Abbreviations: T5/T8, Staphylococcus aureus type 5 and 8 capsular polysaccharides; CI, confidence interval; ClfA, S. aureus clumping factor A; ELISA, enzyme-linked immunosorbent assay; ESRD, end-stage renal disease; GMC, geometric mean concentration; OPK, opsonophagocytic killing; SAE, Serious adverse event; VE, vaccine efficacy.In a previous study in end-stage renal disease (ESRD) hemodialysis patients, a single dose of Staphylococcus aureus type 5 and 8 capsular polysaccharides (T5/T8) conjugated to nontoxic recombinant Pseudomonas aeruginosa exotoxin A investigational vaccine showed no efficacy against S. aureus bacteremia 1 year post-vaccination, but a trend for efficacy was observed over the first 40 weeks post-vaccination. Vaccine efficacy (VE) of 2 vaccine doses was therefore evaluated. In a double-blind trial 3359 ESRD patients were randomized (1:1) to receive vaccine or placebo at week 0 and 35. VE in preventing S. aureus bacteremia was assessed between 3-35 weeks and 3-60 weeks post-dose-1. Anti-T5 and anti-T8 antibodies were measured. Serious adverse events (SAEs) were recorded for 42 days post-vaccination and deaths until study end. No significant difference in the incidence of S. aureus bacteremia was observed between vaccine and placebo groups between weeks 3-35 weeks post-dose 1 (VE -23%, 95%CI: -98;23, p D 0.39) or at 3-60 weeks post-dose-1 (VE -8%, 95%CI: -57;26, p D 0.70). Day 42 geometric mean antibody concentrations were 272.4 mg/ml and 242.0 mg/ml (T5 and T8, respectively) in vaccinees. SAEs were reported by 24%/25.3% of vaccinees/placebo recipients. These data do not show a protective effect of either 1 or 2 vaccine doses against S. aureus bacteremia in ESRD patients. The vaccine induced a robust immune response and had an acceptable safety profile. Further investigation suggested possible suboptimal vaccine quality (manufacturing) and a need to expand the antigen composition of the vaccine. This study is registered at www.clinicaltrials.gov NCT00071214.

Fomites can harbour potentially pathogenic bacteria, and with the increasing trend for children with more complex medical problems to be managed in an ambulatory setting, often by physicians who also work in hospitals, there is a real risk of spreading potentially serious infections to such patients. Simple cleansing with alcohol effectively eliminates the bacterial contamination of the fomites, and should be encouraged.

Background and objectives The calcimimetic cinacalcet reduced the risk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older ($65 years, n=1005) and younger (,65 years, n=2878) patients.Design, setting, participants, & measurements Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified.Results Older patients had higher baseline prevalence of diabetes mellitus and CV comorbidity. Annualized rates of kidney transplantation and parathyroidectomy were .3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups. ConclusionsIn the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone.

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These findings suggest that alteration of the gut microbiome, by an antibiotic, might provide an important strategy in reducing the levels of IS and PCS in ESRD.

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BackgroundLanthanum carbonate (FOSRENOL®) is an effective, well-tolerated phosphate binder. The ability of lanthanum to reduce serum phosphorus levels to ≤5.5 mg/dL in patients with end-stage renal disease (ESRD) was assessed in a clinical practice setting.MethodsA 16-week, phase IV study enrolled 2763 patients at 223 US sites to evaluate the efficacy of lanthanum carbonate in controlling serum phosphorus in patients with ESRD, and patient and physician satisfaction with, and preference for, lanthanum carbonate after conversion from other phosphate-binder medications. Patients received lanthanum carbonate prescriptions from physicians. These prescriptions were filled at local pharmacies rather than obtaining medication at the clinical trial site. Changes from serum phosphorus baseline values were analyzed using paired t tests. Patient and physician preferences for lanthanum carbonate versus previous medications were assessed using binomial proportion tests. Satisfaction was analyzed using the McNemar test. Daily dose, tablet burden, and laboratory values including albumin-adjusted serum calcium, calcium × phosphorus product, and parathyroid hormone levels were secondary endpoints.ResultsSerum phosphorus control (≤5.5 mg/dL) was effectively maintained in patients converting to lanthanum carbonate monotherapy; 41.6% of patients had controlled serum phosphate levels at 16 weeks. Patients and physicians expressed markedly higher satisfaction with lanthanum carbonate, and preferred lanthanum carbonate over previous medication. There were significant reductions in daily dose and daily tablet burden after conversion to lanthanum carbonate.ConclusionsSerum phosphorus levels were effectively maintained in patients converted from other phosphate-binder medications to lanthanum carbonate, with increased satisfaction and reduced tablet burden.Trial RegistrationClinicalTrials.gov: NCT0016012

BackgroundThere is growing evidence that the accumulation of protein- bound uremic retention solutes, such as indoxyl sulfate, p-cresyl sulfate and kynurenic acid, play a role in the accelerated cardiovascular disease seen in patients undergoing chronic hemodialysis. Protein-binding, presumably to albumin, renders these solutes poor-dialyzable.We previously observed that the free fraction of indoxyl sulfate was markedly reduced at the end of hemodialysis. We hypothesized that solute binding might be pH-dependent and attributed the changes in free solute concentration to the higher serum pH observed at the end of standard hemodialysis with dialysis buffer bicarbonate concentration greater than 35 mmol/L. We observed that acidification of uremic plasma to pH 6 in vitro greatly increased the proportion of freeIS.MethodsWe tested our hypothesis by reducing the dialysate bicarbonate buffer concentration to 25 mmol/L for the initial half of the hemodialysis treatment (“isohydric dialysis”). Eight stable hemodialysis patients underwent “isohydric dialysis” for 90 minutes and then were switched to standard buffer (bicarbonate = 37mmol/L). A second dialysis, 2 days later, employed standard buffer throughout.ResultsWe found a clearcut separation of blood pH and bicarbonate concentrations after 90 minutes of “isohydric dialysis” (pH = 7.37, bicarbonate = 22.4 mmol/L) and standard dialysis (pH = 7.49, bicarbonate = 29.0 mmol/L). Binding affinity varied widely among the 10 uremic retention solutes analyzed. Kynurenic acid (0.05 free), p-cresyl sulfate (0.12 free) and indoxyl sulfate (0.13 free) demonstrated the greatest degree of binding. Three solutes (indoxyl glucuronide, p-cresyl glucuronide, and phenyl glucuronide) were virtually unbound. Analysis of free and bound concentrations of uremic retention solutes confirmed our prediction that binding of solute is affected by pH. However, in a mixed models analysis, we found that the reduction in total uremic solute concentration during dialysis accounted for a greater proportion of the variation in free concentration, presumably an effect of saturation binding to albumin, than did the relatively small change in pH produced by isohydric dialysis. The effect of pH on binding appeared to be restricted to those solutes most highly protein-bound.The solutes most tightly bound exhibited the lowest dialyzer clearances. An increase in dialyzer clearance during isohydric and standard dialyses was statistically significant only for kynurenic acid.ConclusionThese findings provide evidence that the binding of uremic retention solutes is influenced by pH. The effect of reducing buffer bicarbonate concentration (“isohydric dialysis:”), though significant, was small but may be taken to suggest that further modification of dialysis technique that would expose blood to a greater decrease in pH would lead to a greater increase the free fraction of solute and enhance the efficacy of hemodialysis in the removal of highly protein-bound uremic retention solutes.