Toxemia Associated with Chronic Kidney Disease: Overview of role of Probiotics

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.

Medical Dialogues have published the above article under the MD Brand Connect Initiative. For more details on Probiotics, click here.

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