Clinical trial NCT03452189
Conditions: End Stage Renal Disease
Sponsor: NYU Langone Health
Start date: 2017-11-27; Completion date: 2018-08-18
Enrollment: 15 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to determine if multiple doses of vancomycin over the course of 3 months will perturb the intestinal flora (microbiome) and result in reduced serum concentration of the uremic toxin indoxyl sulfate and p-cresyl sulfate. The design of the study will permit investigators to assess the variability of serum uremic retention solute concentrations with and without antibiotic over a three-month period.

Detailed description:

Arms: arm 1: After 3 months, initial experimental group will be switched to placebo for 3 months. arm 2: After three months, the control group will be crossed over to weekly oral vancomycin (250mg)
Interventions: intervention 1: Vancomycin intervention 2: Placebo
Intervention descriptions: intervention 1: Oral vancomycin 250mg capsules intervention 2: Placebo Pills distributed by Research Pharmacy labeled "placebo."

Protocol documents:
Prot_SAP_000.pdf: 
The effect of an antibiotic on the production of uremic toxins.   
Principal Investigator: Jerome Lowenstein, MD 
Study Number: S17-00963 
NCT Number: NCT03452189 
Version Date: 11/17/2017 
 
Purpose of the Study and Background 
Purpose of the Study  
In a prior study we observed that the perturbation of the microbiome by one dose of oral 
vancomycin significantly lowered plasma concentrations of two gut-derived uremic retention 
solutes, indoxyl sulfate and p-cresyl sulfate [1].  The aim of this study is four-fold.  First, to 
determine if serial doses of oral vancomycin produce a sustained decrease in the plasma 
concentrations of indoxyl sulfate, p-cresyl sulfate, and other putative uremic retention solutes..  
Second, we aim to provide data regarding the stability of levels of uremic solutes and of the 
composition of the gut microbiome over prolonged periods (three months).  We expect that 
vancomycin will produce a sustained perturbation of the microbiome, with decreased number of 
OTUs and, likely, sustained reduction in indoxyl sulfate and p- cresyl sulfate. Third, we hope to 
determine the duration of any effect of vancomycin on the plasma concentration of uremic 
solutes and the gut microbiome. Variability of the microbiome and uremic solutes over time has 
not been previously examined. Finally, the data derived from this study will provide data 
concerning the possible long-term effects of oral vancomycin administration. 
 
Background 
Observational studies have suggested a relationship between the plasma concentrations of two 
gut-derived uremic solutes, indoxyl sulfate (IS) and p-cresyl sulfate (PCS), and cardiovascular 
disease in patients with chronic kidney disease [2-4].  Both IS and PCS are formed from the 
metabolism of amino acids (tryptophan and tyrosine) by gut flora [5].  Our prior study 
(Nephrology Dialysis and Transplantation, 32, 11 2017, 1809-1817) showed that altering the 
microbiome with a single oral dose of of vancomycin significantly lowered plasma 
concentrations of IS and PCS.  In this study, 10 patients with chronic, stable end-stage renal 
disease were given a single 250 mg dose of oral vancomycin on day 0.  Plasma concentrations of 
IS and PCS were found to decrease significantly across all 10 subjects, using a mixed models 
analysis of the plasma levels of solute on days 0, 2, and 5 (X2=11.57, df=2, p=0.003).  By day 
28, plasma solute concentrations were back to baseline [1]. The gut microbiome had not fully 
recovered at Day 28. 
 
Vancomycin is an antibiotic that interferes with bacterial cell wall synthesis.  It has poor oral 
absorption, and thus oral vancomycin is only FDA approved to treat gastrointestinal infections 
including C. difficile-associated diarrhea and enterocolitis caused by S. aureus.  In this study it 
will be used to perturb the gut microbiome to lower the production of uremic solutes by intestinal 
bacteria.  Dosage selection is based on the prior study which demonstrated a significant decrease 
in IS and PCS with a single dose of 250mg over the course of one week, with uremic solute 
concentrations returning to baseline within 28 days. This dose is well below the dose usually 
prescribed for the treatment of C. difficile infection.  
 


In the prior study the plasma concentrations of IS and PCS returned to baseline after one month.  
With this study we hope to learn whether serial doses of oral vancomycin produce a sustained 
decrease in the concentrations of these two solutes.  Our pilot study showed a 40% decrease in 
plasma concentrations of IS and PCS.  In this study we hope to learn whether the suppression of 
toxin production in sustained, increases, or decreases over time.  It is unclear whether this 
decrease in IS and PCS would produce clinically significant slowing of cardiovascular disease in 
patients with ESRD.  Weekly dosing was chosen because the plasma uremic solute 
concentrations remained significantly decreased at 7 days after 250mg of vancomycin, but had 
returned to baseline by 28 days.  Three months was chosen without data-driven rationale, as 
there are no prior studies of this sort.    
 
Vancomycin was selected for our earlier study (on the advice of Dr. Martin Blaser) because it 
was possible to give the medication by mouth, limiting its effect to the GI tract. We found, as 
predicted that vancomycin had profound effects on the gut microbiome. We have chosen to 
administer vancomycin for the present study because it has proven to affect the gut microbiome 
and to reduce the production of at least two uremic toxins (Nephrology Dialysis Transplantation 
32, 2017, 1809-1817). There are no comparable data for any other orally administered antibiotic. 
 
It remains to be shown if reduction in any uremic solute concentration will improve clinical 
outcomes for dialysis patients.  Nevertheless, any strategy for doing so by reducing uremic toxin 
production by fecal flora through administration of oral non-absorbable antibiotics will require 
their chronic administration.    
 
Experience with longer term administration of oral vancomycin is reported from systematic 
study of the treatment of C.  difficile colitis.  In one trial (Clinical Infectious Diseases 2017; 
64(3):265–71) comparing a 6-week course of oral vancomycin with fecal transplants none of 4 
serious adverse events were deemed related to study procedures.  Experience with less serious 
events is summarized in the table below.  All of these patients received, for their 6 week course, 
dosing of vancomycin higher than proposed in our study. 
 
 
Early Events (0-7 days) 
Late Events (7-14 Days) 
Adverse Event 
FT (n = 16) 
VT (n = 12) 
FT (n = 11) 
VT (n = 12) 
Fever 
1 (6.2) 
0 (0.0) 
2 (18.2) 
1 (8.3) 
Nausea or vomiting 
4 (25.0) 
3 (25.0) 
0 (0.0) 
3 (25.0) 
Abdominal pain/ 
tenderness 
6 (37.5) 
5 (41.7) 
4 (36.4) 
9 (75.0) 
Abdominal 
distension 
6 (37.5) 
4 (33.3) 
3 (27.3) 
4 (33.3) 
Abdominal bloating 
6 (37.5) 
6 (50.0) 
3 (27.3) 
7 (58.3) 
Feeling generally 
unwell 
6 (37.5) 
3 (25.0) 
3 (27.3) 
4 (33.3) 
Mucoid stools 
6 (37.5) 
2 (16.7) 
4 (36.4) 
6 (50.0) 
Bloody stools 
1 (6.2) 
0 (0.0) 
2 (18.2) 
2 (16.7) 
Smelly stools 
6 (37.5) 
2 (16.7) 
3 (27.3) 
6 (50.0) 
Fecal incontinence 
4 (25.0) 
3 (25.0) 
3 (27.3) 
4 (33.3) 
Anorexia 
4 (25.0) 
2 (16.7) 
2 (18.2) 
3 (25.0) 


Fatigue 
5 (31.2) 
5 (41.7) 
4 (36.4) 
8 (66.7) 
Skin rash 
0 (0.0) 
1 (8.3) 
0 (0.0) 
2 (16.7) 
 
Abbreviations:  FT, fecal transplantation; VT, vancomycin  taper. 
a Expressed as No. of reported events with percentage in brackets; 
early events were from days 0–7 and late events were days 7–14. 
b Five of the 16 patients originally randomized to FT recurred within 
7 days of intervention and therefore are not included in the 
measurement of late adverse events. 
 
Longer term administration of oral vancomycin has also been used to prevent colitis in stem cell 
transplant recipients (Blood 2016 128:2225).  In this brief report of a retrospective analysis, 50 
members of a cohort of 105 patients received 126 mg of vancomycin po bid from day of 
admission to discharge (median length of stay = 33.5 days).  Adverse event details are not 
provided in this report, however the authors state that there were no cases of vancomycin-
resistant enterococcal bactermia among the vancomycin recipients. 
 
Tarao et al (Gut, 1990,31, 702-706) administered 8 weeks of vancomycin, 1000mg bid to 13 men 
and 1 woman, as part of a crossover study comparing vancomycin and lactulose.  They did not 
comment on adverse effects in this paper. 
 
More recently Isaac et al (Journal of Antimicrobial Chemotherapy, Volume 72, Issue 1, 1 
January 2017, Pages 128–136) administered vancomycin, 250 mg qid, for 2 weeks to examine 
the effect of vancomycin on the human microbiome of 9 patients with newly diagnosed with 
rheumatoid arthritis. This study was conducted at NYU and approved by the NYU IRB.  The 
authors comment “Altogether, our results demonstrate the negative long-term consequences of 
oral vancomycin administration, which should be taken into account in the decision-making prior 
to prescribing this antibiotic”, suggesting that adverse effects were absent or minor. 
It is important to understand the epidemiologic relationship between vancomycin use and the risk 
of vancomycin resistant enterococci (VRE) acquisition.  As stated in ANTIMICROBIAL 
AGENTS AND CHEMOTHERAPY, July 2008, p. 2403–2406: “Because multiple genes are 
necessary to generate vancomycin resistance in enterococci, acquisition of VRE colonization 
does not occur through mutations in susceptible enterococci in the intestinal tract” (4, 11, 18, 
19). Rather than inducing mutation the emergence of VRE reflects either the overgrowth of 
already present VRE, their acquisition via diet or from contact transmission.   
 
Estimates of the risk of such acquisition therefore have varied widely, depending on the local 
community or institutional prevalence.  We identified 3 studies that exemplify this.  In one study 
(Journal of Infectious Diseases 1996; 173:1129-36) conducted in an environment where VRE 
were present in the food stream, 14/22 (64%, 95%CI 40.7,82) of those given vancomycin for 
treatment of C. difficile developed colonization.  In contrast, in an institution were local 
prevalence was low (Infec Control Hosp Epi 25:413; 2004), 0% of 22 (95%ic 0,14%) individuals 
so treated acquired VRE while in a third study 1 of 12 patients treated acquired VRE (8.3%, 
95%CI=0.2,38.5).  From this perspective pre-existing colonization or acquisition of VRE would 
not be unexpected because ESRD patients are likely to receive vancomycin as treatment and may 
already be colonized.  We propose to look for this in our study and quantify the risk, but we 


don’t feel that the experimental treatment adds meaningfully to the risk of harm to the patients or 
a negative effect that would necessarily preclude the future use of the agent.   
 
While systematically collected data are limited, there is extensive clinical experience with long 
term use of IV vancomycin (for example for treatment of endocarditis or osteomyelitis) and oral 
vancomycin for the indications given above at doses substantially higher than we propose.  We 
believe the totality of the evidence suggest that major adverse effects are unlikely to be seen and 
revised our protocol to incorporate studies for foreseeable ones. 
 
Multiple observational data clearly relate higher concentrations of both of these uremic solutes 
with greater incidence of cardiovascular disease, including 
 
1. 
Meijers BK, Claes K, Bammens B, et al. p-Cresol and cardiovascular risk in mild-
to-moderate kidney disease. Clin J Am Soc Nephrol 2010;5: 1182–1189 
2. 
Melamed ML, Plantinga L, Shafi T, et al. Retained organic solutes, patient 
characteristics and all-cause and cardiovascular mortality in hemodialysis: results from 
the retained organic solutes and clinical outcomes (ROSCO) investigators. BMC Nephrol 
2013; 14: 134 
3. 
Liabeuf S, Barreto DV, Barreto FC et al Free p-cresyl sulfate is a precursor of 
mortality at different stages of chronic kidney disease, Nephrol  Dial and Transplant 
2010;25:1:1183-1191. 
4. 
Wu IW, Hsu KH, Hsu HJ, et al. Serum free p-cresyl sulfate levels predict 
cardiovascular and all-cause mortality in elderly hemodialysis patients–a prospective 
cohort study. Nephrol Dial Transpl. 2012;27:1169–1175 
 
There are no reported studies of the effect of treatments that reduce the plasma concentration or 
production of indoxyl sulfate or p-cresyl sulfate as no long term treatment trials have been 
undertaken. Indeed these studies might be considered a proof of concept to justify one approach 
to the design of such studies. 
 
 
Study Design 
This is a randomized double-blinded placebo-controlled crossover study in which 250mg of oral 
vancomycin will be administered to half of the subjects weekly for 3 months, and the other half 
of subjects will receive a placebo.  After three months, the control group will be crossed over to 
weekly oral vancomycin (250mg) and the initial experimental group will be switched to placebo 
for 3 months.  Plasma concentrations of IS and PCS will be monitored at first weekly for one 
month, then monthly during the 6-month duration of the study.  Stool samples will be collected 
at baseline, then monthly, cultured to determine the presence of vancomycin-resisitant organisms 
and analyzed for microbiome composition.   
 
Oral vancomycin 250mg capsules, packaged inside individual foil-sealed compartments, will be 
stored in the Reseach Pharmacy in a box labeled “vancomycin hydrochloride capsules”.  Placebo 
pills will be stored in a box labeled “placebo”.  Both will be purchased by the PI, shipped to his 
office in Bellevue Hospital, and stored in a locked cabinetin the Research Pharmacy. .  The co-


investigator will deliver the drug or placebo to each subject.This will maintain blinding, as the 
co-investigator will not know the identity of the medication or placebo delivered. 
 
Characteristics of the Research Population 
Number of Subjects: We will enter 16 subjects into this study.  We estimate that this number, 
based on an expected drop-out rate attributable to development of an infection or patients who 
are able to undergo renal trasnsplantation,  will leave us with at least 13 subjects who complete 
the 6-month protocol. National Healthcare Safety Network data published in July 2017 (6) 
reported  a combined infection rate of 0.293% per 100 patient months in patients with a fistula or 
A-V graft.  Based on this data, we anticipate that no more than 3 patients will drop out of the 
study.  Thus we feel that 16 is an appropriate number to insure that we will have at least 13 final 
study subjects.  Subjects will be identified through patient records at the dialysis centers, both 
River Renal and Lower Manhattan Dialysis.  Both of these centers are supervised by Albert 
Matalon MD, and he is the only study team member who is affiliated with these centers.  
Recruitment of subjects will be done by Leland Soiefer and Michelle Chang, and administration 
of vancomycin or placebo will be done under the supervision of the Research Pharmacy and Dr. 
Lowenstein.  Recruitment will occur in person at both locations in order to allow for a greater 
pool of potential subjects.  There will be no functional difference between the two sites for the 
purposes of this study. 
 
Gender of Subjects:  The intended gender distribution is equal between men and women. 
 
Age of Subjects:  All adults, over age 18. 
 
Racial and Ethnic Origin:  There will be no enrollment restrictions based on race or ethnicity. 
 
Inclusion Criteria:  End-stage renal disease receiving thrice-weekly hemodialysis via 
arteriovenous fistula or A-V graft. 
 
Exclusion Criteria: History of prior adverse reactions to vancomycin; history of current or prior 
diarrheal disease; receipt of any antibiotic during the three months that precede the study; history 
of C. difficile infection; elevation of white blood cell count or fever within one week of 
enrollment. 
 
Vulnerable Subjects:  Vulnerable subjects will not be included in this study.   
 
Methods and Procedures 
Methods and Procedures 
16 patients with chronic, stable end-stage renal disease will be recruited while at River 
Renal Dialysis or Lower Manhattan Dialysis for their regular hemodialysis session. 
Subjects will be randomized into two equal groups via computer assignment using the 
website www.randomizer.org.  At day -2, subjects’ blood (5mL) will be collected for 
measurement of IS and PCS pre- and post-dialysis.  Pre- and post-dialysis samples (5mL) 
will again be collected 2 days later (day 0). Each subject in the antibiotic group will 
ingest a 250mg capsule of vancomycin weekly while subjects in the control group will 
take a placebo.  Subsequent pre-dialysis blood samples (5mL) will be obtained weekly 


for one month, and then monthly.  Initial stool samples on day -2 will be collected from 
all subjects, and monthly samples will be obtained after that.  After three months, 
subjects will switch groups with blood and stool sample collection continuing in the same 
fashion.  Blood levels of vancomycin will not be monitored in this study due to the poor 
oral bioavailability of the drug. We will exclude patients that have gastrointestinal 
problems that might lead to absorption of oral vancomycin.  During the study, subjects 
will be interviewed regularly about development of new symptoms including diarrhea or 
fever, changes in diet, sick home contacts, and changes in medication use.  The 
investigators will fill out a monthly clinical questionnaire (attached to IRB submission) 
assessing changes in their clinical status, including changes in GI habits, diet, and 
development of new symptoms.  The total duration of participation for subjects will be 6 
months.  
 
In our prior acute administration study, we obtained the following results for two putative 
uremic toxins. 
 
 
Solute 
Mean 
Concentration 
(μM) on day 
0 
Mean 
Concentration 
(μM) on day 
5 
Mean  
difference 
SD of 
paired 
differences 
p-Cresyl 
Sulphate 
39.9 
18.5 
21.4 
29.2 
Indoxyl 
Sulphate 
29.9 
20.8 
9.1 
21.3 
 
To minimize any risk of harm we desire to minimize the sample size that we require.  Since we 
will be examining the changes within each patient a T test of the paired patient differences is an 
appropriate statistical test.  Based on the data from the acute study a sustained difference of the 
magnitude seen above would provide the proof of concept that we seek.  Based on these 
considerations we consider a sustained 54% decrease in the concentration of PCS at 1, 2, or 3 
months, compared to the initial level, to be a difference worth detecting.  We chose the decrease 
in PCS concentration as the primary outcome because of the greater magnitude of the decrease 
that was found acutely, suggesting that this solute may be more susceptible to antibiotic-induced 
inhibition of synthesis.  
 
Applying the computer program G*power v3.1.2 (http://www.gpower.hhu.de/en.html) using the 
data in the table above, a test of the 1-tailed hypothesis that vancomycin administration will 
reduce the concentration of PCS by the amount seen in the acute study after 1, 2, or 3 months of 
administration with alpha= 0.05 and power = 0.80 would require 13 patients.  The figure below, 
from the program, shows the relation between sample size and power for this test.  Thus, a 
sample size of 16 accounts for the necessary 13  subjects for a power of 0.8, and an additional 3 
to ensure 13 will complete the protocol after accounting for the expected drop-out rate. 


 
 
 
Here is the schedule for collection of samples based on “Day 0” being the first day that either 
oral vancomycin or placebo is administered. 
 
Visit 
Procedures 
Day -2 
Blood, stool 
Day 0 
Blood 
1 week 
Blood 
2 weeks 
Blood 
3 weeks 
Blood 
1 month 
Blood, stool 
2 months 
Blood, stool 
3 months 
Blood, stool 
3 months, 1 week 
Blood 
3 months, 2 weeks 
Blood 
3 months, 3 weeks 
Blood 
4 months 
Blood, stool 
5 months 
Blood, stool 
6 months 
Blood, stool 
 
 
The blood and stool samples will be stored for future research in uremic retention solutes.  
This is mandatory for subject participation, as this is a dynamic field of research and it is 
possible that new uremic retention solutes will be identified after the completion of this 
study. Samples will be banked in the freezer of Dr. Skolnik.  Samples will be banked for 
up to 10 years.  They will be labled using an alphanumeric code. and only the PI will 


have access to them.  Only the PI will have the linking key between the code and 
subjects’ identity. 
 
 
 
Data Analysis   
We plan to examine the difference in mean solute levels between the two groups in a manner 
similar to the prior study.  In the previous study we performed a linear mixed effects model 
analysis using the R statistical program.  The model included the number of days from 
vancomycin administration as a categorical fixed factor, the type of solute (IS or PCS) as a 
categorical fixed factor and subject as a random factor.  If there was a significant overall test for 
a fixed factor, least square means were obtained and differences among the least square means 
were tested using Tukey’s post hoc ‘Honestly Significant Difference’ method, calculated using 
error terms based on the model and Satterthwaite approximate degrees of freedom. The primary 
endpoint is plasma concentration of IS and PCS, and the secondary endpoint is perturbation of 
the gut microbiome. 
 
Data Safety Monitoring Plan 
The PI, Jerome Lowenstein, MD, has established a Data Safety Monitoring Committee 
composed of the following members: 1.Fred Valentine MD  2.Michael Simberkoff MD  3. Lada 
Beara-Lasic MD. 
 
This committee will meet monthly and review accumulating data to determine if either group 
(Drug-first or Placebo-first) is experiencing unexpected toxicity.   The major data that will be 
reviewed will include weekly clinical assessments by the investigator that include stool 
frequency, intercurrent infections including C. difficile colitis, as well as monthly blood 
chemistries and blood counts as routinely collected by the dialysis units, and results of monthly 
stool screening for vancomycin resistant enterococci.  A summary form will be available to the 
DSMB. 
 
Given the small size of the study and the expectation of rapid recruitment, the first interim 
analysis will be conducted when 10 patients have completed 1 month of experience.  The 
expectation is that there will be 5 patients in each arm of the crossover.  P-values will be adjusted 
for the planned repeated examinations of the data.  Given the study size it is likely that interim 
analyses of toxicity will not be powerful, however it may be that the study’s endpoints will be 
statistically significant and early termination can be contemplated. 
 
Once each month the PI will examine the blood and stool samples to ensure each sample is in its 
proper location in Dr. Skolnik’s freezer.  At the three-month mark plasma samples will be sent to 
the lab of Dr. Bjorn Meijers for analysis of plasma IS and PCS concentrations.   
 
Adverse events include development of C. difficile diarrhea, a drug-resistant bacterial infection, 
and the potential for rash.  If a serious adverse event occurs, the PI will be notified, and the 
subject will be taken to the emergency room by the co-investigator.  Any unexpected adverse 
events will be reported to the IRB within one week.  There is abundant evidence that oral 
vancomycin is a safe drug, so we do not anticipate major adverse events.  However, the study 


will be stopped if 6 or more subjects develop an adverse event.  Summary reports from data 
safety monitoring meetings will be submitted via the IRB’s online portal. 
 
Data Storage and Confidentiality 
The data will be stored in a locked cabinet in the office of the PI.  At the start of the study, 
subjects will be assigned an alphanumeric code following randomization.  This will allow us to 
keep deidentified data records.  Each subject will be assigned a letter, and each plasma sample 
and stool sample will receive a number and letter indicating the subject and the chronology of the 
samples.  Only the PI and co-investigators will have access to the data; only the PI will have the 
linking key between the subject ID and the subjects’ identity. 
 
Risk/Benefit Assessment 
Risk 
 
There are no reports of long-term adverse effects of oral vancomycin in the modern era of 
vancomycin production and no reports of adverse effects of a dose as low as 250 mg once 
weekly.   
 
Despite its effectiveness against Clostridium difficile infection (cure rate of ∼90%), a subset of 
cured patients (14%–21%) develop recurrent infections, which are thought to be enhanced by 
microbiota changes promoted by vancomycin. In addition, microbiota alterations induced by 
vancomycin may promote intestinal colonization by other pathogens, including VRE, Klebsiella 
pneumoniae or Escherichia coli. If this happens, the subject will be treated appropriately to 
resolve the infection, including possible admission to the hospital.  The other major risk is 
related to administration of antibiotics when subjects do not have an active infection, namely the 
possibility of developing resistance to the antibiotic, and possibly development of an infection 
with a drug-resistant organism. Oral vancomycin achieves high concentrations in the intestinal 
tract, resulting in suppression of anaerobic organisms, including Bacteroides spp. Such 
disruption of the indigenous microbiota may predispose patients to recurrent CDI due to 
regrowth of the original infecting C. difficile strains or acquisition of new strains (7). There is 
also the potential for rash.  These risks are legitimate considerations, and should be balanced 
against the potential benefit of significantly lowering the blood concentrations of two uremic 
toxins that have been linked to atherosclerotic progression.   
 
Participation in this study will involve monitoring of plasma IS and PCS concentrations and 
collection of stool samples, both of which present minimal risk.  The adverse effect of 
nephrotoxicity is extremely rare with current formulation of oral vancomycin.  We do not believe 
ototoxicity is a significant risk as this type of adverse effect only occurred with administration of 
high doses of IV vancomycin. 
 
Protection Against Risks 
Blood samples will be drawn at the start and end of dialysis from the dialysis access line, in 
order to avoid repeated venipuncture. Patients will be monitored by co-investigators Leland 
Soiefer, MS4 and Michelle Chang, MS4 with supervision by the PI Jerome Lowenstein, MD.  
The co-investigators will use the clinical questionnaire (attached to IRB submission) to monitor 
for development of diarrhea, infectious symptoms, or other new symptoms.  Subjects will be 


removed from the study if they develop significant GI distress such as new diarrhea or colitis.  
Exit criteria also include development of any infection that necessitates treatment with 
antibiotics, and receipt of renal transplant.  
 
Potential Benefits to the patient.  
Subjects will likely experience no change in their clinical status and will most likely not 
experience any personal benefit. Plasma concentrations of IS and PCS may be significantly 
reduced for several months, which could potentially slow atherosclerotic progression.    
 
Investigator’s Qualifications & Experience 
Please see attached CVs. 
 
Subject Identification, Recruitment and Consent/Assent 
Identification 
To identify potential subjects for this study, an investigator will go to River Renal Dialysis Unit 
and Lower Manhattan Dialysis and consider patients with regard to inclusion and exclusion 
criteria by conferring with the staff and reviewing medical records.  The researchers will then 
approach a patient, review and confirm information with them from their record, and explain the 
study including answering any questions the patient may have.   
 
Process of Consent 
The co-investigators will obtain consent by explaining the nature of the study and the science 
behind it, presenting risks and benefits, and answering questions.  Subjects will sign the consent 
form and receive a copy of the signed document. 
 
Subject Capacity 
All subjects will have the capacity to give consent. 
 
Subject Comprehension 
The co-investigators will ask the subject to summarize back the nature and process of the study 
as part of giving consent.  The consent form will also be written in simple English. 
 
Debriefing Procedures 
No debriefing will be necessary in this study. 
 
Consent Forms 
See attached forms. 
 
Documentation of Consent 
The subject will sign the consent form, and the forms will be stored in a locked file cabinet in the 
PI’s office inside Bellevue Hospital.   
 
Costs to the Subject 
Participation in the study will not cost anything to the subjects. 
 
Payment for Participation 


The subjects will not be compensated or paid for participation in the study. 
 
References 
1. Nazzal L, Roberts J, Singh P et al. 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.   Nephrology Dialysis Transplantation 2017; 29: 1-9. 
2. Lindner A, Charra B, Sherrard DJ et al. Accelerated atherosclerosis in prolonged 
maintenance hemodialysis.  N Engl J Med 1974; 290: 697-701. 
3. Sciarretta S, Valenti V, Tocci G et al.  Association of renal damage with cardiovascular 
diseases is independent of individual cardiovascular risk profile in hypertension: data 
from the Italy – Developing Education and awareness on MicroAlbuminuria in patients 
with hypertensive Disease study.  J Hypertens 2010; 28: 251-258. 
4. Weiner DE, Tighiouart H, Amin MG et al.  Chronic kidney disease is a risk factor for 
cardiovascular disease and all-cause mortality: a pooled analysis of community-based 
studies.  J Am Soc Nephrol 2004; 15: 1307-1315. 
5. Meyer TW, Hostetter TH.  Uremic solutes from colon microbes.  Kidney Int 2012; 81: 
949-954. 
6. Nguyen DB, Shugart A, Lines C et al.  National Healthcare Safety Network (NHSN) dialysis 
event surveillance report for 2014.  Clin J Am Soc Nephrol 2017; 12(7): 1139-1146. 
7. Abujamal T, Cadnum JL, Jury LA et al.  Defining the vulnerable period for re-
establishment of Clostridium difficile colonization after treatment of C. difficile infection 
with oral vancomycin or metronidazole.  PLoS One 2013; 8(10): e76269.