Considering Probiotics in CKD- Impact on Disease Progression and Enhancing Quality of Life

For the benefit of CKD patients, probiotics are an emerging approach for restoring the altered gut flora.[1] This review article aims to give a brief insight into how probiotics can help decrease CKD progression and improve quality of life.

Diet, Gut microbiota, and CKD- Dissecting the Intricate Link

In CKD, the colon becomes the primary excretory organ to maintain homeostasis. Increased urea in serum during CKD increases urea influx into the intestinal lumen, where urease-producing bacteria hydrolyze it into ammonia and ammonium hydroxide, increasing intestinal pH and promoting mucosal irritation and structural alterations to the gut barrier. Such adaptive changes are linked to bacterial translocation and endotoxemia, ultimately deteriorating CKD.[1]

Diet has long been known to impact the progression of CKD. Excess sodium, protein, phosphate, or oxalate in the diet may hasten the progression of CKD. Recently, it is indicated in scientific evidence that the diet feeds both the human body and its gut microbiota. Thus, diet may influence kidney disease through the direct effects of specific nutrients on the human body and through modulation of gut microbiota composition or metabolites produced by the gut microbiota from ingested nutrients. e.g., dietary tyrosine is metabolized by the gut microbiota to p-cresol, which human cells convert to the nephrotoxic compound p-cresyl sulfate. Also, dietary tryptophan is metabolized by the gut microbiota to indole, a precursor of uremic toxins with nephrotoxic potential such as indoxyl sulfate [3]; thus, patients with CKD may have to make dietary changes and opt for a low-protein diet.[5]

Whirlwind Clinical Manifestations of CKD – Deteriorating Quality of life

CKD worsens over time if the patient doesn’t receive appropriate pharmacological and non-pharmacological interventions, and CKD over time can result in a myriad of health problems which include [6]

• Raised risk of heart disease and stroke.
• Anemia, or a decreased red blood cell count, can result in fatigue.
• Extra fluid in the body, which can result in high blood pressure, leg swelling, or shortness of breath.
• Prone to infections resulting from weak immunity.
• Low calcium and high phosphorus levels in the blood can lead to bone and heart disease.
• High potassium levels in the blood can result in an irregular or abnormal heartbeat and death.
• Over a period of time, CKD can progress, and the condition of the kidneys deteriorate, leading to end-stage kidney disease (ESKD)

All these repercussions of CKD directly affect an individual, increasing morbidity, and hospitalization and thus decreasing the quality of life and productivity.

Rationale for Applicability of Probiotics in CKD

Probiotics are "live microorganisms that, when provided in suitable proportions, impart a health benefit on the host," according to the World Health Organization and the Food and Agriculture Organization of the United Nations. Probiotic microorganisms like Bifidobacteria longum, Lactobacillus acidophilus, Bacillus coagulans, etc., are some of the most widely available forms of probiotics.

Certain probiotic microorganisms can use urea, uric acid, creatinine, and other toxins to thrive. Overburdened and impaired kidneys cause the accumulation of these poisonous wastes in the bloodstream. Probiotic microorganisms multiply and metabolize uremic toxins, allowing for greater diffusion from the circulating blood into the bowel across the intestinal lining. These microbes are eventually excreted in the faeces. By breaking down toxins, synthesizing vitamins, and defending against infection, useful intestinal microbes can benefit health. Probiotics can thus reduce the burden of toxic waste in CKD patients while improving the quality of life.[2] Another advantage of probiotics is that they allegedly aid in the growth of Bifidobacteria populations, a genus known to play an important role in the function of the intestinal mucosal barrier. The advantages of using probiotics in CKD patients include a protective effect caused by lower levels of inflammatory markers. Probiotic supplementation appears to be associated with significant reductions in serum levels of proinflammatory cytokines TNF-, IL-5, and IL-6, as well as endotoxins and increased levels of anti-inflammatory cytokine IL-10 by the production of short-chain fatty acids (SCFA) [7], thus contributing to slowing the progression of CKD and improving the quality of life.

Benefits of Probiotics in Chronic Kidney Disease (CKD): Review of Clinical Evidence [8]

• A single-center, double-blind, placebo-controlled, randomized cross-over trial was conducted on 30 patients having stage 3-4 CKD by Guida et al. The study lasted 4 weeks, concluding that probiotics such as Streptococcus thermophilus, L. acidophilus, B. longum, and B. coagulans could decrease the plasma p cresol level (0.78 vs 3.05 μg/ml, p < 0.05).
• A single-center, double-blind, placebo-controlled trial for a period of 8 weeks was carried out on 22 CKD patients by Natarajan et al. The study concluded that administering L. acidophilus and B. longum could increase the quality of life by reducing Indoxyl glucuronide (-0.11 mg%, P = 0.058) and C reactive protein (-8.61 mg/L, P = 0.071).
• A single-center, prospective, randomized, double-blind, cross-over, placebo control trial conducted on 16 CKD patients of stages 3-4 were assessed by Ranganathan et al. The study was done for a period of 6 months. It concluded that L. acidophilus, S. thermophilus, and B. longum administration in CKD patients decreased blood urea nitrogen (BUN) (-2.93 mmol/L vs 4.52 mmol/L, p = 0.002), uric acid concentration (24.70 micromol/L vs 50.62 micromol/L, p = 0.050) and increased quality of life.
• A single-center, non-randomized-placebo controlled trial conducted on 22 individuals for a period of 5 weeks by Takayama et al. concluded that probiotics such as B. longum can decrease the concentration of Indoxyl sulfate (3.5 +/- 1.3 mg/dL vs 4.9 +/- 1.7 mg/dL, P < 0.005).
• A multicenter, prospective, randomised, double-blind, cross-over, placebo-controlled trial by Ranganathan et al. included 46 patients with stage 3-4 CKD. The study was done over a period of 6 months, and it concluded that probiotics such as L. acidophilus, S. thermophilus, and B. longum can decrease the BUN (63%, P<0.05) and can increase the quality of life (86%, P<0.05) among CKD patients.
• A single-center, observational trial conducted by Ando et al. on 27 subjects for a period of 6 months concluded that probiotics such as B. longum could slow the progression of kidney disease.
• A multicenter, double-blinded, placebo-controlled, randomised clinical trial was conducted on 42 CKD subjects by Viramontes-Hörner D et al. to assess the efficacy of L. acidophilus and Bifidobacterium. The study was done over a span of 2 months. It concluded that probiotics could improve gastrointestinal symptoms (anorexia, nausea, vomiting, heartburn, stomachache, constipation and diarrhoea) and decrease plasma C reactive protein.

Points to Remember

• CKD is one of the most underdiagnosed conditions, which can directly hamper the quality of life
• Studies have shown how CKD and gut microbiota are linked; dysbiosis can be caused by CKD, and improvement in the gut environment can help decrease the progression of CKD.
• Probiotics can play a vital role in maintaining the gut environment by decreasing the uremic toxins and increasing the population of Bifidobacteria species which can optimize the integrity of the intestinal mucosa.
• Probiotics also help decrease inflammatory mediators and systemic inflammation and thus improve the quality of life among CKD patients.

References

1. El-Kafoury, B.M., Saleh, N.K., Shawky, M.K. et al. Possible protective role of probiotic and symbiotic to limit the progression of chronic kidney disease in 5/6th nephrectomised albino rats. Bull Natl Res Cent 46, 252 (2022). doi.org/10.1186/s42269-022-00936-4

2. Gharat, P.R., Vakharia, M.P., & Ranganathan, D.N. (2019). Specific Probiotics for Chronic Kidney Disease: A Review.

3. Chiara Favero, Alberto Ortiz, Maria D Sanchez-Niño, Probiotics for kidney disease, Clinical Kidney Journal, Volume 15, Issue 11, November 2022, Pages 1981–1986, doi.org/10.1093/ckj/sfac056

4. I-Kuan Wang. The Effect of Probiotics on Chronic Kidney Disease. ClinicalTrials.gov Identifier: NCT03228563. July 25, 2017

5. Ko GJ, Obi Y, Tortorici AR, Kalantar-Zadeh K. Dietary protein intake and chronic kidney disease. Curr Opin Clin Nutr Metab Care. 2017 Jan;20(1):77-85. DOI: 10.1097/MCO.0000000000000342. PMID: 27801685; PMCID: PMC5962279.

6. Centers for Disease Control and Prevention. (2021). Chronic Kidney Disease Initiative. Retrieved from https://www.cdc.gov/kidneydisease/publications-resources/annual-report/ckd-related-health-problems.html

7. Fagundes RAB, Soder TF, Grokoski KC, Benetti F, Mendes RH. Probiotics in the treatment of chronic kidney disease: a systematic review. J Bras Nefrol. 2018 Jul-Sep;40(3):278-286. DOI: 10.1590/2175-8239-jbn-3931. Epub 2018 Jun 21. PMID: 29958304; PMCID: PMC6533949.

8. Laetitia Koppe, Denise Mafra, Denis Fouque, Probiotics and chronic kidney disease, Kidney International, Volume 88, Issue 5, 2015, Pages 958-966, ISSN 0085-2538, https://doi.org/10.1038/ki.2015.255