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Clinical Study
Randomized Controlled Trial of Strain-Specific Probiotic
Formulation (Renadyl) in Dialysis Patients
Ranganathan Natarajan,1Bohdan Pechenyak,1Usha Vyas,1
Pari Ranganathan,1Alan Weinberg,2Peter Liang,3Mary C. Mallappallil,3
Allen J. Norin,3Eli A. Friedman,3and Subodh J. Saggi3
1Kibow Biotech, Inc., 4781 West Chester Pike, Newtown Square, PA 19073, USA
2Mount Sinai School of Medicine, New York, NY 10029, USA
3Downstate Medical Center, State University of NY, New York, NY 11203, USA
Correspondence should be addressed to Ranganathan Natarajan; rangan@kibowbiotech.com
Received February ; Accepted June ; Published July
Academic Editor: Beatrice Charreau
Copyright © Ranganathan Natarajan et al. is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Background. Primary goal of this randomized, double-blind, placebo-controlled crossover study of Renadyl in end-stage renal
disease patients was to assess the safety and ecacy of Renadyl measured through improvement in quality of life or reduction in
levels of known uremic toxins. Secondary goal was to investigate the eects on several biomarkers of inammation and oxidative
stress. Methods. Two -month treatment periods separated by -month washout and crossover, with physical examinations, venous
blood testing, and quality of life questionnaires completed at each visit. Data were analyzed with SAS V.. Results. subjects (%)
completed the study. Observed trends were as follows (none reaching statistical signicance): decline in WBC count (−0.51×109/L,
𝑃 = 0.057) andreductionsinlevelsofC-reactiveprotein(−8.61 mg/L, 𝑃 = 0.071) and total indoxyl glucuronide (−0.11 mg%, 𝑃=
0.058). No statistically signicant changes were observed in other uremic toxin levels or measures of QOL. Conclusions. Renadyl
appeared to be safe to administer to ESRD patients on hemodialysis. Stability in QOL assessment is an encouraging result for a
patient cohort in such advanced stage of kidney disease. Ecacy could not be conrmed denitively, primarily due to small sample
size and low statistical power—further studies are warranted.
1. Introduction
During coevolution with microbes, the human intestinal tract
has been colonized by thousands of bacterial species [,].
Gut-borne microbes outnumber the human body cells by a
factor of ten []. Recent metagenomic analysis of human gut
microbiota has revealed the presence of . million genes,
compared to mere thousand known human genes [–].
Microbial communities perform the majority of biochemical
activities on the planet and play integral roles in human meta-
bolismandimmunehomeostasis[]. Recently, evidence of
benets for human health from intestinal microbiota and
probiotic microbes has expanded rapidly [–].
Probiotics, “live microorganisms which when adminis-
tered in adequate amounts confer a health benet on the host
[],” are predominantly found in fermented dairy foods
(yogurt, ker, and cheese). Although the expansion of aware-
ness and use of probiotics has raced ahead of the scientic
knowledge of mechanisms by which they impact health,
probiotics appear with increasing frequency in various foods,
beverages, and supplements and are increasingly utilized
in clinical settings. As their safety and health benets are
established, it is reasonable to anticipate that they will be
incorporated into a growing number of clinical regimens,
either independently or as adjunct/combined treatments.
Generalawarenessoftherisingglobalprevalenceof
kidney disease has been steadily growing among medical
and public health professionals [–]. Kidney disease is the
eighth leading cause of death in the U.S. [], with approx-
imately . patients in end-stage renal disease (ESRD,
most receiving dialysis) and over million in earlier stages
of chronic kidney disease (CKD) []. As the population
Hindawi Publishing Corporation
BioMed Research International
Volume 2014, Article ID 568571, 9 pages
http://dx.doi.org/10.1155/2014/568571
BioMed Research International
Clostridia
Proteus
Staphylococci
Pseudomonas
Bidobacteria
Eubacteria
Lactobacilli
Bacteroides
E. coli
Enterococci
Streptococci
CKD patients
(C. elmenteitii).
∙Higher Enterobacteria
∙(Enterobacter sp.,
Pseudomonas sp.)
∙Low levels of
Lactobacilli and Bidobacteria
Healthy population
∙ High levels of
Lactobacilli
∙High levels of
Bidobacteria
More good
Few bad
Few good
More bad
Intestinal ora in normal and CKD population
Imbalanced ecosystem has higher number of pathogens
and lower number of benecial microbes, Vaziri et al. (2013).
Potentially harmful bacteria (Clostridia, Proteus, Staphylococci, and Pseudomonas) can cause
diarrhea or constipation and facilitate infections or production of toxins.
Potentially helpful bacteria (Bidobacteria, Eubacteria, and Lactobacilli) inhibit exogenous and
endogenous harmful bacteria, stimulate immune function, aid in digestion and absorption
of nutrients, and synthesize vitamins.
Intermediate bacteria (Bacteroides, Enterococci, and Streptococci) are needed in small
amounts. For example, E. coli synthesizes vitamin K. Source: Gibson and Roberfroid (1995)
∙ Higher Clostridia
F : Dysbiosis in CKD.
continues to age and the epidemiological shi from acute
infectious to chronic metabolic diseases progresses, con-
tributing factors to kidney disease (obesity, diabetes, and
hypertension) become epidemic. Kidney disease may turn
into a major health crisis in the USA and globally. e use
of dietary supplements is a promising approach and should
be included in any strategy to reduce the likelihood of such
crisis.
e role of digestive [] and immune []systems,as
well as inammatory []andoxidativestress[,]func-
tions, in the progression of kidney disease has been empha-
sized by researchers in the past decade. Current data have
highlighted an integrated and perhaps a causal relationship
between the observed clinical outcomes and the role of an
activated immune system in uremia. (Please see Figure for
elucidation of dysbiosis.)
e potential utilization of oral sorbents and probiotics
has been continuously explored as a complementary strategy
for CKD over the past years. Initial in vitro R&D lab studies
were performed including the use of a simulated human
intestinal microbial ecosystem (SHIME), a ve-step bio-
chemical reactor to mimic stomach, small intestine, and
ascending, transverse, and descending colonic environments
[]. Further exploratory studies of orally administered pro-
biotic bacteria were performed in /th nephrectomized rats
[] and mini pigs [], in cats [] and dogs with kidney
failure,andinhumans[,]withCKDandESRD[].
(Two unpublished studies by veterinary doctors: Carol L.
Galka,DVM,CompanionAnimalCareCenter,Caro,MI(𝑛=
2), and Gary van Engelenberg, DVM, CVA, Iowa Veterinary
Acupuncture Clinic, Des Moines, IA (𝑛=6).)
To determine whether daily probiotic bacterial treatment
improves or delays the onset of CKD signs and symptoms,
several pilot-scale human clinical trials were conducted. ey
showed that a proprietary probiotic formulation can utilize
various nitrogenous uremic toxins as nutrients for growth
of benecial gut microbes. Specically formulated probiotic
microbial strains keep uremic toxins from accumulating to
highly toxic levels. In December , two most recent studies
were completed: an open label, observational dose escalation
BioMed Research International
Prescreening
baseline 2 months 2 months
washout
Placebo
Intervention
2 months
Intervention
Placebo
F : Study design.
study in CKD stages and patients at omas Jeerson
University (Philadelphia, PA) [] and the current study. e
former study aimed to conrm the safety and tolerability of
several doses of the formulation as well as to quantify the
improvements in quality of life (QOL) and to explore several
molecular biomarkers. e primary goal of the current study
was to conrm the ecacy of the formulation in eecting
a measurable quality of life improvement and reducing the
levels of commonly known uremic toxins. e secondary goal
was to investigate the product’s eects on some inammation
and oxidative stress biomarkers.
2. Subjects and Methods
2.1. Study Design. A -month randomized, double-blind, pla-
cebo-controlled crossover study of an orally administered,
strain-specic probiotic formulation (Renadyl, Kibow Bio-
tech, Inc., Newtown Square, PA) in ESRD patients receiving
dialysis treatment was initiated at the Downstate Medical
Center (DMC, Brooklyn, NY) in April (Figure ). e
study protocol had been approved by the DMC Institutional
Review Board (NIH registry NCT), and written
informed consent was obtained from each participant at
enrollment. e study participants enrolled voluntarily were
prequalied and selected based on prior medical history and
the inclusion/exclusion criteria.
Primary endpoints were dened as measurable improve-
ment in the quality of life (in accordance with modied
SF questionnaire) and in the levels of biochemical markers,
such as urea and creatinine, hematological values (CBC),
and hepatological function. Secondary endpoints included the
measurements of several biomarkers of inammation and
oxidative stress (indoxyl metabolites, p-cresyl sulfate, serum
pentosidine, 𝛽- microglobulin, NF-𝜅B, and sCD).
During the screening (T), baseline values were obtained,
and each patient was examined, randomly assigned to either
treatment or control group, and initiated on a dose of
capsules thrice daily with meals (Tabl e ). Each capsule
contained either the probiotic formulation— billion CFU
of S. thermophilus KB , L. acidophilus KB , and B. longum
KB —or placebo, which consisted of a : blend of cream-
of-wheat and psyllium husk (both formulation and placebo
manufactured by ADH, Congers, NY). e second visit was
scheduled at the end of month (T), at which point the
rst treatment period ended and the -month washout period
began.Atmonth,thewashoutperiodendedandsecond
treatment period began. e nal follow-up visit occurred
at month (T), the study end. Participants underwent
routine physical examinations and blood draws, completed
T : Randomization and blinding (Tx: treatment; PL: placebo).
Patient number. Period Period
Tx PL
Tx PL
Tx PL
Tx PL
PLTx
PLTx
Tx PL
PL Tx
PL Tx
Tx PL
Tx PL
PL Tx
PL Tx
Tx PL
Tx PL
PL Tx
PL Tx
Tx PL
Tx PL
PL Tx
Tx PL
PL Tx
modiedSF-QOLquestionnaires,andweremonitoredfor
compliance with the study protocol at each visit. (Exception:
at month , patients visited to obtain the product, with no
exams/measures.)
2.2. Inclusion and Exclusion Criteria. e inclusion criteria
dened the potential participant population as those aged –
and diagnosed with CKD stage V (ESRD, currently receiv-
ing hemodialysis treatment).
e exclusion criteria limited the study population by
excluding () pregnant or nursing women, () those with
HIV/AIDs or liver disease diagnoses, () those with active
dependency on controlled substances and alcohol, () those
on anticoagulant therapy regimen, () those refusing to
sign the informed consent form, and () those with social
conditions or medical debilitating disease/disorder, which, in
the judgment of the investigator, would interfere with or serve
as a contraindication to adherence to the study protocol or
ability to give informed consent or aect overall prognosis of
the patient.
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2.3. Laboratory Methods
2.3.1. Biochemistry and Hematology. No changes in the
dialysis prescription of these patients occurred during the
study period. Complete blood counts and serum biochemical
testing were performed at each patient’s dialysis treatment
facility at DMC, either Parkside (PS, patients –, , –)
orKingsCounty(KC,–,–).Glucosewasmonitored
closely, if the patients were diabetic.
2.3.2. Uremic Toxins and Inammation Markers. e sec-
ondaryaimofthestudywastoinvestigatepossiblechanges
in markers of inammation, known to increase in uremia,
such as C-reactive protein and NF-𝜅B, as well as such uremic
toxins as total and free indoxyl sulfate, total and free indoxyl
glucuronide, total and free indole acetic acid (IAA), total and
free p-cresyl sulfate, total and free hippuric acid, pentosidine
sulfate, 𝛽- microglobulin, -carboxyl--methyl--propyl--
furan-propanoic acid (CMPF), and uric acid.
Chemicals were measured by HPLC and ELISA. Periph-
eral blood mononuclear cells (PBMC) were extracted from
whole patient blood samples, using Ficoll-Hypaque to form
the density gradient, and centrifuged. NF-𝜅Blevelswere
assayed using the TransAM p ELISA kit (Active Motif,
Carlsbad,CA).Viabilityofcellswasassessedusingtrypan
blue exclusion. An aliquot of the cells extracted was used
for lysis. e nuclear content from the aliquot was extracted
usingtheprotocolfromthekit.enalsolutionwasdiluted
to , cells/𝜇L using the cell lysis buer in combination
with the protease inhibitor cocktail. e cell extracts were
stored at −∘C. Analysis was performed according to the kit
instructions.
Serum pentosidine and 𝛽- microglobulin were analyzed
using ELISA kits (Novateinbio, cat. no. NB-E, and R &
D Systems, cat. no. DBM, resp.). Other chemicals were
quantied by HPLC on a Waters Alliance (Waters,
Zellik, Belgium) and two detectors in series (Waters pho-
todiode array detector (PDA) and a Waters uorescence
detector (FLD)), using methods of Taki and Niwa []and
Martinez et al. [].
To determine the total serum concentration, 𝜇Lof
sample was diluted with 𝜇L of HPLC water, followed by
heating at ∘Cformin.enthesampleswereplaced
on ice for minutes and subsequently passed through a
molecular lter (Amicon Ultra . mL) with a . Da cut-
o weight. To measure the free fraction, untreated serum
samples were ltered prior to heating. In order to correct
for system performance variations, 𝜇Lofuorescein
( mg/L) was added to 𝜇Lofultraltrateasinternalstan-
dard. Subsequently, this was transferred to an autosampler
vial and 𝜇Lthereofwasinjectedinthecolumn.
e separation was performed at room temperature on
a reversed-phase XBridge C column (. 𝜇m, mm ×
. mm, Waters) with an Ultrasphere ODS guard column
( 𝜇m, mm ×. mm, Beckman Instruments). e mobile
phase consisted of a mM ammonium formate buer
(mobile phase A, pH .) and methanol (mobile phase B).
A gradient elution at a ow of mL/min was performed
with an initial composition of % phase A and held at this
composition for min. en, this increased to % B in
min and this composition was held for min and nally
a reequilibration was done. For uric acid, hippuric acid and
CMPF chromatograms were extracted from the PDA data
at nm, nm, and nm, respectively. Fluorescence
excitationandemissionwavelengthswereoptimizedforthe
other compounds: 𝜆ex = 272nm and 𝜆em = 374nm for
indoxyl sulfate and indoxyl glucuronide, 𝜆ex = 264nm and
𝜆em = 290nm for p-cresyl sulfate and p-cresyl glucuronide,
𝜆ex = 272nm and 𝜆em = 340nm for indole acetic acid,
and 𝜆ex = 443nm and 𝜆em = 512nm for the internal
standard. Five point calibration curves were generated. Good
linearity was observed for all compounds. For the regression
calculation a weighing factor of 1/𝑥 was used for all data
points.
Aer initial analysis, to link some of the results obtained
to the markers of inammation, a sCD biomarker of T-cell
activation was investigated. is marker has previously been
showntobeelevatedinpatientswithCKD[]. Also, lower
levels of sCD have been associated with better prognosis
in kidney transplant patients []. e levels of sCD were
measured by ELISA kit (eBioscience, San Diego, CA, cat. no.
BMS).
2.4. Statistical Methods. All variables were analyzed for
change with reference to the values obtained during the
placebo study period. All measures were modeled via the
PROC MIXED procedure in SAS, similar to an analysis of
variance for repeated measures. Due to the fact that repeated
measurements within each patient may be correlated, the
Mixed Model procedure allows one to model this “correlation
structure,” commonly referred to as a covariance pattern. is
accurate estimate will allow for improved estimates of the
standard errors of measurement and therefore more powerful
tests.
ere are a number of various covariance structures to
choose from. ree of the more common covariance struc-
tures include “compound symmetry” (CS), for correlations
that are constant for any two points in time, “autoregressive
order one” (AR), for correlations that are smaller for time
points further apart, and “unstructured” (UN), which has no
mathematical pattern within the covariance matrix. Other
covariance structures that are usually tested include the
Toplitz (TOEP) and the heterogeneous compound symmetry
structure (CSH).
A likelihood ratio test or a procedure known as Akaike’s
information criterion (AIC) is used to discern which covari-
ance pattern allows for the best t []. erefore the
“compound symmetry” (CS) structure was chosen. Adjusted
means at each time point were then generated with adjusted
standard errors. 𝑃values were not adjusted for multiple
comparisons and the ination of the Type I error.
SAS system soware V . (SAS Institute Inc., Cary, NC)
was used for all statistical analyses.
2.5. Patient Adherence. Patient compliance and adherence
wasassessedbypillcountandstoolculturetoverifyprobiotic
growth during study and absence during placebo period.
BioMed Research International
T : M e a ns.
Variable Tx period 𝑁Mean Std. Dev. Median Min Max
White blood cells (WBC)
Base . . . . .
Placebo (PL) . . . . .
Treatment (Tx) . . . . .
C-reactive protein (CRP)
Base . . . . .
PL . . . . .
Tx . . . . .
Total indoxyl glucuronide (TIG)
Base . . . . .
PL . . . . .
Tx . . . . .
T : Least squares means.
Variabl e Estimat e Std. erro r 𝑡value Pr >|𝑡| Alpha Lower Upper
WBC . . . <. . . .
. . . <. . . .
CRP . . . . . . .
. . . . . −. .
TIG . . . <. . . .
. . . <. . . .
T : Dierences of least squares means.
Variable Tx period Estimate Std. error 𝑡value Pr >|𝑡| Lower Upper
WBC PL-Tx . . . 0.0569 −. .
CRP PL-Tx . . . 0.0707 −. .
TIG PL-Tx . . . 0.0579 −. .
Fecal samples were analyzed at Kibow’s lab for the presence
of the three strains comprising the study formulation using
microbiological methods of plating, enumeration, and count-
ing the colonies on appropriate and specic growth media on
agar plates.
3. Results
3.1. Patient Baseline Demographics and Epidemiology. Among
the participants, the average age was (range –) and
the predominant sex was female (𝑛=16, %). Vital sign val-
ues were as follows: systolic blood pressure (BP) averaged at
mmHg (range – mmHg), diastolic BP— mmHg
(– mmHg), respiration—/min (–), and pulse—
/min (–/min). All medications, prescribed and admin-
istered to each patient prior to the initiation of the study and
the Renadyl regimen, were either continued without change
or reassessed and substituted by an alternative therapeutic
modality, in accordance with the accepted standards of care.
3.2. Study Results. Of participants, (%) completed
three visits. Two patients withdrew consent aer the baseline
visit (T), one of them due to nausea and vomiting. Both of
these patients were on placebo. e capsules administered
were vegetarian gel caps size at a dosage level of two capsules
three times a day. more dropped out aer visit (T): was
transferred to a dierent facility, withdrew consent, and
passed away of unrelated causes (see Section .).
Administration of probiotics was accompanied by the
following trends (not reaching statistical signicance; see
Tables ,,and): decline in WBC count (change of −. ×
9/L, 𝑃 < 0.057) and reductions in the levels of total indoxyl
glucuronide (−. mg%, 𝑃 < 0.058) and C-reactive protein
(−. mg/L, 𝑃 < 0.071). No statistically signicant changes
were observed in the levels of other uremic markers or mea-
sures of QOL.
No major issues were encountered with regard to patient
adherence to the treatment regimen. Average adherence
amounted to .%, with a standard deviation of .%.
3.3. Adverse Events. e study was monitored according to
the best clinical practices as per the nephrology institutional
clinical standards of Downstate Medical Center, State Uni-
versity of New York, Brooklyn, NY. ere was one Severe
Adverse Event with a lethal result, unrelated to the study
protocol—myocardial infarction while sleeping at home
(underlying atherosclerotic and coronary heart disease).
Patient issues included a long-term smoking history at a rate
of several packs per day, continued strenuous employment
despite multiple health conditions, years of dialysis treat-
ment comorbid with severe hyperparathyroidism and hyper-
phosphatemia, accompanied by poor adherence to and com-
pliance with dialysis treatments, medications, diet, and phos-
phate binder regimen, as well as poor to no follow-up with
specialists. Five other patients withdrew consent, due to
BioMed Research International
nausea and vomiting, because of being transferred to a dif-
ferent facility in the state of Maryland, and the other for
unspecied reasons. Also, there was another patient who
withdrew consent, complaining of nausea and vomiting, but
later rearmed consent.
4. Discussion
Toxicity from the accumulation of uremic toxins is a concern
for kidney disease patients. Concentrations of uremic solutes
increase as the disease progresses from CKD to ESRD [].
e European Toxin workgroup (EUTOX) has classied
many uremic toxins based on their molecular weights and
their protein binding property []. ough urea is generally
nontoxic, it can degrade to highly toxic cyanate, which binds
to proteins by carbamylation and modies them, including
serum albumin. Recent study by Berg et al. []showedthat
carbamylated serum albumin is a risk factor for mortality in
patients with kidney failure. As early as , it was shown
thatCKDpatientsfacehigherriskofcardiovascular(CV)
problems, with CV mortality – times higher than in the
general population []. erefore, it may be necessary to
reduce CKD patients’ urea levels either with medication or
through interventions like probiotic supplementation (some
lactic acid bacteria can metabolize urea).
Probiotics have been reported to enhance intestinal
health for centuries []. Scientic proof has now been
obtained that conrms their positive eects on human health
in general []. e application of probiotics in various
diseases has intensied, as extensive research eorts help
understand how they shape human health and how their
composition changes in diseased states []. e application
of probiotics in ESRD management has been investigated
in both experimental and clinical settings []. Recently,
deeper insight was gained into probiotics’ positive eects on
kidney disease progression—possible mechanisms include
anti-inammatory (addressing imbalances of gut dysbio-
sis) and antioxidant (addressing deciencies in free radical
signaling—generation of reactive oxygen species in the gut)
routes [].
4.1. Probiotics and Renal Health. It has been demonstrated
previously that gut microora can aect the concentrations
of uremic toxins in animals. Prakash and Chang were able
to continuously reduce blood urea nitrogen in azotemic
rats by oral administration of microencapsulated genetically
engineered live cells containing living urease-producing E.
coli DH []. Based on this concept, Ranganathan et al.
carried out rat studies using /th nephrectomized animals
fed with a probiotic cocktail of Lactobacilli,Bidobacte-
ria,andS. thermophilus []. Results showed a signi-
cantly prolonged life span for the uremic rats, in addition
to reduced blood urea-nitrogen (BUN) levels. Studies were
subsequently carried out in /th nephrectomized Gottin-
gen mini pigs []. Here, also there was a reduction in
BUN and creatinine levels, indicating that the probiotic
supplementation prevented the accumulation of these toxins
in the blood. ese results were further evaluated clini-
callybyPalmquistinfelineazotemia[]. Studies in cats
showed statistically reduced levels in BUN and creatinine
levels and demonstrated signicantly improved quality of life
(QOL). e product is currently marketed worldwide for cats
and dogs with moderate-to-severe kidney failure (Azodyl,
Vetoquinol SA, http://www.vetoquinol.com/).
In human studies, Simenho et al. demonstrated that
hemodialysis patients who were fed L. acidophilus NCFM had
signicantly lower blood dimethylamine and nitrodimethy-
lamine levels [,]. Simenho was the rst researcher
to demonstrate the growth of pathogenic bacteria which is
referred to as “small bowel bacterial overgrowth” (SBBO).
e NCFM strain is well known, and the genome has been
sequenced by Todd Klaenhammer’s group []. Subsequent
to the success of the formulation for cats and dogs described
above, a similar formulation for humans was evaluated
clinically in a -month randomized, double-blind, placebo-
controlled, crossover trial in CKD stages III and IV patients
in four countries [,]. Forty-six patients were studied
in this trial. BUN levels decreased in patients (𝑃<
0.05), creatinine levels decreased in patients (no statistical
signicance), and uric acid levels decreased in patients (no
statistical signicance). Almost all subjects reported having
experienced a substantial perceived improvement in their
quality of life (𝑃 < 0.05). is product is also currently mar-
keted to CKD patients (Renadyl, Kibow Biotech, Inc., New-
town Square, PA, USA, http://www.renadyl.com/).
Previous multicenter trials in cohorts of CKD stages -
patients showed that concentrations of uremic toxins (urea,
uric acid, and creatinine) were reduced when study subjects
weretreatedwiththestudyformulationatbillionCFU/day
dosage []. Open label, dose escalation observational study
in CKD stages - patients showed statistically signicant
reductions in creatinine and C-reactive protein, signicant
improvements in hemoglobin, hematocrit, and physical func-
tioning (QOL measure), trends toward reduction in BUN,
potassium, and pain (QOL), and no signicant change in
mental, emotional, and social well-being [].
e current study was conducted to assess the safety and
ecacy of the formulation in ESRD patients receiving dialysis
treatment. e results indicate that the administration of the
formulationinESRDpatientsissafeandmightevenhavea
slight protective eect, as indicated by a trend toward reduc-
ing inammation markers. Since NF-𝜅Bpathwayisnei-
ther activated (important in cases of active infections) nor
modulated/suppressed, the formulation appears not to harm
immune function. Levels of sCD are not aected by the
administration either, further conrming that patients are
not immunologically compromised by probiotic treatment.
Further investigation in a larger population, at a higher dose
and over a longer term, might yield mechanistic insights into
the probiotic eects on the inammatory cascade of uremia
and the modulation of T-cells in ESRD. e next clinical trial
bearing this in mind is underway where hemodialysis and
peritoneal dialysis patients will receive B CFU/day for a
period of months to get better statistical data.
Studies by Vaziri et al. [] have shown that renal failure
patients have an imbalanced gut microora, while a recent
review of the studies with pro- and prebiotics summarized
the role of the gut microora in uremia and CKD []. As
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the review states, it is not well recognized that an important
contributing factor to the toxic load leading to CKD origi-
nates in the gut. e microbiota that colonize the gut perform
such functions as regulating the normal development and
function of the mucosal barriers; assisting with maturation
of immunological tissues, which in turn promotes immuno-
logical tolerance to antigens from foods, the environment,
or potentially pathogenic organisms; controlling nutrient
uptake and metabolism; and preventing propagation of path-
ogenic microorganisms. e review concludes that probiotics
and prebiotics are very likely to play a therapeutic role in
maintaining a metabolically balanced gut and reducing pro-
gression of CKD and associated uremia.
In addition, recent studies indicate that such metabolites
as phenols and indoles, which are also uremic toxins, come
from colonic fermentation []. In CKD, protein digestion is
impaired; undigested proteins enter the large intestine and are
fermented by pathogenic bacteria, eventually forming indoles
andphenols,whicharethenconvertedtoindoxylandp-
cresyl sulfates, glucuronides, and other metabolites.
is study investigated whether probiotic supplementa-
tion could lower the concentrations of these putrefactants.
For example, the generation rate of indoles, produced from
amino acid tryptophan, may be altered by probiotics. As
indicated, the values of most biomarkers varied widely and
did not reach statistical signicance (data omitted), the only
exception being a trend toward reduction in the levels of total
indoxyl glucuronide. QOL results, likewise, did not show
any signicance (data omitted), though stability and lack of
deterioration in itself are encouraging, given the advanced
stage of renal failure.
4.2. Study Limitations. e most signicant limitation was
sample size, aecting the statistical power of the study results.
Since this was a pilot trial to establish safety and ecacy,
minimal, limited number of patients were chosen. Future
largertrialsbasedonthendingsofthisESRDandanearlier
CKD probiotic trial [] should be suciently powered.
e likeliest explanation of the lack of statistically sig-
nicant results is that (a) ESRD is an advanced stage of
CKD, patients have multiple complications, and the extent of
disease is already life-threatening enough to qualify patients
for life-sustaining dialysis treatments; (b) dialysis per se does
reduce/remove some of the smaller water soluble molecules
and uremic toxins like urea; (c) the study was at a dosage of
B CFU/day for just two months. Despite the short admin-
istration of the probiotic one of the uremic toxins indoxyl
glucuronide levels showed a decrease. is toxin is generated
by gut dysbiosis and cannot be removed by dialysis; hence,
reductioninthelevelsofthistoxinindicatesapositive
response attributed to the probiotic bacteria present in Ren-
adyl.Inmostcases,thebestresultstobeexpectedfrompro-
biotic supplementation are stabilization of uremic toxin
levels and stabilization or improvement of the quality of life.
Whether more signicant eects are possible—for example,
reduction in duration or even frequency of dialysis sessions—
remains to be determined from future studies employing
larger patient samples.
5. Conclusions
Administration of Renadyl in ESRD patients at the dose of
billionCFUsperdayappearssafeandwelltolerated.Trends
were noted in WBC count, C-reactive protein, and total
indoxyl glucuronide, none reaching statistical signicance.
Other uremic toxins, markers of inammation and oxidative
stress, and quality of life measures did not show statistically
signicant changes. For more denitive results, especially to
conrm the trends observed, a study with a larger sample size
is warranted.
Disclosure
Kibow Biotech, Inc., a privately owned biotechnology com-
pany focused on probiotics, nanced this clinical inves-
tigation at the Downstate Medical Center through
Qualifying erapeutic Discovery Project (QTDP) award, a
US government special grant program to support promising
and emerging technologies. Part of the data was also obtained
in Kibow’s own fully equipped research laboratories.
Conflict of Interests
e authors declare that they have no conict of interests
regarding the publication of this paper.
Acknowledgments
ree abstracts based on the results from this study were
presented in November at the American Society of
Nephrology Annual Convention in Atlanta, GA, by the
Downstate Medical Center team. e authors would also
like to acknowledge Lorraine omas (Downstate Medical
Center) for her assistance in implementing the clinical part
of this study.
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