Effect of Vancomycin on the Gut Microbiome and Plasma Concentrations of Gut-Derived Uremic Solutes
Introduction/UNASSIGNED:Declining renal function results in the accumulation of solutes normally excreted by healthy kidneys. Data suggest that some of the protein-bound solutes mediate accelerated cardiovascular disease. Many of the poorly dialyzable protein-bound uremic retention solutes are products of gut bacterial metabolism. Methods/UNASSIGNED:We performed a blinded-randomized controlled trial comparing the changes in plasma concentrations of a panel of protein-bound solutes and microbiome structure in response to the once-weekly oral administration of 250 mg of vancomycin or placebo over a period of 12 weeks in a cohort of stable patients with end-stage kidney disease. We also examined the pattern of recovery of the solutes and gut microbiome over 12 weeks of placebo administration following vancomycin. Results/UNASSIGNED:. We demonstrated microbiome recovery after stopping vancomycin. However, recovery in the solutes was highly variable between subjects. Conclusions/UNASSIGNED:We demonstrated that microbiome suppression using vancomycin resulted in changes in multiple gut-derived uremic solutes. Future studies are needed to address whether reduction in those uremic solutes results in improvement of cardiovascular outcomes in ESKD patients.
The effect of isohydric hemodialysis on the binding and removal of uremic retention solutes
BACKGROUND:There 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. METHODS:We 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. RESULTS:We 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. CONCLUSION/CONCLUSIONS:These 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.
Correction: The effect of isohydric hemodialysis on the binding and removal of uremic retention solutes [Correction]
[This corrects the article DOI: 10.1371/journal.pone.0192770.].
Effect of vancomycin on plasma concentration of uremic solutes [Meeting Abstract]
Background: Many uremic retention solutes are products of gut bacterial metabolism. Protein-binding renders these solutes poorly dialyzable. In a prior study we observed that a single dose of 250 mg of vancomycin, given by mouth, resulted in a significant (40%) decrease in the plasma concentration of indoxyl sulfate and p-cresyl sulfate over a period of one week. In this study we compared the changes in plasma concentration of a panel of protein-bound uremic retention solutes in response to the once-weekly oral administration of 250 mg of vancomycin or placebo over a period of 8 weeks.
Method(s): Eight subjects with chronic, stable ESRD on thrice-weekly hemodialysis via AV fistula in the River Renal Dialysis Unit in Bellevue Hospital, were randomized to two groups, utilizing a single-blinded procedure. Baseline plasma samples were collected prior to the initial dose of vancomycin or placebo and at weeks one, two, three, four, and eight. Uremic retention solutes were measured by MS-HPLC.
Result(s): Six of the eight uremic retention solutes (Table 1) demonstrated a significant decline in concentration over the eight week period of once-weekly vancomycin administration. The magnitude of the decline makes it more likely that gut production was reduced rather than renal excretion increased. Solute concentrations remained unchanged over the same period of placebo administration.
Conclusion(s): The significant decline in the plasma concentrations of multiple uremic retention solutes provides evidence of the importance of the gut microbiome in the generation of these solutes. The reduction in concentrations of indoxyl sulfate, p-cresyl sulfate, and kynurenic acid, recognized as likely uremic toxins, suggests that altering the gut microbiome might provide a valuable therapeutic strategy in the management of ESRD
Microbiome perturbation by oral vancomycin reduces plasma concentration of two gut-derived uremic solutes, indoxyl sulfate and p-cresyl sulfate, in end-stage renal disease
Background.: Observational studies have suggested a relationship between the plasma concentration of indoxyl sulfate (IS) and p -cresyl sulfate (PCS), small gut-derived 'uremic solutes', and the high incidence of uremic cardiomyopathy in patients with end-stage renal disease (ESRD). IS and PCS are derived from the metabolism of dietary components (tryptophan and tyrosine) by gut bacteria. This pilot study was designed to examine the effects of a poorly absorbable antibiotic (vancomycin) on the plasma concentration of two gut-derived 'uremic solutes', IS and PCS, and on the composition of the gut microbiome. Methods.: Plasma concentrations of IS and PCS were measured by MS-HPLC. The gut microbiome was assessed in stool specimens sequenced for the 16S rRNA gene targeting the V4 region. Results.: The pre-dialysis mean plasma concentrations of both IS and PCS were markedly elevated. Following the administration of vancomycin (Day 0), the IS and PCS concentrations decreased at Day 2 or Day 5 and returned to baseline by Day 28. Following vancomycin administration, several changes in the gut microbiome were observed. Most striking was the decrease in diversity, a finding that was evident on Day 7 and was still evident at Day 28. There was little change at the phylum level but at the genus level, broad population changes were noted. Changes in the abundance of several genera appeared to parallel the concentration of IS and PCS. Conclusions.: 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.
The effect of isohydric hemodialysis on uremic retention solutes [Meeting Abstract]
Background: There is growing evidence that the accumulation of protein-bound uremic retention solutes, such as indoxyl sulfate (IS), p-cresyl sulfate (PCS) and kynurenic acid (KA), 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 had previously observed that the concentration of free solute and its unbound fraction were markedly reduced at the end of hemodialysis. We hypothesized that solute binding might be pH-dependent and the changes attributable to the higher serum pH at the end of hemodialysis. In vitro, acidification of uremic plasma to pH 6 greatly increased the proportion of unbound indoxyl sulfate.
Method(s): We tested our hypothesis by reducing the dialysate bicarbonate buffer concentration to 25 mEq/L for the initial half of hemodialysis ('isohydric dialysis'). Eight stable hemodialysis patients underwent 'isohydric dialysis' and, midway, were switched to standard buffer (37 mEq/L). A second dialysis, 2 days later, employed standard buffer throughout.
Result(s): We found a clearcut separation of blood pH and bicarbonate concentrations 90 minutes following 'isohydric dialysis' (pH = 7.37, HCO3 =22.4 mEq/l) and standard dialysis (pH= 7.49, HCO3 = 29.5). Analysis of free and bound concentrations of uremic retention solutes confirmed our prediction that binding of solute is affected by pH. However, in 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.
Conclusion(s): These findings suggest that modification of dialysis technique that would expose blood to a transient decrease in pH might increase the free fraction of solute and enhance the efficacy of hemodialysis in the removal of protein-bound uremic retention solutes
Efficacy profile of a bivalent Staphylococcus aureus glycoconjugated vaccine in adults on hemodialysis: Phase III randomized study
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 = 0.39) or at 3-60 weeks post-dose-1 (VE -8%, 95%CI: -57;26, p = 0.70). Day 42 geometric mean antibody concentrations were 272.4 mug/ml and 242.0 mug/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.
Conversion to lanthanum carbonate monotherapy effectively controls serum phosphorus with a reduced tablet burden: a multicenter open-label study
ABSTRACT: BACKGROUND: Lanthanum carbonate (FOSRENOL(R)) 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. METHODS: A 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 x phosphorus product, and parathyroid hormone levels were secondary endpoints. RESULTS: Serum 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. CONCLUSIONS: Serum phosphorus levels were effectively maintained in patients converted from other phosphate-binder medications to lanthanum carbonate, with increased satisfaction and reduced tablet burden. TRIAL REGISTRATION: ClinicalTrials.gov: NCT0016012
Renal transplantation in familial dysautonomia: report of two cases and review of the literature
BACKGROUND AND OBJECTIVES: Chronic kidney disease (CKD) is an increasingly recognized complication of familial dysautonomia (FD), a neurodevelopmental disorder with protean systemic manifestations that are the result of sensory and autonomic dysfunction. Progressive renal dysfunction occurs due to chronic volume depletion and cardiovascular lability with supine hypertension and orthostatic hypotension. By age 25, nearly one-half of all patients with FD will have reached stage 3 CKD. Furthermore, dialysis for ESRD in FD patients is associated with multiple complications and poor outcomes. Design, settings, participants, & measurements: We report two patients with FD who developed ESRD at ages 27 and 16, respectively, and underwent renal transplantation. Transplant was performed after 3 months on intermittent hemodialysis (HD) in the first case and after 1 month on twice-weekly continuous veno-venous hemodialysis (CVVHD) in the second case. RESULTS: Both patients tolerated surgery well and have maintained good graft function at 20 and 24 months posttransplantation, respectively. Symptomatic and functional improvements have included lower supine BP and increased sensitivity to antihypertensive agents. CONCLUSIONS: As general supportive care improves the lifespan of FD patients, issues related to the management of ESRD will become more important. Renal transplantation provides a viable alternative to dialysis for FD patients with ESRD
CaSR polymorphism Arg990Gly and response to calcimimetic agents in end-stage kidney disease patients with secondary hyperparathyroidism and in cell culture
AIMS/OBJECTIVE:Calcimimetics are effective in reducing parathyroid hormone (PTH) levels in patients with secondary hyperparathyroidism, but variability in dose response has been noted. We examined SNP Arg990Gly of the calcium-sensing receptor as a possible cause. MATERIALS & METHODS/METHODS:We performed a dose-response study with cinacalcet on 23Â hemodialysis patients (with PTH >300Â pg/ml). Intact (i)PTH levels were measured at baseline and over time post-dose; 17Â patients had iPTH measured at 24Â h post-dose (60Â mg). Arg990Gly status was established by sequencing a section from exonÂ 7 of the CaSR gene. RESULTS:Only 33% of patients homozygous for the arginine allele showed an iPTH suppression of at least 5% of baseline at 24Â h, while 88% of patients with one or two glycine alleles achieved this target (pÂ <Â 0.05). CONCLUSION/CONCLUSIONS:We conclude that Arg990Gly influences the response to calcimimetics in patients with secondary hyperparathyroidism with an odds ratio of 2.6. This corresponds with inÂ vitro data testing the effect of calcimimetic agent R-568 in HEK-293 cells transfected with the two alleles of Arg990Gly: HEK-293 cells expressing glycine-type CaSR were more sensitive to R-568 than arginine-type CaSR (pÂ =Â 0.0001).