parathyroid hormone levels between midweek and post-weekend patients. However, in post-weekend patients, the mean serum phosphate levels were higher compared with midweek patients (5.5 ± 1.4 versus 5.2 ± 1.4 mg/dL, P < 0.001). Also, the range of serum phosphate with the lowest mortality risk [HR ≤ 1.1; midweek: 3.5-4.9 mg/dL (95% confidence interval, CI: 2.9-5.2 mg/dL); post-weekend: 3.8-5.7 mg/dL (95% CI: 3.0-6.4 mg/dL)] showed significant differences in the upper limit (P = 0.021). CONCLUSION: Midweek and post-weekend serum phosphate levels and their target ranges associated with the lowest mortality risk differ. Thus, clinical guidelines should consider the timing of blood withdrawal when recommending optimal target ranges for serum phosphate and therapeutic strategies for phosphate control.

Comparison of the Pharmacological Effects of Paricalcitol Versus Calcitriol on Secondary Hyperparathyroidism in the Dialysis Population.

Management of secondary hyperparathyroidism (SHPT) in dialysis population includes the use of active vitamin D forms, among which paricalcitol was shown to be more effective at reducing parathyroid hormone (PTH) concentrations. A prospective randomized study comparing the effectiveness and safety of peroral paricalcitol and calcitriol in suppressing PTH concentrations in 20 hemodialysis patients was performed comparing the influence of agents on PTH suppression, calcium (Ca) and phosphate (P) level and calcium-phosphorus product (C×P). The study was performed in an "intent to treat" manner with primary end point in reduction of PTH level in the target area of 150 > PTH < 300 ng/L after 3 months. At the time point 3 months after therapy induction paricalcitol and calcitriol were equally efficient at correcting PTH levels, with paricalcitol showing significantly less calcemic effect than calcitriol.

Influence of body mass index on the association of weight changes with mortality in hemodialysis patients.

BACKGROUND AND OBJECTIVES: A high body mass index (BMI) is associated with lower mortality in patients undergoing hemodialysis. Short-term weight gains and losses are also related to lower and higher mortality risk, respectively. The implications of weight gain or loss may, however, differ between obese individuals and their nonobese counterparts. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Current Management of Secondary Hyperparathyroidism: A Multicenter Observational Study (COSMOS) is an observational study including 6797 European hemodialysis patients recruited between February 2005 and July 2007, with prospective data collection every 6 months for 3 years. Time-dependent Cox proportional hazard regressions assessed the effect of BMI and weight changes on mortality. Analyses were performed after patient stratification according to their starting BMI. RESULTS: Among 6296 patients with complete data, 1643 died. At study entry, 42% of patients had a normal weight (BMI, 20-25 kg/m(2)), 11% were underweight, 31% were overweight, and 16% were obese (BMI ≥ 30 kg/m(2)). Weight loss or gain (<1% or >1% of body weight) was strongly associated with higher rates of mortality or survival, respectively. After stratification by BMI categories, this was true in nonobese categories and especially in underweight patients. In obese patients, however, the association between weight loss and mortality was attenuated (hazard ratio, 1.28 [95% confidence interval (CI), 0.74 to 2.14]), and no survival benefit of gaining weight was seen (hazard ratio, 0.98 [95% CI, 0.59 to 1.62]). CONCLUSIONS: Assuming that these weight changes were unintentional, our study brings attention to rapid weight variations as a clinical sign of health monitoring in hemodialysis patients. In addition, a patient's BMI modifies the strength of the association between weight changes with mortality.

Fibroblast growth factor 23 and left ventricular mass index in maintenance hemodialysis patients: standard versus long nocturnal hemodialysis.

Elevated levels of fibroblast growth factor 23 (FGF23) and phosphorus (P) have been linked to greater risks of left ventricular hypertrophy (LVH) in patients with end stage renal disease (ESRD). The aim of this study was to test if differences exist in a long nocturnal HD group in comparison with a group treated with standard daily thrice weekly dialysis. The attempt was to evaluate if elevated FGF-23 levels, intact parathyroid hormone and P might be associated with left ventricular mass index (LVMI). Quantitative echocardiographic analyses were performed at baseline in 50 maintenance HD patients (17 women and 33 men, mean age: 56.4 ± 15.35 years, mean HD vintage: 9.06 ± 8.86 years, all patients are on HD thrice a week-median duration 15 h/week, 10 of them on long nocturnal HD, median duration 24 h/week). LVMIs were calculated. FGF23 was measured in duplicate using a second generation C-terminal enzyme-linked immunosorbent assay and log of FGF-23 values were computed. Mean LVMI was 136.44 ± 44.44 g/m(2) . Serum FGF-23 levels were elevated when compared to population data with preserved kidney function (median 1388.5 RU/mL, range 252 to 24 336 RU/mL). There were no correlations recorded between log FGF-23 levels and LVMI (r = 0.2, P = 0.66). LVMI was significantly lower in HD patients on long nocturnal dialysis procedure (r = -0.31, P = 0.05). Patients treated with long nocturnal HD showed lower LV mass, lower P-values and higher 25-OH-D3 supply. Plasma FGF-23 concentration was comparable between the groups and was not associated with LVMI in our maintenance HD patients.

Effect of switching to nocturnal thrice-weekly hemodialysis on clinical and laboratory parameters: our experience.

Long or frequent hemodialysis schedules are reported to improve clinical outcomes. We report here our experience with an in-center, nocturnal, thrice-weekly hemodialysis program. We retrospectively analyzed the effect of switching 10 patients (8 male, age 45 ± 11 years, renal replacement therapy vintage 12 ± 8 years) from regular, 4-5 h, thrice-weekly hemodialysis to 8 h nocturnal, in-center hemodialysis as regards dialysis efficiency, chronic kidney disease-metabolic and bone disease (CKD-MBD) parameters, blood pressure, and anemia. With more intense dialysis, the mean predialysis creatinine and urea decreased significantly (1092 ± 195 vs. 961 ± 154 µmol/L, P < 0.01 and 30.8 ± 4.6 vs. 25.5 ± 2.9 mmol/L, P < 0.01), while the decrease in potassium was insignificant (5.9 ± 0.7 vs. 5.6 ± 0.5 mmol/L), but in 3/10 patients, dialysate potassium was increased. Three months after starting nocturnal hemodialysis, no significant influence on pre-dialysis blood pressure was observed (143/80 vs. 140/80 mmHg), but antihypertensive medications were reduced in two patients. The mean dry weight reduced (74 ± 12 to 72 ± 12 kg) and the mean ultrafiltration increased insignificantly (3123 ± 1174 to 3434 ± 1341 mL). Serum calcium was stable, while phosphate reduced insignificantly (1.5 ± 0.5 to 1.2 ± 0.2 mmol/L), but 6/10 patients were able to discontinue phosphate binders, the dose was reduced in one, and phosphate was added to dialysate in 3/10 patients. Intact parathyroid hormone values were within the target range, except in patients post-parathyroidectomy. There were no differences in hemoglobin (121 ± 6 vs. 122 ± 8 g/L), and the mean epoetin dose decreased insignificantly (5950 ± 3947 vs. 5250 ± 4238 IU/week). To conclude, improved phosphate and potassium control and reduction in phosphate binders were observed after switching to nocturnal hemodialysis. There was an insignificant reduction of epoetin dose and antihypertensive medications.

Use of phosphate-binding agents is associated with a lower risk of mortality.

Hyperphosphatemia has been associated with higher mortality risk in CKD 5 patients receiving dialysis. Here, we determined the association between the use of single and combined phosphate-binding agents and survival in 6797 patients of the COSMOS study: a 3-year follow-up, multicenter, open-cohort, observational prospective study carried out in 227 dialysis centers from 20 European countries. Patient phosphate-binding agent prescriptions (time-varying) and the case-mix-adjusted facility percentage of phosphate-binding agent prescriptions (instrumental variable) were used as predictors of the relative all-cause and cardiovascular mortality using Cox proportional hazard regression models. Three different multivariate models that included up to 24 variables were used for adjustments. After multivariate analysis, patients prescribed phosphate-binding agents showed a 29 and 22% lower all-cause and cardiovascular mortality risk, respectively. The survival advantage of phosphate-binding agent prescription remained statistically significant after propensity score matching analysis. A decrease of 8% in the relative risk of mortality was found for every 10% increase in the case-mix-adjusted facility prescription of phosphate-binding agents. All single and combined therapies with phosphate-binding agents, except aluminum salts, showed a beneficial association with survival. The findings made in the present association study need to be confirmed by randomized controlled trials to prove the observed beneficial effect of phosphate-binding agents on mortality.

COSMOS: the dialysis scenario of CKD-MBD in Europe.

BACKGROUND: Chronic kidney disease-mineral and bone disorders (CKD-MBD) are important complications of CKD5D patients that are associated with mortality. METHODS: COSMOS is a multicentre, open cohort, prospective, observational 3-year study carried out in haemodialysis patients from 20 European countries during 2005-07. The present article describes the main characteristics of the European dialysis population, the current practice for the prevention, diagnosis and treatment of secondary hyperparathyroidism and the differences across different European regions. RESULTS: The haemodialysis population in Europe is an aged population (mean age 64.8±14.2 years) with a high prevalence of diabetes (29.5%) and cardiovascular disease (76.0%), and 28.7% of patients have been on haemodialysis more than 5 years. Patients from the former Eastern countries are younger (59.3±14.3 versus 66.0±13.9), having a lower proportion of diabetics (24.1 versus 30.7%). There were relevant differences in the frequency of measurement of the main CKD-MBD biochemical parameters [Ca, P and parathyroid hormone (PTH)] and the Eastern countries showed a poorer control of these biochemical parameters (K/DOQI and K/DIGO targets). Overall, 48.0% of the haemodialysis patients received active vitamin D treatment. Calcitriol use doubled that of alfacalcidiol in the Mediterranean countries, whereas the opposite was found in the non-Mediterranean countries. The criteria followed to perform parathyroidectomy were different across Europe. In the Mediterranean countries, the level of serum PTH considered to perform parathyroidectomy was higher than in non-Mediterranean countries; as a result, in the latter, more parathyroidectomies were performed in the year previous to inclusion to COSMOS. CONCLUSIONS: The COSMOS baseline results show important differences across Europe in the management of CKD-MBD.

Long-term citrate anticoagulation in chronic hemodialysis patients.

In some cases, long-term (>3 months) citrate anticoagulation is needed in maintenance hemodialysis patients due to a persistent bleeding risk. In this retrospective observational study, we present our experience and assess its safety and effects on mineral and bone disorder parameters. Sixteen patients (mean age 67 ± 15 years) were treated with long-term citrate anticoagulation. The indications were: recurrent gastrointestinal bleeding in nine patients, heparin-induced thrombocytopenia, retroperitoneal hematoma, chronic subdural hematoma, proliferative diabetic retinopathy, vascular malformations in the brain in one patient, and others in two patients. Metabolic complications and intact parathyroid hormone (iPTH) were analyzed. Citrate anticoagulation was performed for 4 months to 6.3 years (median 12 months). Ionized calcium was stable during the procedures; hypocalcemia (<0.9 mmol/L) was rare (2.1% of procedures), and there was one case of severe symptomatic hypocalcemia. There were no clinically significant acid-base disturbances and no clotting problems. In the short term (1-3 months after starting citrate), the iPTH increased in 73% of patients (from 325 ± 310 to 591 ± 793 pg/L, P = 0.11, N = 11). In the long term (1-2 years), an increase in iPTH was observed in 3/6 patients. The time period (before/after starting citrate) was a significant predictor of iPTH using main-effects anova (P < 0.001). To conclude, long-term citrate anticoagulation in chronic hemodialysis patients is safe. Mild hypocalcemia during dialysis with citrate anticoagulation may contribute to a short- and long-term increase in iPTH in these patients. Further studies on long-term citrate anticoagulation are necessary.

Membrane plasma exchange for the treatment of thrombotic thrombocytopenic purpura.

The aim of our report is to present our 11-year experience with therapeutic membrane plasma exchange therapy for the treatment of idiopathic thrombotic thrombocytopenic purpura syndrome (TTP). In 56 patients, membrane plasma exchange therapy was initiated immediately and performed once or twice daily until the platelet count normalized. During each plasma exchange procedure, 1-1.5 plasma volumes (3606 +/- 991 mL) were replaced with fresh frozen plasma. In 37 females and 19 males (44 +/- 21 years), 1066 plasma exchange procedures were performed. The average duration of treatment was 23 +/- 17 days. The average number of plasma exchanges was 19 +/- 17 per patient. Renal impairment was detected in 36% of patients. At the initiation of plasma exchange treatment, the average platelet count was 31 +/- 30 x 10(9)/L and reached 199 +/- 95 x 10(9)/L thereafter. Fifty-two of 56 (93%) patients demonstrated an excellent response to plasma exchange therapy, of whom 48 patients (86%) attained complete remission with a platelet count of more than 100 x 10(9)/L. Four patients died soon after the initiation of plasma exchange therapy, when only 1-3 procedures had been performed. During the follow-up period, six patients with complete remission had 1-5 subsequent relapses each year. One of them died of acute hemolytic reaction during the tapering of plasma exchange procedures. Three patients underwent additional splenectomy. Our experience with primary TTP supports the plasma exchange treatment with fresh frozen plasma as a mandatory, up-to-date therapy. Close monitoring during all 1066 procedures showed no serious side-effects.

Total metal concentrations in serum of dialysis patients and fractionation of Cu, Rb, Al, Fe and Zn in spent continuous ambulatory peritoneal dialysis fluids.

Total metal concentrations were determined in the serum of 12 continuous ambulatory peritoneal dialysis (CAPD) patients and in fresh and spent CAPD fluids by electrothermal and flame atomic absorption spectrometry (ETAAS, FAAS). Concentrations of Cu in serum of CAPD patients ranged from 720 to 1780 ngcm(-3), Rb from 128 to 346 ngcm(-3), Al from 10 to 72 ngcm(-3), Fe from 800 to 2300 ngcm(-3) and Zn from 659 to 1310 ngcm(-3). The accuracy of the analytical procedure was checked by the analysis of the reference material Seronomtrade mark, Trace Elements in Serum. Good agreement between the certified and determined values was obtained for Al, Cu, Fe and Zn. The data on the total metal concentrations in CAPD fluids indicated that during CAPD fluid exchange the losses of Cu from 5.0 to 35 ngcm(-3), of Rb from 50 to 110 ngcm(-3) and of Al from 3.0 to 14.0 ngcm(-3) occurred through the peritoneal membrane. Although fresh CAPD fluids contained traces of Fe (3.0-5.0 ngcm(-3)), the transfer of this element took place through the peritoneal membrane into spent CAPD fluid (13.0-38.0 ngcm(-3)). Zn concentrations were in general lower in spent (20.0-80 ngcm(-3)) than in fresh CAPD fluids ( approximately 100 ngcm(-3)). To follow the mechanisms of the transfer of trace elements through the peritoneal membrane of CAPD patients, fractionation of metals was carried out in spent CAPD fluids by size exclusion chromatography with UV and AAS detection, applying Superdex HR 10/30 column. The chromatographic run was followed at 278 nm and separated metal species also determined 'off line' in 1 cm(3) fractions by ETAAS or FAAS. From the UV chromatograms and AAS analysis of trace elements in the separated fractions it was demonstrated that Cu, Al, Fe and Zn were bound to proteins and only partially to low molecular weight (LMW) species, while Rb was associated exclusively with LMW species. For characterisation of the high molecular weight (HMW) binding proteins, fractions containing trace elements were subjected to SDS-PAGE electrophoresis. Al and Fe were presumably bound to transferrin, but due to its low concentration in spent CAPD fluids, it was not possible to confirm its presence in the separated fractions. About 10% of Al and 15% of Fe corresponded to LMW species. A fraction of HMW proteins of Cu in spent CAPD fluids was most probably bound to albumin and Zn to albumin and globulins. About 50% of Cu and Zn existed in LMW proteins, while Zn was also found partially in ionic form.