“Enteric Dialysis®” – From Concept to Reality

[In conjunction with standard care of therapy]

Natarajan Ranganathan, Ph.D., (rangan@kibowbiotech.com)

Kibow Biotech, Inc. Newtown Square, PA 19073, USA.

Abstract:
Since the article published in the Journal of Nephrology and Therapeutics in 2015,
exponential advances have been made in probiotics, prebiotics, the gut microbiome,
dysbiosis, and recognition of the modulation of the gut microbiome and its impact on
disease. Many of these advancements have come in the form of diets, understanding
environmental factors, natural products, enzymes, drugs, GMO and non-GMO molecules,
genes, and microbes. Advancements in study methods such as metabolomics, proteomics,
metagenomics and related technologies have provided the tools needed to study
microbiome interactions with the host, the molecules these microbes synthesize, and the
composition of the microbes that make up the microbiome. These technologies can now
help us pinpoint which microbe produces a specific biomarker of interest. Without these
technological advances and the instrumentation they utilize, this would be nearly
impossible. As a result, scores of medical/scientific papers and several review articles have
recently been published in relevant medical and scientific journals. As such, this article is
primarily aimed in independently updating the recent scientific progress, understanding, and
knowledge gained on the emerging concept of “Enteric Dialysis®”. This concept is being
rapidly recognized and accepted as a potential pathway towards maintenance of good
health, facilitating the healing process and promising potentials to address several diseases.
This author will attempt his best efforts to provide his personal views and latest advances in
connecting the importance of the Gut Microbiome and dysbiosis resulting in inflammation
attributing to various disease states. This article is mainly designed to educate patients, and
healthcare professionals who may not be familiar with the subject matter described herein.
With the recent gains in research and knowledge, Enteric Dialysis® is transforming from a
concept to reality, and can potentially provide a promising future for those with Chronic
Kidney Disease (CKD) along with standard care of therapy.

Introduction:
Dr. Ranganathan and his colleague, Usha Vyas’ review article: “Probiotics, Prebiotics and
Synbiotic: Gut and Beyond” was published in Gastroenterology Research and Practice
Journal in 2012 [1]. Their 2012 article has inspired researchers in the field of the kidney and
gut microbiome and as a result modulating the gut microbiome to improve health and treat
disease has raced ahead of its time. There are hundreds of probiotic/prebiotic products and
various formulations commercially available in the form of foods, beverages and dietary
supplements. Probiotics and prebiotics are manufactured in c-GMP/US FDA approved
facilities either as medical foods or dietary supplements only. As of now, there exists no
probiotic manufacturing facility with a Drug Master File (DMF) documentation needed for
manufacturing these products as a drug product. Thus, no probiotic or prebiotic formulation
can be considered a drug. Over 76% Americans buy and consume one or more dietary

1
supplements on their own discretion. This is mainly because of the belief that in general,
dietary supplements are safe, inexpensive, and mostly efficacious for intended claims made.
They’re also conveniently sold over the counter at pharmacies and online. These products
are mainly targeted toward gut, immune and digestive health. It is also becoming more
apparent that with the availability of newer instrumentation and technology, and greater
understanding of the role of the gut microbiome and its modulation with various kinds of
natural, synthetic and biological actives towards various healthcare applications are rapidly
being accomplished both for veterinary and human uses. Several more review articles have
been published by host of scientific experts pertaining to the Gut-Brain and Gut-Kidney
connection. This book chapter is specifically intended on the role of uremia, uremic toxins,
and Gut Microbiome targeted to understanding the field of Chronic Kidney Disease
applications. In this aspect, several recent reviews related to Gut-kidney connection and, as
well as modulation of the Gut microbiome have been cited for added knowledge and
scientific progress made as of this writing.

Probiotics: They are defined by the Food and Agriculture Organization (FAO) and World
Health Organization (WHO) as “live microorganisms which when administered in adequate
amounts, confer a health benefit on the host” (2002) [2]. Probiotics are characterized and
named according to its Genus, Species and Strains. In addition, only those well
characterized and precisely defined strains possessing specific health benefits are classified
as Probiotics. Probiotics are quantified as Colony Forming Units (CFU, generally billions of
CFU/gm). In humans, the probiotics which are used for various applications need to be well
documented and proven to be safe for consumption. They need to have a “Generally
Regarded As Safe” status termed as ‘GRAS’ certified [3].

Probiotic bacteria have a large role to play in our health and well-being. They work by
different mechanisms in the body, depending on the strain of the bacteria leading to various
beneficial or therapeutic properties. (Figure 1). Many strains produce bacteriocins namely
lactacin and bisin which inhibit the growth of pathogenic bacteria [4, 5, 6]. Many strains
also modulate inflammation in the gut. They lower the levels of pro-inflammatory bio
markers like IL-1β, and C-reactive protein and also middle molecules like IL-6 and TNF-α
and up-regulate the levels of anti-inflammatory markers like IL-10 [7-11]. L. acidophilus
metabolizes uric acid and decreases production of dimethylamine, trimethylamine, TMAO
and nitrosamines. Secondly it also reduces small intestinal bacterial overgrowth (SIBO) in
renal failure patients [12, 13].

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Figure 1: Various beneficial properties of probiotic microorganisms

Not all probiotic bacteria give the same beneficial effects. Each species of probiotic bacteria
is further characterized by a strain number which imparts its unique property like a DNA
fingerprint.
As shown in figure 2, two different strains of Lactobacillus acidophilus when consumed give
different beneficial effects. Supplementation with L. acidophilus NCFM® tended to increase
the specific serum IgA [10]. The strain significantly reduced the incidence and duration of
fever, upper respiratory infection symptoms and antibiotic use compared to a placebo [14]
whereas Lactobacillus acidophilus LA-05®, which is a proprietary strain from Chr-Hansen has
the property to reduce constipation, diarrhea, lactose intolerance and side effects associated
with antibiotics [15-18]. Lactobacillus acidophilus LA-05® and Bifidobacterium lactis BB-12®
are generally used together.

The US Food and Drug Administration (FDA) has designated the strains LA-5® and NCFM®
as Generally Recognized As Safe (GRAS).This is a very important criteria to be looked into
when buying any probiotic containing products for human consumption.

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Figure 2: Comparison of two strains of L. Acidophilus. L. acidophilus NCFM® and
Lactobacillus acidophilus LA-05®

Lactobacillus acidophilus NCFM® Lactobacillus acidophilus (LA-5®)

https://www.optibacprobiotics.co.uk/live-cultures/probiotics-database/lactobacillus-
acidophilus-ncfm
https://www.chr-hansen.com/en/probiotic-supplements-and-infant-formula/cards/product-
cards/lactobacillus-acidophilus-la-5

A large number of probiotic products are available commercially as dietary supplements on

the market for various applications (Table 1) They now appear with increasing frequency in
various foods, beverages, supplements, and are readily utilized in alternative and
complementary medical practice strategies. Due to direct consumer advertising, the average
population has been convinced of the positive role that probiotics play in health and disease.
This has led to marketing and consumption of a number of probiotic supplements available
for purchase online or in pharmacies without their benefit being scientifically proven in a
rigorous clinical trial. Probiotic microbes are also predominantly found in fermented dairy
foods such as yogurt, kefir, cheese and other fermented foods.

Table 1: Commercially available probiotic products

Product Company/Manufacturer Use(Label Claims)

Align® Proctor & Gamble Digestive Health
(1 billion CFU)
1 probiotic strain
VSL#3® Sigma-Tau Pharmaceuticals Dietary management of IBS and
(112 billion CFU) Ulcerative Colitis
3 Bifidobacterium strains
4 Lactobacillus strains
1 Streptococcus strain
Colon Health® Phillips Digestive Health
(1.5 billion CFU)
1 Lactobacillus strain
2 Bifidobacterium strains

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RenadylTM Kibow Biotech, Inc. Promotes healthy kidney function for
(45 billion CFU) CKD patients
1 Streptococcus strain
1 Lactobacillus strain
1 Bifidobacterium strain
DelProTM Pure Research Products, LLC Immune System Health
(10 billion CFU)
3 Lactobacillus strains
2 Bifidobacterium strains

Ultimate Flora® ReNewLife Immune Health

(3 billion CFU)
1 Bacillus strain
3 Lactobacillus strains
2 Bifidobacterium strains
Culturelle® Kids Culturelle Gastrointestinal health
Packets (5 billion CFU)
1 probiotic strain

Florastor Kids Biocodex Digestive health and Intestinal flora

(5 billion CFU) balance
1 Saccharomyces strain

ProtectisTM Bio Gaia Good gut health or for temporary

(100 million CFU) stomach problems
1 Lactobacillus strain

Prebiotics: They are defined as “non-digestible, but fermentable, foods/ingredients that

allow specific changes, both in the composition and/or activity, in the gastrointestinal
microflora that confers benefits upon host well-being and health [19]”. Well known
examples of prebiotics include inulin, oligofructose, galacto-oligosaccharide, lactulose [20],
xylo-oligosaccharides [21] and Beta-glucans [22]. Commercially available fibers are all
mainly formulated for digestive health. Some of these are Benefiber, Metamucil and Citrucel
manufactured by large pharmaceutical companies.

Prebiotics stimulate the growth or activities of specific microbial genera and species in the
gut microbiota, in order to confer health benefits to the host. In general, prebiotics favor the
growth of bifidobacteria and lactobacilli over potentially harmful proteolytic and putrefactive
bacteria. All currently known prebiotics are carbohydrates, and there are many different
carbohydrates marketed world-wide as prebiotics. Dietary fibers contain prebiotics and
consumption of dietary fiber has been shown to be beneficial [23, 24]. Commercially
available prebiotics are manufactured from various plant sources and have been shown to
impart various health benefits. Some of the prebiotics available on the market are shown in
table 2.

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Table 2: Commercially available Prebiotics

Prebiotic Structure Source

Inulin Chicory, wheat, onion,
bananas, garlic,
asparagus, Jerusalem
artichoke.

β(1,3)(1,6)-glucans Mushrooms, Yeast cell

walls

Arabinogalactan Larch wood, gum Arabic

Xylo-oligosaccharide Bamboo shoots, fruits,

vegetables, milk, and
honey

β(1,3)(1,4)-glucans Oats, Barley

Galactooligosaccharide Lactose

Fructooligosaccharide Jerusalem artichoke,

chicory, Blue Agave
garlic, asparagus, jícama,
and leeks

Table 3: Fiber supplements available in the US market

Product Company/Manufacturer Use (Label Claims)

Metamucil® P&G Digestive Health

2 Prebiotics

Benefiber® GSK Digestive Health

1 Prebiotic
Mirafiber® Bayer Digestive Health
1 Prebiotic

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 Citrucel® GSK Digestive Health
1 Prebiotic
Kibow FortisTM Kibow Biotech, Inc. Digestive health, Immune
5 Prebiotics Health, Flora maintenance
Prebiotics XOS + Jarrow Formulas Supports intestinal and immune
GOS 2 Prebiotics function
Alive! ® – Liquid Nature’s Way Digestive health
Fiber with Prebiotic
1 Prebiotic
Prebiotic Hyperbiotics® Supports healthy digestion,
4 Prebiotics weight loss and metabolism
Prebiotic Fiber BeLive® Digestive Health
Gummies 1 Prebiotic
Nexabiotic® DrFormulas Supports bowel motility
1 Prebiotic

Synbiotics: The combination of probiotics and prebiotics is generally known as synbiotics.

Many products are available on the market which contains both of these (Table 4).

Table 4: Synbiotic products on the market

Product Company/Manufacturer Use (label Claims)

Probiolicious Probiotic Rainbow Light Digestive Health

GummiesTM (1 billion CFU)
4 Prebiotics
1 Probiotic
Primadophilus® Nature’s Way Digestive Health
Children (3 billion CFU)
1 Prebiotic
7 Probiotics
Probiotics with ChildLife The probiotic blend is for intestinal
Colostrum® (4 billion CFU) health, the colostrum is for immune
1 Prebiotic support, and the prebiotics support
3 Probiotics good bacterial growth for healthy
digestion and immune function
FloraTummys® FloraTummys Supports immune health, restore
Probiotic Sprinkles (5 billion CFU) friendly bacteria, and reduce
Kids 1 Prebiotic diarrhea, constipation and gas
2 Probiotics
Pro-Kids® Hyperbiotics Immune System Health
(3 billion CFU)
1 Prebiotic
4 Probiotics
Little Ones® LoveBug Digestive Health
(3 billion CFU)
1 Prebiotic
5 Probiotics

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Berry-licious Fruit GoLive Gut health
Punch® (15 billion CFU)
6 Prebiotics
15 Probiotics
Just For Kids® SunBiotics Digestive Health
(5 billion CFU)
5 Prebiotics
5 Probiotics

The expansion of our awareness and use of probiotics, however, has raced ahead of the
scientific basis for the mechanisms by which they impact health. Probiotics are increasingly
utilized in clinical settings for various health applications [25]. In kidney failure, there are
multiple factors associated; the role of digestive [26] and immune systems [27], as well as
inflammatory [28] and oxidative stress [29, 30] functions in the progression of kidney
disease have been emphasized 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 [31].

Human Microbiome: The Human Microbiome Project by the NIH in US and the MetaHIT
project in Europe showed that we have diverse groups of microbes in and on our body
systems [32]. The Human Microbiome Project (HMP) is a United States National
Institutes of Health (NIH) initiative with the goal of identifying and characterizing
the microorganisms, which are found in association with both healthy and diseased humans
(the human microbiome) using tools such as metagenomics (which provides a broad genetic
perspective on a single microbial community), as well as extensive whole genome
sequencing. The microbiology of five body sites was studied: oral, skin, vaginal, gut,
and nasal/lung. Tools for deep sequencing of bacterial 16S rRNA sequences amplified
by polymerase chain reaction from human subjects were used. HMP researchers reported
that this plethora of microbes contribute more genes responsible for human survival than
humans contribute. Where the human genome carries some 23,000 protein-coding genes,
researchers estimated that the human microbiome contributes some 8 million unique
protein-coding genes or 360 times more bacterial genes than human genes. The Human
Microbiome Consortium published findings showing that even within healthy individuals that
is a lot of diversity [33].

Gut Microbiome: During coevolution with microbes, the human intestinal tract has been
colonized by thousands of bacterial species [34, 35]. Gut-borne microbes outnumber the
human body cells by a factor of ten – i.e. =>100 trillion versus 10 trillion [36]. Recent
metagenomics analysis of human Gut microbiota has revealed the presence of 3.3 million
genes, compared to a mere 23,000 known human genes [37-39] (Figure 3). Microbial
communities perform the majority of biochemical activities on the planet and play integral
roles in human metabolism and immune homeostasis in human physiology and function
[40]. Evidence for various beneficial roles of the intestinal microbiota and, concomitantly,
probiotic microbes in human health and disease have been expanding rapidly in recent
years [41-45]. Beneficial impacts have been noted for gastrointestinal disorders, functional
bowel disorders, inflammatory bowel disease and ulcerative colitis, diarrhea, cardiovascular
disorders, cancer, hepatic function, metabolic conditions including obesity/diabetes, lipid
metabolism, neuropsychiatric disorders (depression and anxiety), chronic fatigue syndrome,
autism, psychoneuroimmunity, and neurodermatology, immune function (incl.
immunomodulation/ inflammation), allergies and, autoimmune disorders[46](Figure 4). In
Chronic Kidney Disease the gut microbiome has been shown to be altered [47-50].

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Figure 3: Comparison of the Human Genome and Gut Microbiome

Figure 4: Diseases influenced by gut microbiota

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Gut Dysbiosis, Leaky Gut Syndrome, Small Bowel Bacterial Overgrowth
(SBBO) or Small Bowel Intestinal Over (SIBO) growth:

With the recent research and knowledge gained from it, Enteric Dialysis® is transforming
from a concept to reality, and can potentially provide a promising future for those with
Chronic Kidney Disease (CKD) with standard care of therapy.

Due to the expanded understanding of the complexity of the gut microbiome, it is evident
that CKD patients have a distinctly altered microbiome composition [47]. This altered
composition is commonly known as dysbiosis. Dysbiosis can be explained as an imbalance
of beneficial and pathogenic microbes. An individual with dysbiosis will have higher
quantities of pathogenic microbes and lower quantities of beneficial microbes. Dysbiosis will
cause impairment in the epithelial barrier, and structure and function of epithelial tight
junctions. This is commonly known as “leaky gut syndrome” and is related to almost all gut
diseases [27]. CKD causes dysbiosis; the pathogenic bacteria convert urea into ammonia,
and generate several other toxins. This disrupts enterocyte tight junctions, resulting in
translocation of bacteria and toxins into circulation [48-50]. Once in circulation, the bacteria
and toxins cause systemic chronic inflammation. Small Bowel Bacterial Overgrowth (SBBO)
is a condition describing the growth of large numbers of bacteria in the small intestine [51,
52]. Dr. Simenhoff and his fellow researchers were the first to report SBBO in dialysis
patients [13]. Dr. Simenhoff attributed SBBO to increased toxicity due to the production of
various amines like methylamine, dimethylamine, N, N-nitrosoamine, trimethyl amine, and
trimethylamine-oxide. The researchers also showed that biomodulation of the toxic and
nutritional effects of small bowel bacterial overgrowth in end-stage kidney disease using
freeze-dried Lactobacillus acidophilus [12].

A study published in 2004, showed that SBBO is also a common cause of chronic diarrhea
[53]. Already established common causes of chronic diarrhea include inflammatory bowel
disease, irritable bowel disease, celiac disease, giardiasis and idiopathic secretory diarrhea.
In this study involving 87 subjects, the cause of chronic diarrhea SBBO was found in 48% of
those with chronic diarrhea.

While the large intestine typically harbors a high number of bacteria, the small intestine
does not. Too many bacteria living in the small intestine (SBBO) will metabolize nutrients
that would otherwise be utilized by the host. The breakdown of these nutrients in the small
intestine can also damage the intestinal lining making it more difficult for the host to absorb
nutrients. This can result in malnutrition, loss of body mass, increased
inflammation/oxidative stress and ultimately resulting in poor quality of life among CKD
patients.

There are two tests commonly used to diagnose SIBO, one is to perform anaerobic and
aerobic colony counts of small intestine luminal contents [54]. The other test is a breath
test, which measures small bowel bacterial contamination indirectly [55]. The breath tests
are more popular and rely on the recovery and quantification of gas produced by bacteria
living in the small bowel. Subjects will ingest substrate, and the gas produced by the
breakdown of said substrate by bacteria (which is exhaled) is analyzed via gas
chromatography to measure exhaled hydrogen and/or methane [56-58]. While the breath
test is easy to perform it is difficult to interpret, lactulose or glucose hydrogen breath tests
are the most common. Proof of SIBO is said to be found when hydrogen concentrations are
greater than 10 parts per million after a 50 gram glucose load [59].

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Chronic Kidney Disease: General awareness of the rising global prevalence of kidney
disease has been steadily growing among medical and public health professionals [60-62].
Kidney disease is the eighth leading cause of death in the U.S. [63], with approximately
600,000 patients in end-stage renal disease (ESRD, most receiving dialysis) and over 26
million in earlier stages of chronic kidney disease (CKD) [64]. As the population continues to
age and the epidemiological shift from acute infectious to chronic metabolic diseases
progresses, contributing factors to kidney disease (obesity, diabetes, and hypertension)
become epidemic. Kidney disease may turn into a major health crisis in the USA and
globally. Existing worldwide statistical data on the incidence and prevalence of kidney
disease and kidney failure, the resulting mortality, the high cost of treatment, and
associated socioeconomic and political consequences present a compelling and urgent need
for an effective, easy to use and affordable alternative adjunct treatment modality to be
available to the global kidney patient population. A latest research by the George Institute
for Health published in the Lancet [65] shows that every year over two million people
globally die as they do not have access to treatment for kidney failure (dialysis or
transplantation). Despite ongoing R&D drug developments by several pharma/biotech firms,
the use of dietary supplements is also a promising and inexpensive approach and should be
included in any strategy to reduce the likelihood of such epidemic CKD crisis.

The Uremic syndrome: It is said to consist of nitrogenous waste retention, deficiency in

kidney derived hormones such as erythropoietin and vitamin D (anemia and renal
osteodystrophy) and the enzyme renin, and reduced acid excretion with acidosis. Untreated
uremia may progress to coma and eventual death. Toxicity due to the accumulation of
various uremic toxins (recent findings and literature reports to include Indoxyl Sulfate and
para-Cresyl Sulfate, in particular) is a concern for CKD and ESRD patient populations.
Concentrations of uremic solutes have been shown to increase as the disease progresses
from CKD to ESRD [66, 67]. The European Toxin workgroup (EUTOX) has classified many
uremic toxins based on their molecular weights and their protein binding property [68].
Though urea is generally nontoxic, it can degrade to the highly toxic cyanate, which, in turn,
binds to proteins by carbamylation, including serum albumin, and modifies them. Recent
studies by Berg et al. [69] have shown that carbamylated serum albumin is a risk factor for
mortality in patients with kidney failure. As early as 1998, it was shown that CKD patients
are at a higher risk of cardiovascular problems. The renal axis has a role to play in the blood
pressure [70]. Death due to cardiovascular disease is higher by 10 to 20 times in these
patients as compared with the general population [71]. Increased levels of uremic toxins
also cause dysregulation of the Gut Microbiome (Dysbiosis) which in turn promotes
inflammation and oxidative stress. This further accelerates the progression of CKD
symptoms including progressive decline of the GFR to End Stage Renal Disease requiring
dialysis. Therefore, some believe it to be necessary to reduce the levels of urea in chronic
renal failure patients by medication or other interventions and strategies, such as a
probiotic therapy (some representatives of the lactic acid bacteria population have the
capacity to metabolize urea). Probiotics and prebiotics have for centuries been reported to
enhance intestinal health [72]. Scientific proof has now been obtained that confirms their
positive effects on human health in general [73]. Recently, the application of
probiotics/prebiotics in various diseases has intensified, as understanding of how the gut
microbiota shapes human health and how their composition changes significantly in any
disease conditions and, more so, in CKD progression [74-78] (Figure 5).

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Figure 5: Gut microbiota in normal and CKD population

The Gut Kidney Axis:

As mentioned earlier, the dysbiosis seen in CKD patients has been known for several
decades as well as its role in metabolic disturbances in CKD. CKD stages III-V (ESRD) are
complicated further by alterations in bowel microbes throughout the gastrointestinal tract.
Advancing CKD brings advanced dysbiosis in the gut thus leading to higher concentrations
of urea, uric acid, oxalate, creatinine and other toxins. Some of these “other toxins” are
produced by pathogenic bacteria residing in the gut, which results in disruption of the
epithelial lining and systemic inflammation. In addition to causing several physiological
issues, these other toxins promote the growth of more harmful bacteria, accelerating the
dysbiosis. Short Chain Fatty Acids (SCFAs) are important molecules for humans as they help
to regulate inflammation and the immune system. When a state of dysbiosis is achieved,
lower levels of SCFAs are produced, thus helping to facilitate a chronic state of inflammation
and decrease immune system function. As a result of dysbiosis, restrictive diets and
medication, people with CKD suffer from GI conditions frequently [47, 79, 80]. In an effort
to combat dysbiosis, Dr. Ranganathan and his research team have developed a
probiotic/prebiotic formulation known as Renadyl™. Renadyl™ has undergone a
pharmaceutical like validation in in vitro models, animal models (rats, mini-pigs, cats, and
dogs) [81-84], and three clinical trials in humans (CKD III and IV, and Dialysis patients).
These studies have shown that Renadyl is able to metabolize and remove uremic toxins [85-
90] in patients with various stages of CKD. While microbiome composition studies have not
been completed in human models, three customer surveys have been carried out so far.
Improved quality of life has been seen in customers using Renadyl (figure 6) [91, 92] and,
in the most recent survey given to Renadyl users, 88% of survey respondents indicated that
Renadyl had improved their overall quality of life [93].

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Figure 6: Quality of life in customers using Renadyl

Treatment modalities for CKD:

In CKD patients there are profound changes in the colonic structure and function resulting in
abnormal generation and absorption of toxins, dysbiosis, impaired epithelial disarray and as
well SBBO. Generally most of these patients are treated with one or more distinct drug
therapies such as antibiotics, EPO, Vit D, ACE drugs or ARB inhibitors, K or P binders,
diuretics etc., to address the corresponding symptoms. Dietary changes are also
recommended. A supplement called ketoacids is one of the dietary supplements
recommended. These supplements provide protein without overloading the diseased kidneys
with too much phosphorus or urea that would come from foods. However, in the United
States, these supplements are expensive and not routinely covered by insurance
companies. Likewise it is also quite expensive for CKD patients who have little or no
financial resources worldwide. Another treatment to remove uremic toxins is by using an
adsorbent called kremezin or AST-120. Oral charcoal sorbents like AST-120 (9 gm/day,
about USD$270/ month supply), manufactured by Kureha Chemical Industry Co. Ltd. and
marketed as a drug under the brand name Kremezin is being used mainly in Japan and has
been reported to have mixed clinical findings in other countries. AST-120 has little affinity
for urea but does bind with uric acid, creatinine, indole and phenol metabolites. In addition,
it also possesses the negative impact in binding to several of the drugs that most of the
CKD patients consume every day. AST-120 is a specially coated charcoal and possesses
similar properties of activated charcoal in binding characteristics to scores of aromatics,
steroidal and heterocyclic compounds. Table 5 shows a comparison of both treatment
modalities and pro/prebiotics.

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Table 5: Comparison of different treatments for reduction of uremic toxins

Concept of “Enteric Dialysis® - Addressing the causes and not the symptoms:

The kidney/s is a single organ system possessing three distinct functions. These are:
secretory (hormonal), regulatory (homeostasis) and excretory (urinary elimination). The
currently existing drug interventions address only the individual deficiencies on the
pathophysiology and biochemical functions of the kidney. These three functions are in a
dynamic equilibrium in any healthy individual, and so is the Gut Microbiome with trillions of
microbes.

Using Probiotics and Prebiotics: Probiotics, prebiotics and their combination termed as
synbiotics could also play a role in reducing the generation and elimination of uremic toxins,
more so in conjunction with standard care of therapy according to individual CKD patient,
nutritional needs and disease conditions.The modulation of the intestinal microbiota
composition with the use of probiotics/prebiotics could potentially minimize the deleterious
effects of its imbalance, thereby improving the health of the gastrointestinal tract,
strengthening the immune system, restoring the bioavailability of micronutrients, exerting
anti diabetic actions, improving dyslipidemia and allergic disorders, and reducing the risk of
other health problems. The mechanism by which probiotics exert their favorable effects
seems due to direct utilization of several uremic toxins as its nutrients for the gut microbial
growth with its inherent capabilities of multiplying and doubling every 20 to 25 minutes.
The increased growth of these gut microbes are then eliminated by the natural defecation
process which has been referred to as “Enteric Dialysis” in this chapter. In addition, the
probiotics change the intestinal pH, inhibits the growth of pathogens (through the
production of antibacterial compounds, competitive exclusion of pathogens in receptor
binding sites and competition for available nutrients), and suppression of mutagenic and
carcinogenic processes and ultimately affords protection of the intestinal/gut barrier.
Despite several reported observational or pilot scale/small scale studies, quality intervention
trials investigating this novel treatment in CKD are still lacking for its full clinical validation.
Hence, a well-designed RCT protocol with the power needed for subject enrollment and
statistical significance changes in defined primary or secondary end points are needed. The
published studies and, as well the proposed “SYNERGY” [94] clinical trials are aimed to
assess the effectiveness of synbiotics (co-administration of pre- and probiotics) as a
potential treatment targeting the synthesis of uremic toxins, specifically, indoxyl sulfate (IS)

14
and p-cresol sulfate (PCS). These and other biomarkers evaluated like doubling of the
serum creatinine has been re-evaluated and being proposed with the general acceptance of
GFR decline as an end point for clinical trials in CKD. The earlier end point “doubling of
serum creatinine” is a late event in several CKD patients and also subject to several of the
aforementioned variable subject matters discussed. It is also subject to enrolled patients
primary disease status, diet, life style and several other factors including genetic makeup
and dysbiosis of the gut Microbiome. This also requires a long time of follow-up and large
sample size in clinical trials. Thus, there is a great interest in alternative GFR-based end
point to shorten the duration of clinical trials, reduce sample size, and extend their conduct
to patients with earlier stages of CKD.

Possible pathways or mechanism of “Enteric Dialysis®”

The probiotic strains in Renadyl work in the gut by three distinct mechanisms
(Figure 7):

1. All three strains in Renadyl produce bacteriocins namely lactacin and bisin which
inhibit the growth of pathogenic bacteria [4-6]. This, in turn, leads to reduced
generation of gut related uremic toxins. Secondly, it also reduces small intestinal
bacterial overgrowth (SIBO) in renal failure patients [12, 13].
2. The three strains metabolize various uremic toxins thus reducing the burden on the
failing kidneys. S thermophilus metabolizes urea, uric acid and creatinine. L
acidophilus metabolizes uric acid and also decreases production of dimethylamine,
trimethylamine, TMAO and nitrosamines. B longum metabolizes creatinine and
reduces levels of protein bound uremic toxins like phenols and cresols [87-89].
3. These strains also modulate inflammation in the gut. They lower the levels of pro-
inflammatory bio markers like IL-1β, and C-reactive protein and also IL-6 and TNF-α
and up regulate the levels of anti-inflammatory markers like IL-10 [7-11].

Figure 7: Possible pathways for Renadyl’s action

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Drug like validation of a dietary supplement:
Probiotics and Prebiotics are widely used for digestive and immune health. Renadyl™; a
Pro/Prebiotic dietary supplement has demonstrated its potential to reduce serum uremic
toxins in a drug like validation with in vitro (Lab and SHIME), animal studies (5/6th
nephrectomized rats, minipigs, cats and dogs) [81-84] and human clinical trials [85-90].

Routine Dialysis Versus the concept of “Enteric Dialysis”: Previous research has
suggested that longer dialysis sessions can provide benefits without increasing the risks of
complications [95-97]. However, some nephrology professionals find this view highly
debatable. (http://kidney.niddk.nih.gov/about/ResearchUpdates/ KidneyWin13/1.aspx). The
controversy centers on the invasive nature of hemo/peritoneal dialysis that has significant
potential for causing greater infections and higher mortality, particularly when sessions are
frequent. However, the use of a well-researched, clinically documented and safe
probiotic/prebiotic dietary supplement formulation has the potential to safely perform
continuous 24/7 uremic toxin removal and stabilize the gut Microbiome and its dysbiosis.
Table 6 and figure 8 show the advantages of Enteric Dialysis with standard care of therapy.

Table 6: Benefits of Enteric Dialysis over hemo and peritoneal dialysis:

Dialysis Type
Parameters
Peritoneal Hemo Enteric

Surgical procedure needed Y Y N

Invasive Catheter AV fistula N

Chances of Infection Y Y N

Dietary restrictions Y Y N

Quality of Life Poor Poor Improved

Figure 8: Benefits on adding Renadyl™ with standard care of therapy in Pre-dialysis and
Dialysis patients.

16
New end points proposed for CKD clinical trials [US FDA/NKF]:

Enteric Dialysis is safe and well tolerated. It is non-invasive and less expensive. Hemo/
Peritoneal Dialysis are unable to reduce protein bound uremic toxins like indoles and cresols
and other middle molecules. It is painful and associated with poor quality of life (yo-yo
effect) and blood associated infections like Hepatitis C. Imbalanced gut microflora is not
restored and gut associated uremic toxins are produced. Renadyl™ on the other hand, by
removing uremic toxins, reducing levels of protein bound uremic toxins, production of
bacteriocins to restore gut imbalance and reducing inflammation, provides benefit to
patients in all stages of pre dialysis and dialysis and with a variety of comorbid conditions. It
appears to have a stabilizing effect on the overall health status and improved quality of life
(QoL).

We also conducted three biennial customer surveys (2013, 2015 and 2017). The results of
the first two surveys have been published [91, 92]. However due to HIPPA regulations we
were unable to get the detailed medical records. In the recent 2017 survey, the customers
voluntarily provided us with their eGFR before and after taking Renadyl. The data was
analyzed independently by Prof Alan Weinberg at the Mount Sinai Health System in NY
(http://www.mountsinai.org/profiles/alan-d-weinberg). Results show an increase of 3.5
mL/min/1.73m² which translates to an 11.6% improvement in GFR. [93]. The summary of
this recent survey is shown in figure 9.

“The US Food and Drug Administration currently accept halving of glomerular filtration rate
(GFR), assessed as doubling of serum creatinine level, as a surrogate end point for the
development of kidney failure in clinical trials of kidney disease progression. A doubling of
serum creatinine level generally is a late event in Chronic Kidney Disease (CKD); thus, there
is great interest in considering alternative end points for clinical trials to shorten their
duration, reduce sample size, and extend their conduct to patients with earlier stages of
CKD. However, the relationship between lesser declines in GFR and the subsequent
development of kidney failure has not been well characterized. The National Kidney
Foundation and Food and Drug Administration sponsored a scientific workshop to critically
examine available data to determine whether alternative GFR-based end points have
sufficiently strong relationships with important clinical outcomes of CKD to be used in
clinical trials. Based on a series of meta-analyses of cohorts and clinical trials and
simulations of trial designs and analytic methods, the workshop concluded that “a confirmed
decline in estimated GFR of 30% over 2 to 3 years may be an acceptable surrogate end
point in some circumstances, but the pattern of treatment effects on GFR must be
examined, specifically acute effects on estimated GFR. An estimated GFR decline of 40%
may be more broadly acceptable than a 30% decline across a wider range of baseline GFRs
and patterns of treatment effects on GFR. However, there are other circumstances in which
these end points could lead to a reduction in statistical power or erroneous conclusions
regarding benefits or harms of interventions. We encourage careful consideration of these
alternative end points in the design of future clinical trials” [98].

17
Figure 9: Effect of Renadyl compared to Normal Progression and Preferred NKF/FDA
Endpoint

Summary and Conclusions:

A marker of dialysis adequacy in the eighties of last century, Kt/V (urea) helped to improve
dialysis efficiency and to standardize the procedure. However, in 2015 Vanholder [99] based
on various clinical studies and modifications of dialysis concluded that Kt/V (urea) is too
simple a concept for the complexities of uremia and today’s dialysis. However, clinical
research after 2015 showed that urea had an important role to play in diabetes [100] and a
study at the Albert Einstein College of Medicine NY showed that elevated serum levels of
BUN was associated with an increased burden of coronary artery disease on cardiac
catheterization [101]. This led back to the importance of urea in renal failure with a
publication again by Vanholder in 2017 [102] titled “Urea and chronic kidney disease: the
comeback of the century? (in uraemia research)”. Therefore, the use of a well-researched,
clinically documented and safe probiotic/prebiotic dietary supplement formulation has the
potential to safely perform continuous 24/7 uremic toxin removal and stabilize the gut
Microbiome and its dysbiosis. Hence, the concept of “Enteric Dialysis” with continuous
removal of uremic toxins may be the key to reducing the GFR by at least 30 to 40%
assuming that standard patient care and therapeutic regiments are maintained. Several
additional multi-site clinical trials are needed to document US FDA’s recently accepted 30%
to 40% reduction in GFR and to document the delayed progression of CKD in various
randomized clinical trial (RCT) interventional studies. In summary, probiotics and prebiotics
offer safe, inexpensive, convenient adjunctive therapy for the care of CKD patients
worldwide. By modulating the gut Microbiome, probiotics and prebiotics also possess an
attractive potential to reduce inflammation with the ultimate outcome of an improved
quality of life for CKD patients worldwide.

Acknowledgements: The author wishes to express his deep appreciation and sincere
thanks to all his R&D colleagues – Usha Vyas, Anthony Irvin, Kevin Hanlon, Pari
Ranganathan and Dr. Daniel Lawson who have helped and guided in formatting, editing this
article.

18
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