Chronic kidney disease (CKD) affects
between 8% and 16% of the global population and is frequently misdiagnosed by
patients and professionals. CKD is more
common in low and middle-income countries than in high-income countries and is
defined by a glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m2,
albuminuria of at least 30 mg per 24 hours, or markers of kidney damage (e.g.,
hematuria or structural abnormalities such as polycystic or dysplastic kidneys)
that persist for more than three months. (1)
CKD prevalence (Globally and in India) –With a global prevalence of up to
16%, CKD is one of the world’s most frequent chronic diseases. In India,
estimates reveal that the prevalence of CKD is 13–15 %, with stages 1, 2 and 3
at 6.62%, 5.40% and 3.02%, respectively. (2) Given the rising number of people
with diabetes and/or hypertension, identified as significant risk factors for
CKD, the global prevalence of the disease is projected to rise sharply. (3)
Nephrologists must recognise and
treat CKD early since it is related to unfavourable clinical outcomes such as
end-stage kidney disease (ESKD), cardiovascular disease, and increased
mortality. (1)
Gut Dysbiosis & Toxic Uremia in CKD: Exploring the
Mechanisms-Unlike
healthy individuals, where homeostasis is maintained via interactions between
the host and gut microbiota, research reveals that individuals with CKD have
quantitative and qualitative changes in their gut microbiota.
Distinguished by an increase in
pathogenic flora in comparison to synbiotic flora, dysbiotic intestinal
microbiota generates uremic toxins (including indoxyl sulfate (IS) and p-cresyl
sulfate (PCS), which have been linked to increased inflammation, increased
oxidative stress, and increased risk of cardiovascular diseases (CVD), CKD
progression, and mortality from CKD. (3) By virtue of the kidney–gut axis interaction, dysbiotic microbiota is now regarded
as being increasingly prevalent in the chronic kidney disease (CKD) population.
(4) The mechanisms via which a dysbiotic gut can affect kidney functioning are
summarised below.
- Diet, microbiota-derived uremic toxins, immune-mediated
factors, and metabolites such as short-chain fatty acids (SCFAs) all interact
with the kidneys via complex pathways. (4) - Urea promotes the growth of proteolytic bacteria
(Actinobacteria, Proteobacteria, and Firmicutes) by inducing the translocation
of bacteria or their fractions into the bloodstream and increasing the
permeability of the intestinal wall, which may promote accelerated
atherosclerosis and systemic inflammation. The buildup of uremic toxins with
the advancement of renal failure may exacerbate their harmful effects in CKD patients.
(4) Uremic toxins are categorised as-small water-soluble molecules,
protein-bound chemicals, and medium molecules. Although all three types of
toxins are harmful to the body, the most dangerous are those that are hardest
to eliminate with dialysis, i.e, the protein-bound uremic toxins (PBUTs). - The most researched microbial toxins are p-cresyl-sulfate
(PCS) (formed from tyrosine and phenylalanine phenolic metabolites after liver
sulphation) and indoxyl-sulfate (IS) (which is derived from tryptophan indole
metabolites after liver sulphation). They have been linked to the advancement
of renal failure and cardiovascular morbidity and mortality in patients with
CKD. (5)
Reducing the burden of traditional
uremic and microbiota-related toxins in CKD patients is pivotal in this
context.
The emerging role of Probiotics: Definition of Probiotics
and why it’s should be given to CKD patients- Probiotics are defined by the International Scientific Association for
Probiotics and Prebiotics (ISAPP) as “live microorganisms that, when
supplied in suitable proportions, impart a health benefit on the host.” Bifidobacteria longum, Lactobacillus
acidophilus, and Streptococcus thermophilus are the most widely explored
probiotics. (4)
In recent years, therapeutic
regulation of the gut microbiota has been proposed as one of the modalities in
the integrated management of CKD to delay the decline of kidney function,
prevent and treat CKD-related comorbidities, and improve the gut milieu.
Probiotics are now among the most
commonly used therapeutic agents to modulate gut dysbiosis. (4) Along these
lines, a meta-analysis of the effects of probiotics in CKD patients found that
probiotic administration may reduce inflammatory markers and oxidative stress
levels, thus highlighting a significant role in lowering CKD-related
complications. (6)
Ideal composition of Probiotics & Mechanism of action of
commonly used probiotics in uremic toxin reduction:
Probiotics are ideal when they
possess specific characteristics, like-should have ‘generally regarded as safe’
status, with minimal risk of initiating or being related to disease aetiology.
Probiotic organisms should preferably be of human origin, be capable of
surviving and growing in the in vivo circumstances at the intended site of
injection, and hence be able to endure low pH and high concentrations of both
conjugated and deconjugated bile acids. It should be non-pathogenic,
non-allergic, and non-mutagenic/carcinogenic. (7)
- The SYNERGY study, which included 37
patients with stage 4-5 non-dialyzed CKD, found a reduction in serum p-cresyl
sulfate; a significant change in gut microbiota composition and intestinal
bacterial metabolism was found in most patients after taking Lactobacillus and Bifidobacteria. (8) - S.thermophilus is a bacteria that breaks down urea, uric
acid, and creatinine. S.thermophilus (KB19), L.acidophilus (KB27), and B.longum
(KB31)
generate bacteriocins, lactacin and bisin, which impede pathogen development
and reduce uremic toxins. Bifidobacterium
longum lowers the concentration of protein-bound uremic toxins such as
phenols and cresols. (9) - Rathi et al. studied 30 pre-dialysis
CKD patients with enteric-coated gelatin capsules containing lyophilised S.thermophilus, L.acidophilus, and B.longum
in a dosage of 15 million CFUs, as well as lactitol monohydrate as a prebiotic.
The findings revealed a considerable improvement in several CKD markers. (9) - Probiotics have been demonstrated to
significantly reduce colon-derived uremic toxins in individuals approaching an
advanced stage of CKD. (10,11) Patients with stage 3 and stage 4 chronic renal
failure experienced a >10% reduction in serum urea concentrations when
treated with Lactobacillus casei. (10) - In a double-blind, randomised,
placebo-controlled trial, Guida et al. observed a substantial reduction in
total plasma p-cresol levels in patients with CKD stages 3 and 4. The trial
included thirty patients in 3-4 CKD stages and used synbiotic agents including Bacillus
coagulans, L. acidophilus, and B. longum. A significant
decrease in the total plasma p-cresol concentration was seen on assessments
done on 15 and 30 days following the treatment (2.31 and 0.78 vs 3.05 g/ml, p<0.05).
(12) - The National Health and Nutrition Examination Survey (NHANES) investigated
the association between probiotics intake and CKD; frequent intake was
associated with a lower likelihood of proteinuria. (13)
CKD population who will be benefited from Probiotics
supplementation
- In
CKD, administering probiotics to
hemodialysis patients helps reduce the toxins produced by the small intestine,
such as serum dimethylamine (DMA) and nitrosodimethylamine. (14) - Probiotics significantly help reduce the blood
urea nitrogen level in patients with stages III and IV CKD. (15) - In
hemodialysis patients, probiotics supplementation helps reduce indoxyl sulfate,
homocysteine and triglyceride levels. (16) - Studies
have documented the improving the quality of life through probiotics
supplementation in patients with stages III and IV CKD. (15)
Conclusion- Chronic-kidney disease (CKD) is characterised by the buildup
of various uremic toxins, which are not eliminated by failing kidneys. These
uremic toxins pose major cardiovascular disease risk factors. Individuals with
CKD have different quantitative and qualitative microbiome compositions.
Growing evidence now highlights that
therapeutic regulation of the gut microbiota is one of the approaches in the
integrated management of chronic kidney disease (CKD). Probiotic treatment may
help improve symptoms and quality of life, reduce inflammation, and slow the
progression of chronic kidney disease. S.thermophilus,
L.acidophilus, B.coagulans, and B.longum have demonstrated significant
beneficial effects in managing uremia in CKD patients.
References
1. Chen, T. K., Knicely, D. H.,
& Grams, M. E. (2019). Chronic Kidney Disease Diagnosis and
Management. JAMA, 322(13), 1294. doi:10.1001/jama.2019.14745
10.1001/jama.2019.14745
2. Varma, P. P. (2015). Prevalence
of chronic kidney disease in India – Where are we heading? Indian Journal
of Nephrology, 25(3), 133-135.
3. Pei M, Wei L, Hu S, et al.
Probiotics, prebiotics and synbiotics for chronic kidney disease: protocol
for a systematic review and meta-analysis. BMJ Open 2018;8:e020863.
doi:10.1136/ bmjopen-2017-020863
4. Tian, N.; Li, L.; Ng, J.K.-C.;
Li, P.K.-T. The Potential Benefits and Controversies of Probiotics Use in
Patients at Different Stages of Chronic Kidney Disease. Nutrients 2022,
14, 4044. https://doi.org/ 10.3390/nu14194044
5. De Mauri, A.; Carrera, D.;
Bagnati, M.; Rolla, R.; Vidali, M.; Chiarinotti, D.; Pane, M.; Amoruso,
A.; Del Piano, M. Probiotics-Supplemented Low-Protein Diet for Microbiota
Modulation in Patients with Advanced Chronic Kidney Disease (ProLowCKD):
Results from a Placebo-Controlled Randomized Trial. Nutrients 2022, 14,
1637. https://doi.org/10.3390/ nu14081637
6. Zheng, H.J.; Guo, J.; Wang, Q.;
Wang, L.; Wang, Y.; Zhang, F.; Huang, W.-J.; Zhang, W.; Liu, W.J.; Wang,
Y. Probiotics, prebiotics, and synbiotics for the improvement of metabolic
profiles in patients with chronic kidney disease: A systematic review and
meta-analysis of randomized controlled trials. Crit. Rev. Food Sci. Nutr.
2021, 61, 577–598.
7. Ravinder Nagpal, Ashwani Kumar,
Manoj Kumar, Pradip V. Behare, Shalini Jain, Hariom Yadav, Probiotics,
their health benefits and applications for developing healthier foods: a
review, FEMS Microbiology Letters, Volume 334, Issue 1, September 2012,
Pages 1–15,
8. Rossi, M.; Johnson, D.W.;
Morrison, M.; Pascoe, E.M.; Coombes, J.S.; Forbes, J.M.; Szeto, C.-C.;
McWhinney, B.C.; Ungerer, J.P.J.; Campbell, K.L. Synbiotics Easing Renal
Failure by Improving Gut Microbiology (SYNERGY): A Randomized Trial. Clin.
J. Am. Soc. Nephrol. 2016, 11, 223–231.
9. Anupama, P. H., Prasad, N.,
Nzana, V. B., Tiwari, J. P., Mathew, M., & Abraham, G. (2020). Dietary
Management in Slowing Down the Progression of CKDu. Indian Journal of
Nephrology, 30(4), 256-260.
10. Miranda, A.P.; Urbina, A.R.;
Gomez, E.C.; Espinosa, C.M.L. Effect of probiotics on human blood urea
levels in patients with chronic renal failure. Nutr. Hosp. 2014, 29,
582–590.
11. Poesen, R.; Evenepoel, P.; de
Loor, H.; Delcour, J.A.; Courtin, C.M.; Kuypers, D.; Augustijns, P.;
Verbeke, K.; Meijers, B. The Influence of Prebiotic Arabinoxylan
Oligosaccharides on Microbiota Derived Uremic Retention Solutes in
Patients with Chronic Kidney Disease: A Randomized Controlled Trial. PLoS
ONE 2016, 11, e0153893.
12. Guida B, Germanò R, Trio R, et al. Effect of short-term synbiotic
treatment on plasma p-cresol levels in patients with chronic renal
failure: a randomized clinical trial. Nutr Metab Cardiovasc Dis.
2014;24(9):1043-1049. doi:10.1016/j.numecd.2014.04.007
13. Wagner, S., Merkling, T.,
Metzger, M., Koppe, L., Laville, M., Frimat, L., Combe, C., Massy, Z. A.,
Stengel, B., & Fouque, D. (2022). Probiotic Intake and Inflammation in
Patients With Chronic Kidney Disease: An Analysis of the CKD-REIN Cohort.
Frontiers in Nutrition.
14. Simenhoff ML, Dunn SR, Zollner GP, et al.
Biomodulation of the toxic and nutritional effects of small bowel
bacterial overgrowth in end-stage kidney disease using freeze-dried
Lactobacillus acidophilus. Miner Electrolyte Metab.
1996;22(1-3):92-96.
15. Ranganathan N, Ranganathan P, Friedman EA,
et al. Pilot study of probiotic dietary supplementation for promoting
healthy kidney function in patients with chronic kidney disease. Adv
Ther. 2010;27(9):634-647. doi:10.1007/s12325-010-0059-
16. Takayama F, Taki K, Niwa T.
Bifidobacterium in gastro-resistant seamless capsule reduces serum levels
of indoxyl sulfate in patients on hemodialysis. Am J Kidney Dis.
2003;41(3 Suppl 1):S142-S145. doi:10.1053/ajkd.2003.50104