A pharmacoeconomic analysis of phosphate binders cost-effectiveness in the RISCAVID study.

BACKGROUND: A pharmacoeconomic analysis of the RISCAVID database aimed at assessing the cost effectiveness of phosphate binders in preventing CV mortality and morbidity over 7 years was performed. METHODS: Morbid or fatal events occurring in 750 chronic HD patients were recorded. Statistical analysis evaluated the distribution of variables and the effect of sevelamer on survival. A cost-effectiveness evaluation was performed using a probabilistic model based on a Markov chain. RESULTS: Multivariate analysis showed that treatment with sevelamer was associated with a reduced stroke incidence by 52% (p = 0.04) and reduced levels of C-reactive protein (p < 0.01). Cost-effectiveness evaluation evidenced a 33% decrease in hospital-days for patients treated with sevelamer, with and without comorbidities compared to patients undergoing calcium binders treatment. CONCLUSION: Treatment with sevelamer was associated with a reduced risk of stroke in HD patients, with a clear saving on disease-related costs for the Italian National Healthcare System.

A vitamin E-coated polysulfone membrane reduces serum levels of inflammatory markers and resistance to erythropoietin-stimulating agents in hemodialysis patients: results of a randomized cross-over multicenter trial.

BACKGROUND: Oxidative stress is prevalent in dialysis patients and has been implicated in the pathogenesis of cardiovascular disease and anemia. Vitamin E is a fat-soluble antioxidant that plays a central role in reducing lipid peroxidation and inhibiting the generation of reactive oxygen species. The aim of this cross-over randomized study was to compare the effects of a vitamin E-coated polysulfone (Vit E PS) membrane and a non-vitamin E-coated polysulfone (PS) membrane on inflammatory markers and resistance to erythropoietin-stimulating agents (ESAs). METHODS: After a 1-month run-in period of standard bicarbonate dialysis with a synthetic membrane, 62 patients of both genders, and older than 18 years, dialysis vintage 48 ± 27 months, BMI 22 ± 3 (from 13 different dialysis units) were randomized (A-B or B-A) in a cross-over design to Vit E PS (treatment A) and to PS (treatment B) both for 6 months. C-reactive protein (CRP) and interleukin-6 (IL-6) concentrations were determined by a sandwich enzyme immunoassay at baseline and every 2 months; red blood cell count, ESA dose and ESA resistance index (ERI) were assessed monthly. RESULTS: Hemoglobin (Hb) levels significantly increased in the Vit E PS group from 11.1 ± 0.6 g/dl at baseline to 11.5 ± 0.7 at 6 months (p < 0.001) and remained unchanged in the PS group. Although ESA dosage remained stable during the observation periods in both groups, ERI was significantly reduced in the Vit E PS group from 10.3 ± 2.2 IU-dl/kg/g Hb week at baseline to 9.2 ± 1.7 at 6 months (p < 0.001). No significant variation of ERI was observed in the PS group. A significant reduction in plasma CRP and IL-6 levels was observed in the Vit E PS group: CRP from 6.7 ± 4.8 to 4.8 ± 2.2 mg/l (p < 0.001) and IL-6 from 12.1 ± 1.4 to 7.5 ± 0.4 pg/ml (p < 0.05). In the PS group, CRP varied from 6.2 ± 4.0 to 6.4 ± 3.7, and IL-6 from 10.6 ± 2.1 to 9.6 ± 3.5 (p = n.s.). CONCLUSIONS: Treatment with Vit E PS membranes seems to lead to a reduction in ESA dosage in HD patients; in addition, a low chronic inflammatory response may contribute to a sparing effect on exogenous ESA requirements.

Effect of simvastatin on plasma asymmetric dimethylarginine concentration in patients with chronic kidney disease.

BACKGROUND: The endogenous inhibitor of nitric oxide (NO) synthase, asymmetric dimethylarginine (ADMA), is a strong cardiovascular (CV) risk marker in patients with chronic renal insufficiency. Statins have pleiotropic effects and are currently considered as potential ADMA-lowering agents. METHODS: We investigated the effect of simvastatin on plasma ADMA levels in 35 patients with chronic kidney disease (CKD) by performing a secondary analysis of a randomized double-blind placebo-controlled trial where patients were randomized to receive simvastatin or placebo for 6 months. RESULTS: Plasma ADMA was higher in CKD patients (0.84 +/- 0.14 micromol/L) than in healthy subjects (0.69 +/- 0.10 micromol/L) (p<0.001). In CKD patients, ADMA at baseline was related directly with triglycerides (r=0.42, p=0.01) and inversely with HDL cholesterol (r=-0.37, p=0.03) and creatinine clearance (p=0.03). As expected, simvastatin caused significant reductions in total cholesterol, LDL cholesterol and triglycerides, as well as in C-reactive protein (CRP; -28%, p=0.001) and IL-6 (-20%, p=0.05) but failed to decrease plasma ADMA both in crude and adjusted analyses. CONCLUSIONS: Simvastatin does not modify plasma ADMA. Because raised ADMA is known to prevent the favorable effect of statins on myocardial blood flow, cointerventions aimed at lowering or antagonizing ADMA may either prompt or potentiate the cardiovascular protective effect of simvastatin.

Simvastatin and fluvastatin reduce interleukin-6 and interleukin-8 lipopolysaccharide (LPS) stimulated production by isolated human monocytes from chronic kidney disease patients.

BACKGROUND: Statins reduce lipid levels, inflammation and cardiovascular events in patients with coronary artery disease; CKD patients show increased risk of cardiovascular and increased plasma levels of IL-6 and IL-8. AIM: To evaluate the in vitro effect of simvastatin (S) or fluvastatin (F) on the lipopolysaccharide (LPS) stimulated secretion of IL-6 and IL-8 from monocytes of chronic kidney disease patients (CKD) in K-DOQI stages 3-5. METHODS AND SUBJECTS: Monocytes enriched peripheral blood (PBMC) from 28 CKD (15 in K-DOQI stages 3-4, Group I, and 13 in K-DOQI stage 5 on hemodialysis, Group II) and 10 healthy subjects (HS), were isolated by Ficoll-gradient centrifugation. Cells were incubated with LPS 100 ng/ml or with LPS plus increasing doses of statins (from 10(-6) to 10(-8) M ) for 24 h. Surnatant IL-6 and IL-8 concentrations were determined by EIA. RESULTS: Basally the mean concentration of IL-6 and IL-8 was higher in patients than in HS and in Group II than in Group I (IL6: HS 285 +/- 77 pg/ml, Group I 365 +/- 178 pg/ml, Group II 520 +/- 139 pg/ml- IL8 HS 180 +/- 75 pg/ml, Group I 1722 +/- 582 pg/ml, Group II 4400 +/- 1935 pg/ml). After addition of LPS the mean concentration of IL-6 and IL-8 increased in all groups (IL6: HS 1740 +/- 178 pg/ml, Group I 3754 +/- 672 pg/ml, Group II 4800 +/- 967 pg/ml; IL8: HS 450+/-132 pg/ml, Group I 9700+/-2837 pg/ml, Group II 11608 +/- 2316 pg/ml). After the addition of LPS plus increasing doses of S or F from 10(-10) to 10(-6) M, a significantly lower cytokine concentration compared to the data after LPS alone was observed (IL6: HS 45%, Group I 75%, Group II 50%; IL8: HS 100%, Group I 65%, Group II 35%). CONCLUSIONS: These data confirm that cytokine release is increased in CKD patients and that is highest in the most severe patients. Furthermore they suggest that fluvastatin or simvastatin can be used in order to reduce the high cardiovascular risk.

In vivo and in vitro effects of simvastatin on inflammatory markers in pre-dialysis patients.

BACKGROUND: The beneficial effects of statins in reducing cardiovascular events have been attributed predominantly to their lipid-lowering effects, recent studies suggest that these effects might be due to their anti-inflammatory properties. We here investigate the in vivo and in vitro effects of simvastatin on cytokine production in pre-dialysis chronic renal failure patients. METHODS: Our clinical study has been designed as a randomized double-blind placebo controlled study. A total of 55 chronic kidney disease (CKD) patients at stages 3 and 4 (mean creatinine clearance 45 ml/min, range 15-60) were randomly assigned to receive simvastatin 40 mg/day or placebo, added to their ongoing treatment, for 6 months. Blood samples were obtained at baseline, and after 3 and 6 months of observation for the determination of lipids, inflammatory markers and renal function. For the in vitro studies, the effect of increasing doses of simvastatin on cytokine production [namely interleukin (IL)-6 and IL-8] in human cultured monocytes from 10 healthy subjects (HS) and 15 CKD patients stimulated by lipopolysaccharide (LPS) was investigated. RESULTS: A significant reduction in total cholesterol from 221+/-44 mg/dl to 184+/-41 mg/dl (3 months) and to 186+/-39 mg/dl (6 months) (P<0.02) and low-density lipoprotein cholesterol from 139+/-40 mg/dl to 104+/-29 mg/dl (3 months) and to 100+/-31 mg/dl (6 months) (P<0.001) was observed in the 28 patients treated with simvastatin. In this group, C-reactive protein (CRP) levels significantly decreased from 2.6 mg/l [interquartile range (IQR 4.9)] to 2.0 mg/l (IQR 1.9) (P = 0.03) at 6 months (P<0.05). A parallel reduction of IL-6 levels from 5.1 pg/ml (IQR 3.8) to 3.5 pg/ml (IQR 3.1) (P = 0.001) at 6 months was also observed. No significant reduction in inflammatory markers [CRP from 5.1 mg/l (IQR 1.9) to 5.4 mg/l (IQR 1.3) (P = NS) at 6 months] or plasma lipids [LDL-cholesterol from 127+/-32 mg/dl to 131+/-21 mg/dl (6 months)] was observed in the 27 patients of the placebo group. In the in vitro studies, the average value for cell-associated IL-6 and IL-8 was higher in CKD (155+/-95 pg/ml monocytes for IL-6 and 722+/-921 pg/ml monocytes for IL-8) vs HS (137+/-87 pg/ml monocytes and 186+/-125 pg/ml monocytes) (P<0.01) and was not affected by simvastatin alone. LPS resulted in a significant increase in cytokine production (IL-6: 1954+/-321 pg/ml monocytes for CKD and 1451+/-237 pg/ml monocytes for HS; P<0.001); the simultaneous addition of increasing doses of simvastatin to these cultures induced a dose-dependent inhibition of IL-6 and IL-8 production in stimulated peripheral blood mononuclear cells in all groups. CONCLUSIONS: These results indicate that simvastatin in commonly used doses has an in vitro and in vivo anti-inflammatory effect in CKD patients, and may play an important role in counteracting the mechanisms involved on the pathogenesis of cardiovascular disease.

Effects on inflammatory and nutritional markers of haemodiafiltration with online regeneration of ultrafiltrate (HFR) vs online haemodiafiltration: a cross-over randomized multicentre trial.

BACKGROUND: HFR [double chamber haemodiafiltration (HDF) with reinfusion of regenerated ultrafiltrate] is a novel dialytic method which combines the processes of diffusion, convection and adsorbance. In this technique an adsorbent cartridge of resin and charcoal may regenerate the ultrafiltrate suggesting its use as an endogenous substitution fluid. The aim of this multicentre randomized cross-over study was to compare HFR to online HDF in terms of inflammatory and nutritional parameters. METHODS: After a 1 month run-in period of standard bicarbonate dialysis (HD) with a synthetic membrane, 25 chronic dialytic patients were randomized (A-B or B-A) to be treated by HFR (A) with a two-chamber filter (SG 8 Plus - high permeability Polysulphone HF 0.7 m2 + SMC 1.95 sqm; Bellco, Mirandola, Italy) or by online sterile bicarbonate HDF. Each study period of 4 months was separated by 1 month of HD and the entire length of the study was 10 months. CRP levels were measured by a highly sensitive nephelometric assay (Dade, Behring) with a sensitivity of 0.1 microg/ml. Cytokine concentrations were determined by EIA [Interleukin (IL) 6, Biosource, USA and IL-10 Bender MED-Systems, Vienna]. The sensitivity thresholds were < 5 pg/ml for IL-6 and < 8 pg/ml for IL-10. Serum leptin was determined with a ELISA method (Biosource, USA). All parameters were determined monthly in patients starting a midweek dialytic session. RESULTS: Plasma CRP and IL-6 were significantly reduced during the 4 months of HFR and HDF: CRP from 8.0 +/- 3.2 to 5.6 +/- 3.4 mg/l with HFR (P < 0.05) and from 9.4 +/- 4.3 to 5.9 +/- 3.9 mg/l with HDF (P < 0.05). IL-6 decreased from 14.8 +/- 6.3 to 10.1 +/- 3.2 with HFR (P < 0.02) and from 12.1 +/- 4.2 to 9.6 +/- 3.7 with HDF (P = ns) with a percentage decrease after 4 months of 32% with HFR vs 21% with HDF. During the 1 month wash-out period with HD, CRP increased from 5.7 +/- 3.6 to 8.7 +/- 3.9 mg/l (P < 0.01) and IL-6 from 10 +/- 3.4 to 13.5 +/- 5.2 pg/ml (P < 0.01). A significant increase in IL-10 was detected either in HFR (from 4.8 +/- 2.1 to 6.89 +/- 1.7 pg/ml) and in HDF (from 3.3 +/- 1.7 to 8.95 +/- 4.3 pg/ml; P < 0.05) after 4 months. No significant variation in serum leptin levels were observed during the study. CRP and IL-6 were highly correlated (r = 0.54; P < 0.001) as was serum albumin and prealbumin (r = 0.39; P < 0.001). Serum albumin was negatively correlated with CRP (r = -0.26; P < 0.01) and IL-6 (r = -0.19; P < 0.05); serum prealbumin was correlated with IL-6 (r = 0.37; P < 0.001) and with CRP (r = 0.24; P < 0.01). CONCLUSIONS: Haemodiafiltration with online regeneration of ultrafiltrate and online HDF are highly biocompatible techniques and no significant difference between HFR and online HDF was observed in terms of reduction of inflammatory markers. Further studies with a longer follow-up are needed to evaluate the clinical relevance of the online endogenous reinfusion to counteract the chronic inflammatory state of the uraemic patient.