Gut microbiota in kidney disease and hypertension

Accepted Manuscript Title: Gut Microbiota in Kidney Disease and Hypertension Authors: C. Antza, S. Stabouli, V. Kotsis PII: DOI: Reference:

S1043-6618(17)31319-1 https://doi.org/10.1016/j.phrs.2018.02.028 YPHRS 3840

To appear in:

Pharmacological Research

Received date: Revised date: Accepted date:

15-10-2017 20-2-2018 21-2-2018

Please cite this article as: Antza C, Stabouli S, Kotsis V.Gut Microbiota in Kidney Disease and Hypertension.Pharmacological Research https://doi.org/10.1016/j.phrs.2018.02.028 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Gut Microbiota in Kidney Disease and Hypertension C. Antza1, S. Stabouli2, V. Kotsis1

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Hypertension Center, 3rd Department of Internal Medicine, Papageorgiou

1st Department of Pediatrics, Aristotle University Thessaloniki. Greece

Corresponding Author: Prof. V Kotsis, MD, Ph.D

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3rd Department of Internal Medicine, Aristotle University,

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Hospital, Aristotle University Thessaloniki, Greece

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ESH Hypertension-24h ambulatory blood pressure monitoring center of excellence,

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Papageorgiou Hospital,

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Aristotle University Thessaloniki, Greece

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Phone number: +306974748860

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E-mail: [email protected]

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Graphical abstract

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Abstract

The human gut microbiota is being composed of more than one hundred trillion microbial cells, including aerobic and anaerobic species as well as gram-positive and negative species. Animal based evidence suggests that the change of normal gut responsible for several clinical implications including blood pressure

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microbiota is

increase and kidney function reduction. Trimethylamine-N-Oxide, short-chain fatty

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acids and inflammatory factors are originated from the gut microbes and may induce changes in arteries, kidneys and blood pressure. Prebiotics and probiotics change the

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gut microbiota and may reduce high blood pressure and ameliorate chronic kidney

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disease suggesting a new treatment target in patients for the initial stages of

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hypertension concomitant with other life style changes such as increased physical

Abbreviations

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exercise and weight reduction to reduce cardiovascular disease complications.

BP: blood pressure, HTN: hypertension, CKD: Chronic Kidney Disease, SNS:

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Sympathetic Nervous System, DM: diabetes mellitus, TMAO: Trimethylamine-N-

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Oxide, SCFAs: short-chain fatty acids, Olfr78: olfactory receptor 78, eGFR: estimated glomerular filtration rate, MI: myocardial infraction, RCT: randomized

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controlled trial

Keywords: gut microbiota, microbiome, gut dysbiosis, kidney-disease, hypertension

1. Introduction The human gut contains more than one hundred trillion microbial cells. Most of the bacterial species are anaerobes (97%). Microbiota including species, such as 2

Bacteroides,

Fusobacterium,

Eubacterium,

Bifidobacterium,

Lactobacillus,

Clostridium, Escherichia Coli, Enterococcus, Staphylococcus, and Streptococcus Spp. Microbiome is host specific, advance and modified throughout lifetime according to exogenous and endogenous factors. Most common phyla are Firmicutes, Bacteroidetes and Actinobacteria. (1, 2)

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Microbes that have a creative ability of products helpful for the host are

defined as ‘probiotic’ and include Lactobacillus and Bifidobacterium spp. Potentially

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pathogenic organisms including aerobic enteric bacteria such as Clostridium spp and Candida albicans are portion of the microbiota. Lack of balance in the proportion or

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distribution of gut microbes characterized by decreased numbers of the beneficial and

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increased numbers of the harmful bacteria, such as fungi or anaerobic bacteria is

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possible to promote many diseases. Colonization resistance is the inhibitory ability of

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the normal gut microbes to prevent the overgrowth of invading microbes. The symbiotic nature of the host and microbes is attributed to nutrient substance exchange.

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The host supply food to the microbes that provide breakdown products, such as vitamins and short-chain fatty acids. The maintenance of a healthy microbiome is

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believed to be the key to a healthy long life. The balance between the gut microorganisms’ colonies is important for the body homeostasis and responsible for

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the proper gastrointestinal tract action, food and drug metabolism. It also contributes to reduce pathogen-invasion, to stimulate the immune system and synthesis of

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vitamins. The observation that ex-germ-free animals demand increased caloric intake to maintain the same body weight as normal animals suggest that microbiota increase host caloric profit. This can be explained by calories availability from otherwise indigestible oligosaccharides. Another possible explanation could be the increasing nutrient uptake from the intestinal epithelium from induced pancreatic lipase activity

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and effective dietary lipids hydrolysis and finally by the upregulation of the intestinal epithelium sodium/glucose co-transporter to increase glucose uptake. Microbiota composition may also regulate appetite behavior controlling autoantibodies targeting hormones that regulate appetite. Gut microbiota was also shown to abolish lipoprotein lipase inhibition promoting fatty acid uptake into adipocytes. (3, 4) The balance of gut

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microbiota species depends on many factors such as the diet, physical activity,

genetic, and epigenetic factors such as antibiotic use. Obese leptin deficient mice had

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a 50% reduction in the colonies of Bacteroidetes and a correspondent increase in

those from Firmicutes a situation known as dysbiosis. Similarly in human obese

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individuals the Bacteroidetes-to-Firmicutes ratio is changed compared to lean.(4)

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Dysbiosis controls the production and liberation of toxins, hormones and peptides. In

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recent years, there is evidence that suggests a possible association for the impairment

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of kidney function and the elevation of blood pressure (BP) due to dysbiosis. (5-7)Gutderived hormones gastrin and glucagon-like peptide-1 may upregulate sodium

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homeostasis that link to hypertension.(8, 9) Upregulated serotonin, dopamine, and norepinephrine production may also increase BP from sympathetic activation (10)

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The gut microbiota are responsible for the transformation of choline and phosphatidylcholine to produce trimethylamine, which oxidizes and synthesize

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ΤΜΑΟ. (11) Products of colonic fermentation includes the SCFAs acetate, butyrate and propionate that have anti-inflammatory properties which may protect from

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vascular and kidney damage. (12) Uremic solutes p-cresol sulfate and indoxyl sulfate are microbes metabolites cleared from the circulation by tubular secretion may also interact with the cardiovascular system. (13) The aim of this review is to determine possible mechanisms by which dysbiosis may promote hypertension (HTN) and chronic kidney disease (CKD).

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Hormones, peptides and toxins produced from gut microbes are the possible link between gut microbes and the disease. The possible role of probiotics to prevent and treat dysbiosis induced hypertension and CKD will also be discussed.

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2. Animal models for the relationship between gut microbiota and hypertension or chronic kidney disease

The Dahl salt-sensitive rats become hypertensive after 3 weeks of consuming

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high salt diet and die from 6 to 10 weeks after the diet initiation. Renal lesions develope after 4 weeks consumption of the high-salt diet. These rats were not

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hypertensive until the age of 20 weeks when they consume low salt diet. The Dahl

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salt-resistant rats are normotensive whether fed the low or high salt diet. (14) Cecal

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specimen of Dahl salt-sensitive or resistant rats were analyzed to sequence bacteria

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species. Bacteria of the phylum Bacteroidetes were found in higher volume in the Dahl salt-sensitive compared with the salt-resistant rats. Both strains were retained on

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a high-salt diet and after administration of antibiotics for ablation of microbiota, researchers found that a single bolus transplantation of cecal content from salt-

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resistant rats to sensitive rats was enough to elevate BP for all their life-span and

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reduce the longevity of the species. Fecal bacteria of the family Veillonellaceae found at lower levels concomitant with increased plasma acetate and heptanoate. (15) Another study noticed a significant fecal decrease in microbial enrichment and

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increased Firmicutes/Bacteroidetes ratio in the spontaneously hypertensive rat as well as other hypertension rat models i.e. the chronic angiotensin II infusion model. High BP levels were reduced with the use of minocycline which also reduced the Firmicutes/Bacteroidetes ratio.(16) Nutrition with a diet high in fiber increases gut species that generate SCFAs such as acetate. Diet rich in fiber or insert of magnesium 5

acetate in the potable water reduced BP in the deoxycorticosterone acetate-salt mice model decreasing gut dysbiosis namely the ratio of Firmicutes to Bacteroidetes and increasing the acidify species. (17) Finally, germ-free mice were found to be protected from vascular leukocyte adhesion, aortic vessel wall infiltration of neutrophils and monocytes, kidney inflammation, cardiac fibrosis and systolic dysfunction, vascular

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endothelial dysfunction and attenuation of blood pressure increase in response to AngII. (18)

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Nephrectomized spontaneously hypertensive rats were reported to have

decreased numbers of Lactobacillus species compared to control animals.

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Lactobacillus populations numbers were negatively related to urinary protein

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excretion. Lactobacillus supplementation decreased urinary protein excretion, serum

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urea nitrogen levels and uremic toxins i.e. indoxyl and p-cresyl sulfate in the 6-week-

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old 5/6 nephrectomized spontaneously hypertensive rats. Renal sclerosis was restored by Lactobacillus treatment in these rats.

These findings suggest that gut

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Lactobacillus has a possible role against the CKD progression. (19) High-fiber diet in Male Sprague-Dawley rats with adenine-induced CKD reduced cecal pH, increased

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diversity and Bacteroidetes-to-Firmicutes ratio. Indoxyl sulfate and p-cresol

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concentrations were diminished and as a result kidney function was improved. (20)

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3. Dysbiosis, hypertension and chronic kidney disease

The pathophysiological mechanisms of HTN are multiple and complex.

Sympathetic

nervous

system

(SNS),

renin–angiotensin–aldosterone

system,

vasopressin system, natriuretic peptides, the immune system, the adipose tissue and adipokines interact for the development of HTN. (21) HTN, obesity and diabetes mellitus (DM) are associated with the early loss of kidney function and CKD (22, 23), 6

but the high prevalence of the disease can not only be attributed to the already known factors. Life style including increased salt, alcohol and carbohydrate consumption with reduced consumption of fruits and fiber in every day food intake affects the gut microbiota. Different pathophysiological mechanisms may contribute to the

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development of HTN and CKD from gut microbiota dysbiosis such as production of

uremic toxins mainly trimethylamine-N-oxide (TMAO), reduced prophylactic SCFAs,

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increased sympathetic activity, enhanced inflammation and immune response,

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reduced nitric oxide and peptides that block the angiotensin-I converting enzyme.

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3.1 Trimethylamine-N-Oxide

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The gut microbiota are responsible for the transformation of choline and phosphatidylcholine to produce trimethylamine (TMA), which oxidizes and

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synthesize ΤΜΑΟ. (11) Hepatic flavin monooxidases (FMO) catalyze the conversion

carnitine

has

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of TMA to TMAO. A role for gut microbes in TMAO generation from dietary been

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Anaeroplasmataceae,

proposed

in

rats

and

Prevotellaceae,

humans.

Deferribacteraceae, Enterobacteriaceae,

Anaerococcushydrogenalis, Clostridium asparagiforme, Clostiridium hathewayi,

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Clostridium sporogenes, Escherichiafergusonii Proteuspenneri, Providencia rettgeri and Edwardsiella tarda are microbiota species producing TMA. (11, 24-26)

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Vegans/vegetarians produce significantly less TMAO from L-carnitine through a microbiota-dependent mechanism. Plasma L-carnitine levels predict additional risk for established CVD, MI, stroke or death among subjects with elevated TMAO concentrations. Mice fed with L-carnitine for an extended period of time had changed their cecal microbial composition causing an increase in TMAO synthesis and

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atherosclerosis. Dietary supplementation of TMAO in mice with unimpaired intestinal microbe species diminishes reverse cholesterol transport in vivo promoting atherosclerosis. Atherosclerosis susceptibility can be transmitted with gut microbial transplantation from atherosclerosis-prone mice depending on TMAO levels. (27-29) In normotensive animals BP was not affected by TMAO levels, however

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TMAO may prolong the hypertensive effect of Ang II suggesting a chronic upregulation of BP when a patient has increased TMAO levels. (30) TMAO and

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choline levels increase in chronic kidney disease, diabetes and metabolic syndrome and these co-founders should be considered when studies were interpreted. In a cohort

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study, patients who underwent coronary angiography for possible CAD had no

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differences in the TMAO plasma levels when angiographically assessed coronary

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heart disease was present or not. TMAO plasma levels could not also predict

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cardiovascular events for 8 years follow-up, but these results were not confirmed in other studies. (31) CKD patients with increased TMAO levels had poorer long-term

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survival and all-cause mortality. Long term dietary habits, which are responsible for increased TMAO levels, contribute to gradual renal fibrosis and chronic kidney

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disease in animal models. (32) TMAO levels were higher in hemodialysis patients compared to the control group. (33) Hemodialysis Caucasian patients with TMAO

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levels over the 80th population percentile had higher risk of sudden cardiac and anycause death compared to patients with the lower quintile of TMAO.(34) Elevated

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TMAO levels were related with the number of infracted coronary arteries after adjustment of CKD stage, lipid levels and other co-factors that may associated with CAD in patients who underwent cardiovascular surgery.(35)

3.2 Short-Chain Fatty Acids

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SCFAs are originated from non-digestible carbohydrates that pass unmetabolized the small intestine and disintegrate from gut bacteria. The amount and type of fiber in the food change gut microbiota predominant species and consequently the type and amount of SCFAs produced. Products of colonic fermentation includes the SCFAs acetate, butyrate and propionatehave with anti-inflammatory and histone

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deacetylase properties. (12) Acetate, propionate and butyrate decrease TNFa release from neutrophils, NF-kB activity, suppressed IL-6 mRNA and protein release and

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inhibited immune-related gene expression. (36) Indigestible in the small intestine

oligosaccharides are fructooligosaccharides, oligofructose and xylooligosaccharides.

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These oligosaccharides are fermented in the large bowel to SCFA, which can be

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absorbed and used by the host. After 14 days of oligosaccharide-diet, SCFAs levels

of

anaerobes

and

reduced

total

aerobes.

(37)

After

6

week

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amounts

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were higher in treated rats accompanied by increased Cecal bifidobacteria and total

galactooligosaccharide diet at pigs, fecal bifidobacteria and lactobacilli were

adaptation. (38)

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increased and SCFAs production were higher compared with production before diet

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Therapy with acetate, propionate, and butyrate improved renal dysfunction in an acute kidney injury model of renal ischemia-reperfusion. Low levels of local and

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systemic inflammation, oxidative cellular stress, cell activation and apoptosis was suggested as the possible protecting mechanism. In addition, SCFAs improved

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mitochondrial biogenesis which may protect kidney epithelial cells hypoxia. (39) Olfactory receptors are transmembrane G protein-coupled receptors that related to the chemosensory process. Olfactory signaling pathway found in the kidney has a functional role in filtration rate and renin release. Olfactory receptor 78 (Olfr78) interfere with renin secretion in the renal juxtaglomerular apparatus stimulated from

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SCFAs. SCFA receptors Olfr78 and G protein-coupled receptor 41 (Gpr41) are present in smooth muscle cells of small resistance vessels that regulate BP. Propionate an ex vivo vasodilator induced an acute hypotensive effect in wild-type mice, while treatment with orally administered antibiotics reduced the gut microbial biomass and significantly increased blood pressure in Olfr78−/− animals. (40, 41) In conclusion,

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increased gut production of SCFAs may reduce BP levels via chemosensory

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receptors in the kidneys and the vessels.

3.3 Immune System and Inflammation

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Gut dysbiosis is associated with gut inflammation. The main local or

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systematic inflammation pathways are the activation of the nuclear factor- kappa B

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and the formulation of pro-inflammatory cytokines and coexistence of acquired

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immunosuppression that decrease immune response. (42-44) Renin-Angiotensin System is associated with increased expression of pro-inflammatory cytokines

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involving both the innate and the adaptive immune response. Links between Angiotensin II, the innate immune system and the pathogenesis of hypertension have

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been reported. (45) Angiotensin II triggering toll like receptor 4 activation in the

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kidney, vasculature and central nervous system may contribute to hypertension. Chemokine receptor expression and inappropriate inflammation is enhanced in

hypertension. T lymphocytes and monocytes/macrophages are mediators of

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hypertensive inflammation, and these cells migrate in response to several chemokines. Chemokines CCL2 and CCL5 have long been implicated in hypertension induced tissue injury. (46) Bacterial endotoxin is a lipopolysaccharide and the major outer membrane element of the gram-negative bacteria. Endotoxin is liberated when host defense

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mechanisms or autolysis destroy bacterial cell wall. Endotoxin breaks the intestinal barrier and burst into the circulation a situation that is defined as translocation. Gut bacteria promote the inflammation due to endotoxin. (43) Elevated levels of circulating endotoxin were common in patients with advanced CKD and significantly associated with reduced survival. (47)

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Gut microbiota seems to be responsible in animals for the angiotensin IIinduced HTN, vascular malfunction and kidney inflammation. (18) Hypertensive

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patients have a decreased microbial richness and diversity, decreased bacteriodetes

numbers and increased inflammatory cells especially Th17 cells that produce pro-

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inflammatory cytokines i.e. TGF-b1, TNF-α, IL-1b and IL-6. (48) SCFAs and lactate

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downregulate the proinflammatory answer of intestinal epithelial cells which is

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protective against HTN. (49)

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4. New targets for the treatment of hypertension and chronic kidney disease?

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As gut microbiota seems to be implicated to both for CKD and HTN, the regulation of gut microbial health may be help in the treatment of these two diseases

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beyond the classical approach. (50) Prebiotics are non-digestible from the upper gastrointestinal tract ingredients that reach the lower gut as substrates for gut

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microbes fermentation. Lipid metabolism was improved in rats fed with chicory extract. (51) In treated hypertensive patients, increased daily fiber and protein consumption reduced ambulatory daytime and 24 hours systolic BP. (52) Daily fiber supplementation was able to reduce diastolic BP, independently of the body weight. (53) In addition, the consumption of lupin kernel flour, a low carbohydrate-high

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protein and fiber flour, could decrease blood pressure. (54) Another randomized, double-blind trial showed that a fiber rich diet had a moderate BP lowering effect over a six weeks period of intervention.(55) The reducing effect of prebiotics on HTN has been attributed to their ability to reduce body weight, to attenuate insulin resistance and to increased absorption of minerals such as calcium. (56-58) The prebiotic

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arabinoxylan oligosaccharides could not establish an effect on microbiota derived uremic retention solutes excretion in CKD patients. (59) When prebiotics and

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probiotics were used along with low protein diet in CKD patients, kidney function declined slower compared to that of patients that had the low protein diet only. (56)

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Probiotics are products containing an adequate dose of live microbes that have

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been proved in target-host studies to favor a health benefit when administered in

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specific amounts. (60) Daily consumption of fermented milk products (yoghurt)

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including Enterococcus faecium and two strains of Streptococcus thermophiles reduced systolic BP. (61) Lactobacillus plantarum 299v decreased F2-isoprostanes,

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interleukin 6 and reduced monocytes adhesion in heavy smokers compared to control subjects. (62) Purple sweet potato yogurt a fermented probiotic rich in γ-aminobutyric

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acid content showed that hypertension-induced cardiac myocyte apoptosis was decreased in treated rats. Increased levels of phosphorylated insulin-like growth

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factor-I receptor was found suggesting that the purple sweet potato yogurt may attenuate cardiomyocyte apoptosis by stimulating phosphorylated insulin-like growth

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factor-I receptor dependent survival signaling pathways. (63) Fermented milk with both Lactobacillus casei and Streptococcus thermophilus reduced systolic BP after 8 weeks of intervention and reduced total cholesterol, triglycerides levels and increased HDL levels. (64) A meta-analysis of fourteen randomized placebo-controlled trials reported that the probiotic fermented milk reduced significantly the systolic and

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diastolic BP by 3.1 mmHg and by 1.09 mmHg respectively compared with placebo. (65) There are also evidence that the use of probiotics helps patients with CKD to decrease creatinine or uric acid levels. (66, 67) Lactobacillus casei shirota in 16 x 109 colony-forming units dose decreased more than 10% the serum urea levels in stage 3 or 4 CKD patients. (68) Residual renal function was preserved in hemodialysis

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patients treated with probiotics due to their effect to reduce serum endotoxin levels

and pro-inflammatory cytokines, and to enhance anti-inflammatory cytokine IL-10

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concentrations. (69, 70)

Synbiotics are diet supplements composed of both probiotics and prebiotics.

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(71) Despite that prebiotics and probiotics alone help BP levels, an animal study

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shows that a synbiotic supplement of Lactobacillus plantarum HEAL19 with

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fermented blueberry could not reduce blood pressure in hypertensive rats. (72) In

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levels.(Table 1 and 2) (73)

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patients with CKD, synbiotics decreased serum p-cresyl sulfate but not indoxyl sulfate

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5. Gaps in evidence and conclusion

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The balance of gut microbiota species has a close relationship with CKD and HTN. The regulation of sodium homeostasis, upregulated production of hormones and metabolites such as p-cresol sulfate, indoxyl sulfate, TMAO and SCFAs interact

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with the cardiovascular system (Figure 1). Treatment of gut dysbiosis with prebiotics and probiotics could be beneficial for patients with HTN at stage I or prehypertension since the BP reduction is expected to be modest. Despite some evidences from RCTs most of these studies have included small numbers of patients. Even meta-analysis included only hundreds of patients, 13

suggesting that bigger studies are needed for better interpretation and understanding of the results. Despite that there is a new area of future research as we are not really aware of what species and the doses that are beneficial to health.

There is no

evidence in the literature about the effect of gut microbiota on children with HTN or kidney dysfunction. Research could focus on the effect of prebiotics and probiotics in

with dysbiosis that had probiotic treatment has a potential interest.

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children. Prevention of the development of HTN or CKD in adulthood in children

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Understanding of the pathophysiological mechanisms involved in microbiota

induced hypertension may be the key for the development of new drugs in the field.

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More evidence about fecal microbiota transplant in animals and humans is required to

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Formatting of funding sources

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establish microbiota effects in hypertension.

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This research did not receive any grant from public funding agencies, commercial, or

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not-profit sectors.

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Declaration of interest

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Conflicts of interest: None

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Figure Legend: Mechanisms of microbiota induced hypertension. The imbalance between promoting and protecting microbes is essential for hypertension development. Increase caloric availability, lipids hydrolysis and glucose uptake promote obesity which is an important risk factor for hypertension. Increased gastrin and glucagon-like peptide 1 promote salt sensitivity and volume overload

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hypertension. TMAO, proinflammatory cytokines and altered innate immune system promote vessels and kidneys damage causing arterial stiffening, endothelial

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dysfunction and reduction in GFR promoting hypertension.

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Table 1. Design

Intervention

Clinic or 24hABPM

SBP dif

95% CI

P

DBP dif

95% CI

P

Low Fiber

24hABPM

-5.9

-8.1, -3.7

0.001

-1.4

-3, 0.2

0.112

High Protein

Low Protein

24hABPM

-5.9

-8, -3.8

0.001

-2.6

-4.2, -1

0.006

Lupin Kernel flour

White bread

24hABPM

-2.6

-4.7, -0.6

0.01

0.8

-0.5, 2.2

0.22

Fiber Probiotic Fermented Milk Fiber

Low Fiber Placebo Placebo

Clinic Both Both

-1.8 -3.10 -1.13

-4.3, 0.8 -4.63, -1.56 -2.49, 0.23

0.17 N/A N/A

-1.2 -1.09 -1.26

-3, 0.5 -2.11, -0.06 -2.04, -0.48

0.17 N/A N/A

45

He J Dong Jia-Yi55 Streppel MT48

RCT RCT Meta-analysis Meta-analysis

ED

Lee YP44

RCT

PT

Burkev

M

High Fiber 42

Control

A

Study

A

CC E

Table1. Randomized control trials and meta-analysis for the use of nutrition supplementation with prebiotics and probiotics on 24h or clinic systolic and diastolic BP values

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Design RCT

Intervention Low Protein Diet+Prebiotic+Probiotic

Control Low Protein Diet only

Ranganathan N56

RCT

Probiotic Bacterial Formulation

Ranganathan N57

RCT

Miranda Alatriste PV58

RCT

Placebo

16X109 lactobacillus casei shirota

8X109 lactobacillus casei shirota

M

Probiotic

RCT

Renadyl(Probiotic)

Placebo

Wang IK60

RCT

Probiotic

Placebo

Rossi M63

RCT

Synbiotic

Placebo

CC E A

Placebo

ED

PT

Natarajan R59

A

Study Pavan M46

Outcome GFR Blood urea nitrogen levels Creatinine levels Uric acid Quality of life Blood urea nitrogen levels Uric acid Creatinine levels

Influence + + + + + + + +

P 0.001 <0.05 >0.05 >0.05 <0.05 0.002 0.05 >0.05

Blood urea levels

+

<0.05

WBC CRP Indoxyl glucuronide Quality of life Serum TNF-a IL-5 IL-6 Endotoxin IL-10 Serum indoxyl sulfate Serum p-cresyl sulfate

+ + + + + + + + + + -

0.057 0.071 0.058 >0.05 <0.05 <0.05 <0.05 <0.05 <0.05 >0.05 <0.05 0.03

Albuminuria

Table 2. Randomized control trials of prebiotics, probiotics and synbiotics in patients with chronic kidney disease: Positive effect on kidney function, inflammation and uremic toxins

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