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Renal Nutrition Forum
A Peer Reviewed Publication of the Renal Dietitians Dietetic Practice Group
Volume 33 • Number 1
In This Issue
1
Feature Article
2
Letter from the Editor
8
Advances in Practice
12
MNT Update
15
Transplant Update
20
Awards and Scholarships
21
App Review
22
Website Extras
24
Recently Published
25
Calendar of Events
26
RPG Chair Message
27
RPG Executive Committee
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The Relationship Between Gut
Microbiota and CKD: Why Use
Prebiotics in CKD Patients?
Lindsey Zirker, RD, CSR, LD
Consultant Dietitian
Idaho Kidney Center
Idaho Falls, ID
Email: [email protected]
This article has been approved for 1.0 CPE
unit. The online CPEU quiz and certificate of
completion can be accessed in the Members
Only section of the RPG website via the My
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expiration date is January 15, 2015.
Abstract
Intestinal integrity and gut microbiota play
a significant role in immunity and in digestion
of carbohydrates and protein. Chronic kidney
disease (CKD) progression and current
treatment modalities disrupt normal intestinal
microbiota, cause increased production of
organic solutes, and are associated with
bacterial translocation and inflammation.
These may play a role in the poor outcomes
currently observed in CKD. As dietitians
better understand this important relationship,
therapeutic recommendations such as pro- and
prebiotics may help to restore balance to the gut
and improve outcomes for those with CKD.
Introduction
Dialysis patients present an interesting
challenge for renal dietitians. Each patient
is unique and requires specific nutritional
recommendations to provide optimal care.
Despite the differences however, one challenge
ties them all together: improving albumin
levels. It is known that multiple variables
contribute to low albumin: inflammation,
(CKD, diabetes or other chronic disease,
infection, recent surgeries, inadequate
dialysis and the hemodialysis process itself
are pro-inflammatory), low protein intake
or assimilation, protein wasted during
peritoneal and hemodialysis, acidosis, and
blood loss. Although dietitians educate,
order supplements, provide meal plans, and
re-educate, nutritional status may remain
compromised. Perhaps it is because for
many patients there is a major source of
inflammation that is largely overlooked: the
gut.
It is widely known and accepted that the gut
is a source of uremic toxins, which contribute
to increased inflammation and cardiovascular
disease- two major reasons for high mortality
rates among CKD patients (1,2). Yet, most
of the research and treatment for CKD
focuses on managing other symptoms and
does not consider the effect these symptoms
and treatments have on the microbiota, the
microbes present in the intestine. Outcomes
for CKD may be improved by examining the
relationship between CKD and microbiota
in the gut, and then implementing therapy to
restore the symbiotic relationship.
The Symbiotic Relationship
The intestine is home to billions of
microbes, with 400 to 500 different types of
bacteria that account for 40 to 60% of the
contents of the intestine. There is a symbiotic
relationship between the body and the bacteria
in the gut (3). Intestinal microbiota play a
role in immunity, digestion of carbohydrates
– Continued on page 3.
Renal Nutrition Forum 2014 • Vol. 33 • No. 1
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Feature Article...
and protein, and micronutrient homeostasis by metabolism of
carbohydrates and amino acids (4).
Intestinal Role in Immunity
About 80% of the body’s immune system is connected to the
intestines (5). This indicates that numerous mechanisms, such as the
protective effects of probiotics and the intestinal wall barrier help or
harm the immune system.
Beneficial bacteria help to prevent bacterial translocation, when
bacteria cross the intestinal barrier and gain entry to the blood stream.
They compete with pathogenic microbes for growth and keep them
in small enough numbers to be harmless. However, pathogenic
microbiota may cause illness, inflammation and strain on the immune
system if they are left unchecked (6).
In addition to beneficial bacteria in the intestine, the body has
a mechanical barrier- a thin epithelial layer that prevents bacteria
translocation. This barrier’s protective effect is accomplished in
part by a mucus layer and antimicrobial proteins. The proteins act
as a type of armor to prevent actual contact between the epithelial
layer and the microbiota (7). The highly controlled transport systems
within the intestinal wall also play a protective role (4,8).
Microbiota in Carbohydrate and Protein Metabolism
Anaerobic bacteria in the gut help the body to further digest
carbohydrates and protein through a process called fermentation.
Saccharolytic bacteria ferment carbohydrates and produce hydrogen,
methane, and short-chain fatty acids such as butyrate, propionate,
and acetate. These end-products are beneficial to the individual. For
example, butyrate is a source of energy for the epithelium in the
colon (1,3).
Proteolytic bacteria metabolize protein in the gut when proteases
and peptidases hydrolyze polypeptide chains to create small peptides
and amino acids. The proteolytic bacteria in the colon ferment the
amino acids. This process creates end-products, like short and
branched chained fatty acids as well as ammonia, phenols, indoles,
and amines. Some of these end-products are toxic, necessitating
removal from the body via the intestines or the kidney (1,3).
Pathology of Dysbiosis in CKD
It is common that those with chronic disease have abnormal
microbiota when compared to healthy individuals (1). Diet and
impaired protein absorption, increased intestinal transit time,
medications, and uremia may all contribute to unfavorable changes in
microbiota.
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Renal Diet and Protein Absorption
Dietitians are well acquainted with the limitations of the renal
diet. Potassium restriction often limits fruit, vegetable and whole
grain intake, which in turn reduces dietary fiber present in the
intestine and may play a role in altering microbiota (3,4).
Protein malnutrition is common and associated with increased
morbidity and mortality among CKD patients. In an observational
study that evaluated protein assimilation, it was found that those
with CKD had impaired assimilation compared to those without
CKD (9). The high protein diet, if on dialysis, and impaired protein
digestion and absorption increases protein availability in the gut.
This favors proteolytic bacterial activity and increases uremic
organic solute production (1). Malnutrition also reduces intestinal
cell replication which may lead to breakdown of the intestinal wall
and promote bacterial translocation (8).
Increased Transit Time
Constipation is common among dialysis patients. Constipation
is reported for more than half of patients on hemodialysis, 63%,
and about 29% of patients on peritoneal dialysis, compared to
only 10 to 20% of healthy individuals (3). This is likely related to
decreased fiber and fluid intake, but may also be related to a more
sedentary lifestyle, use of phosphate binders, and primary disease
states such as diabetes which can lead to gastroparesis. Increased
transit time leads to increased amounts of proteolytic bacteria
traveling upstream in the intestines, decreasing saccharolytic
bacteria activity as well as increasing time for bacteria metabolism
and intestinal absorption of organic solutes (3).
Medications
Antibiotic use is common among those with CKD. In 2007,
41% of dialysis patients were prescribed an antibiotic (10).
Unfortunately, probiotics are easily killed by antibiotics, while
more pathogenic strains seem to become resistant. Often,
pathogenic bacteria that are left to grow freely will remain at
higher than normal levels even though the competing bacteria are
once again present. Although the individual may be reintroduced
to the bacteria that were destroyed, the levels will not return to
normal (6).
Uremia
Uremia is a multifaceted aspect of CKD. Although the exact
mechanisms are unclear at this time, it seems that organic solutes
contribute to the breakdown of the intestinal wall barrier and
bacterial translocation (7).
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Organic solutes provide significant insight into the glomerular
filtration rate (GFR). As GFR declines, organic solutes in the
blood will rise, namely creatinine and urea (11). When this
occurs, passive diffusion and other glandular secretions transport
urea into the intestine in an effort to reduce the levels in the
blood stream. Bacteria in the intestine hydrolyze urea via urease
and form ammonia. This leads to an acidic (decreased) intestinal
pH and inflammation in the intestine known as uremic
enterocolitis (4).
Protein-bound Uremic Solutes
Organic solutes are typically classified by their molecular
weight (MW) and ability to bind to protein. There are three
basic categories: small MW and water soluble compounds,
protein bound compounds, and larger MW compounds or
“middle molecules” (12). Dialysis (peritoneal and hemodialysis)
is able to filter out many of these organic compounds, but
appears to be particularly ineffective at removing protein-bound
organic solutes. Two organic solutes in particular are p-cresyl
sulfate (PCS) and indoxyl sulfate (IS). PCS is metabolized
by anaerobic bacteria in the gut. Tyrosine and phenylalanine
are metabolized to 4-hydroxyphenylacetic acid and then
decarboxylated to p-cresyl, which is then metabolized to PCS by
cystolic sulfotransferase (12). IS is also produced by bacterial
metabolism in the gut. Protein that has been broken down to
tryptophan is metabolized in the intestine by bacteria to indole.
It is then absorbed and transported to the liver where it is
converted to IS (12).
Many studies have shown that these two protein-bound
organic solutes contribute significantly to renal and vascular
toxicity (12). In the kidney, IS increases expression of
inflammatory markers such as transforming growth factor beta
1 (TGF 1) and decreases superoxide scavenging activity. This
leaves the kidney vulnerable to free radical activity and speeds
the progression of kidney failure and complications (13).
Inflammation and free radical activity are not limited to
the kidney. IS and PCS may also contribute to cardiovascular
disease (CVD). In the case with IS, endothelial cell repair
is reduced by production of oxidative stress and promotes
atherosclerosis. IS levels have also been positively correlated
with aortic calcification and vascular stiffness (12). These
factors significantly contribute to poor cardiovascular health. In
addition, Mejiers et al showed a positive correlation between
PCS and increased cardiovascular events independent of GFR
and other studies have shown a strong relationship between PCS
levels and CVD (12,14).
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Probiotic and Prebiotic Therapy
Clearly, there is a an opportunity to support intestinal health and
improve outcomes for CKD patients. One of the major therapies
being investigated is supplementation of probiotics. The World Health
Organization defines probiotics as “live microorganisms, which, when
administered in adequate amounts, confer a health benefit on the host” (15).
Probiotics can be found in dietary supplements, fermented dairy
foods, as well as in fermented soy and vegetable products and some
juices. When ingested, the probiotics enter into the intestine and
begin to replenish the friendly bacterial environment. The current
body of evidence support probiotics uses independent of CKD for
constipation; diarrhea (travelers, antibiotic associated and infectious);
vaginal, respiratory, stomach and skin infections; periodontal disease;
inflammatory bowel disease and irritable bowel disease (15).
Prebiotics are defined as “a nondigestible food ingredients that
beneficially affect the host by selectively stimulating the growth and/
or activity of one or a limited number of bacteria in the colon, and
thus improve host health” (16). There are several substances that may
leave the small intestine undigested, but only certain ones are also
able to promote saccharolytic bacterial growth: inulin, oligofructose,
galactos-oligosaccharides, high molecular weight inulin, and
fructooligosaccharides (FOS) (16).
Probiotic and Prebiotic Therapy in CKD
Probiotics and prebiotics present several possibilities for improving
outcomes in CKD patients. Based on current knowledge, probiotic
supplementation may alter the microbiota in the gut and will likely
increase saccharolytic activity and promote increased amounts of
beneficial by-products for the host. Increased saccharolytic activity
may also decrease proteolytic activity, thus decreasing production
of protein-bound uremic solutes and intestinal inflammation (2,3).
Decreased inflammation may result in a healthier intestinal wall which
will help to prevent bacterial translocation and interruption of the
intestinal transport systems (4,7,8).
Prebiotics work symbiotically with the probiotics to benefit the host.
In addition to providing fuel for saccharolytic bacteria, prebiotics may
also increase transit time (alleviate constipation), increase fecal weight
(improve diarrhea) with fewer side effects and increase quality of
life among patients (16). The increased transit time will also provide
a friendly environment for saccharolytic bacteria thus decreasing
proteolytic bacteria production of PCS and IS (3).
Research on Probiotics in CKD Patients
The current body of research has established that the process of CKD
alters gut microbiota. More specifically, there are increased levels of
Renal Nutrition Forum 2014 • Vol. 33 • No. 1
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Feature Article...
PCS and IS from proteolytic bacteria activity, and this contributes to
the poor outcomes due to the impact on the cardiovascular system
(1,3,4,12,17).
Use of probiotics to decrease IS and PCS is not well established.
To date, only one study has shown a significant decrease in IS and
PCS with treatment using prebiotics in hemodialysis patients (19).
Studies using probiotics in CKD populations have shown
promising results. A double-blind, placebo, crossover study in
CKD patients found that blood urea nitrogen (BUN) levels were
significantly lower with probiotic therapy, although creatinine
differences were insignificant (20). Another randomized, doubleblind placebo, crossover trial investigated the benefit of using
probiotics. Results indicated that BUN and creatinine levels
decreased, although not significantly. However, the quality of life
assessment reflected an 86% overall improvement (p<0.05) (5).
Rossi et al conducted a meta-analysis of studies evaluating
use of probiotics and prebiotics in reducing PCS and IS (19).
They concluded that there seems to be a beneficial effect of using
probiotics and prebiotics to reduce PCS and IS in hemodialysis
and healthy populations despite small sample size. The review of
Table 1. Health Benefits of Probiotic Strains (6,22)
Species and Strain
General GI
Health
Health
B. animalis DN-173 010, (1)
B. infantis 35624
B. lactis Bb-12
B. lactis HN019, DR10 (2)
L. acidophilus NCFM (2)
L. casei DN-114 001, (3)
L casei Shirota
L. fermentum RC-14
L. plantarum 299v
L. reuteri SD2112, ING1, MM53,
ATCC 55730 (4)
L. rhamnosus GG, LGG, (5)
L. rhamnosus GR-1
Viral
Diarrhea
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
*
x
x
x
x
x
studies shows a high tolerance of probiotic therapy with only 15%
reporting intolerance to the therapy.
Recommendations for Therapy
More research is needed to support the hypothesis that probiotics
can improve outcomes by decreasing IS and PCS. However, there
is sufficient evidence supporting the use of probiotics in CKD
patients due to antibiotic associated diarrhea, C. difficile and other
maladies probiotics have shown to alleviate (6). While foods are
a preferable source for most nutrients, many probiotic foods are
also high in potassium and phosphorus which must be limited in a
renal diet. Because of this, supplements are likely to show the most
therapeutic benefit for those with CKD, although inclusion of some
probiotic foods may be beneficial as recommended.
Probiotic Recommendations
It is impossible to recommend a blanket dose and strain for all
CKD patients due to the unique make up and multitude of factors
influencing microbiota in the gut. However, based on available
research, some general recommendations are appropriate. Table 1
is a summary of probiotic strains and their potential health benefits.
Antibiotic
Assoc.
Diarrhea
C. Difficile Urinary Cold &
Diarrhea
Tract
Resp
Infection Virus
x
x
x
x
x
x
x
Product
including
species
Activia
Align
Yo-Plus
Danisco
DanActive
Yakult
x
GoodBelly
x
*
x
x
Culturelle
Femdophilus
L. rhamnosus HN001, DR200 (2)
x
x
S. boulardii lyo
x
x
*
*
*
Florastor
x: strain shows positive response in
human and animal studies
*: recommended by 2005 Yale
Note: This table shows the species that have been used in studies, not the products. The product
University Workshop
simply contains the species studied.
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Feature Article...
Probiotic Safety
There are some who question the safety of providing bacteria
to immune-compromised individuals. Of the few studies that
have been conducted, a minimal number of negative events have
been reported (17,23). Probiotic strains are not pathogenic and
probiotic-related infections are rare occurrences. Nevertheless, as
with all supplements and medications, a healthcare provider should
take the individual’s case into consideration before recommending
probiotics and continue to monitor the individual (23).
A patient’s dietary restrictions and serum levels of potassium
and phosphorus should also be taken into consideration.
While the studies reviewed for this article did not report
altered potassium and phosphorus levels, food products and
supplements should be investigated to determine if they fit
within the patient’s diet parameters.
In choosing a probiotic supplement, several considerations should
be taken into account such as strain and dose. Below are listed a few
resources available to guide healthcare providers.
• Natural Medicine Comprehensive Database: for evaluation of
specific products
• References from this article (2,6,17,19,22)
• Manufacturer’s Website: in the section for professionals, many will
have studies listed
In recommending an amount, dose will vary by strain and the overall
health of the individual, however many studies use doses from 1 to
10 billion CFUs and see beneficial results (19). Prebiotics will also
facilitate bacterial growth (24).
Table 2. Partial List of Commercial Food Products Containing Prebiotics that are Available to Consumers. Reprinted from Journal
of the American Dietetic Association, 108(3), Douglas LC, Sanders ME, “Probiotics and prebiotics in dietetics practice”, Pages 510-21,
Copyright 2008, with permission from Elsevier (22).
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Feature Article...
Prebiotic Recommendations
To date no specific recommendations for prebiotics have been
made for CKD patients. However, health benefits are seen with
an intake of 3 g of short-chain FOS up to 8 g for mixed short and
long-chain inulin. In the case of resistant starches, 20 g per day is
recommended although lower doses have shown benefits (22). Table
2 shows common products containing various types of prebiotics as
well as health claims.
Conclusion
CKD outcomes may be improved by addressing CKD-induced
dysbiosis with pre- and probiotic supplementation. More research
will help to further explain the exact processes and appropriate
probiotic therapy. In the meantime, evidenced-based use of prebiotics
and probiotics may prove helpful in restoring normal gut microbiota
and improving patient quality of life.
References
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3. Evenepoel P, Meijers BK, Bammens BR, Verbeke K. Uremic
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