Faculty Bibliography

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.

OBJECTIVE:The aim of the study was to determine the main factors contributing to hospital readmissions and their potential preventability after a coronavirus disease 2019 (COVID-19) hospitalization at 2 New York City hospitals. METHODS:This was a retrospective study at 2 affiliated New York City hospitals located in the Upper East Side and Lower Manhattan neighborhoods. We performed case reviews using the Hospital Medicine Reengineering Network framework to determine potentially preventable readmissions among patients hospitalized for COVID-19 between March 3, 2020 (date of first case) and April 27, 2020, and readmitted to either of the 2 hospitals within 30 days of discharge. RESULTS:Among 53 readmissions after hospitalization for COVID-19, 44 (83%) were deemed not preventable and 9 (17%) were potentially preventable. Nonpreventable readmissions were mostly due to disease progression or complications of COVID-19 (37/44, 84%). Main factors contributing to potentially preventable readmissions were issues with initial disposition (5/9, 56%), premature discharge (3/9, 33%), and inappropriate readmission (1/9, 11%) for someone who likely did not require rehospitalization. CONCLUSIONS:Most readmissions after a COVID-19 hospitalization were not preventable and a consequence of the natural progression of the disease, specifically worsening dyspnea or hypoxemia. Some readmissions were potentially preventable, mostly because of issues with disposition that were directly related to challenges posed by the ongoing COVID-19 pandemic. Clinicians should be aware of challenges with disposition related to circumstances of the COVID-19 pandemic.

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.

[This corrects the article DOI: 10.1371/journal.pone.0192770.].

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

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