Optimizing chronic kidney disease management: The potential of a multi-strain probiotic formulation

Table 1 Clinical and pre-clinical trial data of the impact of probiotics in chronic kidney disease

Investigator name	Probiotics used	Study characteristics	Results obtained
Clinical studies in chronic kidney disease patients
Natarajan et al[68]	Streptococcus thermophilus, Lactobacillus acidophilus, and Bifidobacterium longum	A randomized, double-blind, placebo-controlled crossover study in 22 subjects	Reductions in levels of C-reactive protein (-8.61 mg/L) and total indoxyl glucuronide (-0.11 mg%) were observed and it was concluded that the probiotic formulation was safe to administer to ESRD patients on haemodialysis
		Group A: Treatment group
		Group B: Control group
Hida et al[71]	Bifidobacterium infantis, Lactobacillus acidophilus, and Enterococcus faecalis	Single-centre, randomized, controlled, observational trial	Lebenin led to reduction in the enterobactericiea populations along with p-cresol and indole in haemodialysis-refractory uremic patients
		Group A (n = 12): Control
		Group B (n = 20): Treatment
Takayama et al[72]	Bifidobacterium longum strain, Lactic acid bacillus	Single-centre, non-randomized, placebo-controlled trial in 22 patients for a duration of 5 weeks	It was observed following the study period that the pre-hemodialysis serum levels of IS significantly decreased in Bifidobacterium-treated patients (before: 4.9 +/- 1.7 mg/dL, after 5 weeks: 3.5 +/- 1.3 mg/dL). However, they did not decrease in the Lac B-treated patients (before: 4.8 +/- 1.4 mg/dL, after 5 weeks: 5.2 +/- 2.0 mg/dL). It was concluded that the administration of Bifidobacterium species to haemodialysis patients was effective in reducing the serum levels of IS by correcting the intestinal microflora
Nakabayashi et al[73]	Symbiotic: Lactobacillus casei strain, Shirota and Bifidobacterium breve strain, Yakult + pre- biotic (galacto-oligosaccharides) three times a day for 2 weeks	Single-centre, observational trial in 9 haemodialysis patients for a duration of 4 weeks	It was observed that the synbiotic treatment resulted in normalization of bowel habits and a decrease of serum p-cresol levels in haemodialysis patients
Simenhoff et al[74]	Oral Lactobacillus acidophilus	Single-centre, observational trial in 8 haemodialysis patients	Lactobacillus acidophilus was observed to improve small bowel pathobiology by modifying metabolic actions of small bowel bacterial overgrowth, reducing in vivo generation of toxins and carcinogens and promoting nutrition with no adverse side effects
Rossi et al[75]	Synbiotic: Lactobacillus, Bifidobacteria and Streptococcus genera + prebiotic (inulin, fructooligosaccarides, and galactooligosaccarides)	Randomized, double-blind, placebo-controlled, crossover trial in 37 patients of stage 4-5 CKD for a duration of 6 weeks	Synbiotic therapy in CKD patients did not significantly reduce serum IS levels (-2 μmol/L) but did decrease serum PCS levels (-14 μmol/L) and favourably modified the stool microbiome
Wang et al[76]	Bifobacterium bifidum, Bifidobacterium catenulatum, Bifidobacterium longum, and Lactobacillus plantarum	A randomised, double-blind, placebo-controlled trial in 39 peritoneal dialysis patients (21 in the probiotics group and 18 in the placebo group) for a duration of 12 months	The levels of serum TNF-α, IL-5, IL-6, and endotoxin were significantly decreased after 6 months of probiotic treatment, while levels of serum IL-10 were significantly increased. On the other hand, there were no significant changes in levels of serum cytokines and endotoxin in the placebo group after 6 months. The residual renal function was preserved in patients receiving probiotics
Viramontes-Hörner et al[77]	Synbiotic: Lactobacillus acidophilus and Bifidobacterium lactis + prebiotic (inulin)	A randomized, placebo-controlled, double-blinded, clinical trial in 42 haemodialysis patients for a duration of 2 months	The intervention group showed a significant reduction in the prevalence of monthly of vomit, heartburn, and stomach ache, as well as a significant decrease in GIS severity compared with control group after 2 months of the study. Also, no symbiotic-related adverse side effects were shown in these patients. Clinical studies with longer follow-up and sample size are required to confirm these results
		Group A (n = 22): Intervention group nutritional counselling + symbiotic gel (Lactobacillus acidophilus NCFM and Bifidobacterium lactis – 11 × 106 CFU; 2.31 g of a prebiotic fibre (inulin); 1.5 g of omega-3 fatty acids (eicosapentaenoic and docosahexaenoic acids); and vitamins (complex B, folic acid, ascorbic acid, and vitamin E)
		Group B (n = 20): Control group nutritional counselling + placebo
Ranganathan et al[78]	Lactobacillus acidophilus, Bifidobacterium longum, and Streptococcus thermophilus, for a total of 1.5 × 1010 CFU	A 6-month prospective, randomized, double-blind, placebo-controlled crossover trial in 46 outpatients of CKD stages 3 and 4; group A: Placebo; group B: Probiotic	It was observed following the treatment period that the oral ingestion of probiotics (90 billion CFUs/day) was well tolerated and safe. BUN levels decreased in 29 patients (63%) creatinine levels in 20 patients (43%), and uric acid levels in 15 patients (33%). Almost all subjects experienced a substantial overall improvement in QOL (86%)
		After 3 months crossover; group A: Probiotic; group B: Placebo
Miranda Alatriste et al[67]	Lactobacillus casei Shirota	A simple randomized, controlled clinical trial in 30 patients of stage 3-4 CKD for a duration of 8 weeks	Upon evaluation, it was observed that the patients treated with 16 × 109 CFU showed a > 10% decrease in the blood urea concentrations and it was significant as compared to the baseline measurement
		Group A: 8 × 109 CFU Lactobacillus casei Shirota
		Group B: 16 × 109 Lactobacillus casei Shirota CFU
Pavan[79]	Synbiotic: Prebiotic + probiotic	A 12-month prospective, randomized, controlled, open-label, observational trial in 24; patients of CKD stage 3-4	It was observed that prebiotic and probiotic supplementation was able to delay the declining glomerular filtration rate than receiving LPD alone (-11.6 ± 8.6 vs-3.4 ± 4.6 mL/minute per 1.73 m2 per year)
		Group A (n = 12): LPD + prebiotic + probiotic supplementation
		Group B (n = 12): LPD only (protein 0.8 g/kg body weight/day)
Cruz-Mora et al[80]	Synbiotic: Lactobacillus acidophilus and Bifidobacterium lactis + prebiotic (inulin) + 1.5 g of omega-3 fatty acids (eicosapentaenoic and docosahexaenoic acid) and vitamins (complex B, folic acid, ascorbic acid, and vitamin E)	Single-centre, double-blind, placebo-controlled trial in 18 patients of ESRD diagnosis with renal replacement therapy (haemodialysis)	It was observed at the end of the study duration that the probiotic supplementation led to an increase in the Bifidobacterial counts in fecal samples and improved GIS (test group start 12 and end 9) compared with control group (start 11 and end 11)
		Group A: Nutritional counselling + symbiotic gel (Lactobacillus acidophilus and Bifidobacterium bifidum 2 × 1012 CFU)
		Group B: Nutritional counselling + placebo
Guida et al[81]	Synbiotic: Lactobacillus acidophilus, Bifidobacterium bifidum, Lactobacillus casei, Lactobacillus rhamnosus, and Bifidobacterium longum + prebiotic (inulin, fructooligosaccharides, maltodextrin, corn starch, magnesium stearate, silicon dioxide)	A double-blind randomized placebo controlled clinical trial in 30 patients of stage 3-4 CKD	It was observed that the probiotic formulation lowered total plasma p-cresol concentrations however, it did not ameliorate GIS in non-dialyzed CKD patients but the investigators concluded that synbiotics deserved attention as possible tools to delay CKD progression towards ESRD
		Group A: Placebo (n = 12)
		Group B: Synbiotic (n = 18)
Ranganathan et al[82]	Streptococcus thermophilus, Lactobacillus acidophilus and Bifidobacterium longum	A 6-month, prospective, randomized, controlled, double blinded, crossover, placebo-controlled pilot scale trial in 16 patients of stages 3-4 CKD	Probiotic supplementation was associated greater mean reduction of BUN concentration (-2.93 mmol/L) as compared to the placebo (4.52 mmol/L). No GI or infectious complications were noted in any subject and their QOL was improved
Taki et al[83]	Bifidobacterium longum	Single-centre, non-randomized-placebo controlled trial in 27 heamodialysis patients for a duration of 12 weeks	It was observed that the oral administration of Bifidobacterium longum in a gastroresistant capsule significantly decreased the serum levels of homocysteine in HD patients (before: 39.2 ± 3.6 µmol/L; 12th week: 34.8 ± 2.8 µmol/L). The most effective dose of Bifidobacterium longum for decreasing the serum levels of homocysteine (reduction rate: 13.3%) was found to be 6.0 × 109 CFU/day
Ando et al[84]	Bifidobacterium longum	Single-centre, observational trial in 27 patients of CKD patients all stages for a duration of 6 months	A significant retardation of the progression of renal failure was observed in patients and there was no adverse effect observed in any case
Studies in experimental chronic kidney disease
Andrade-Oliveira et al[85]	Bifidobacterium adolescentis or Bifidobacterium longum	Evaluation of the role of SCFA in an acute kidney injury mice model bilateral kidney ischemia reperfusion injury 2 weeks	Treatment with SCFAs, especially acetate, reduced kidney damage after kidney ischemia and reperfusion injury. Also, low levels of activated neutrophils and macrophages, infiltrating macrophages and activated dendritic cells (CD11c+CD40+) were observed in acetate-treated mice
Ranganathan et al[86]	Sporosarcina pasteurii	18 Sprague-Dawley uremic rats (5/6 nephrectomy) of 16 weeks	It was observed that feeding with 109 CFU of Sporosarcina pasteurii prolonged the lifespan of uremic rats by at least 22.3% thus increasing the average survival time after surgery from 115.8 ± 16.02 days to 148.5 ± 5.7 days. Moreover, it attenuated the increase in BUN levels in the treatment group. Whereas, in the placebo group, average BUN levels increased by 120 ± 5.8% from baseline to time of death, indicating progression of azotemia in nephrectomized animals
		Group A: Control group
		Group B: Placebo group
		Group C: Probiotic group
Prakash et al[87]	Polymeric membrane artificial cells (semipermeable microcapsules) containing genetically engineered live Escherichia coli DH5 cells	An observational study to determine the effect of semipermeable microcapsules containing genetically engineered live Escherichia coli DH5 cells in male Wistar uremic rats (5/6 nephrectomy)	In the treatment group, it was observed that the bacteria were able to reduce urea levels from 52.08 ± 2.06 to 10.58 ± 0.85 mg/dL by day 7. This suggested that the genetically engineered cells normalized the plasma urea level in uremic rats with induced kidney failure
		Group A: Normal rats receiving empty microcapsules
		Group B: Uremic rats receiving empty microcapsules
		Group C: Uremic rats receiving semipermeable microcapsules containing genetically engineered live Escherichia coli DH5 cells
Ranganathan et al[88]	Various combinations of probiotics	A prospective, blinded, placebo-controlled pilot-study to evaluate the effect of probiotic combination in 5/6th nephrectomized Sprague-Dawley rats with chronic renal failure	Following the 16 weeks of treatment, regimens C and D significantly prolonged the life span of uremic rats, in addition to showing a reduction in BUN levels, concluding that supplementation of probiotic formulation to uremic rats slowed the progression of azotemia, thus leading to prolonged life span of uremic rats
		Group A: Casein based diet + Control
		Group B: Placebo (casein-based diet without probiotics)
		Group C: Bacillus pasteurii
		Group D: Sporolac (R)
		Group E: Kibow cocktail
		Group F: Chr. Hansen cocktail
		Group G: Econom

QOL: Quality of life; ESRD: End-stage renal disease; CFU: Colony-forming units; PCS: P-cresyl sulfate; IS: Indoxyl sulfate; CKD: Chronic kidney disease; TNF-α: Tumor necrosis factor alpha; IL: Interleukin; GIS: Gastrointestinal symptoms; BUN: Blood urea nitrogen; SCFA: Short chain fatty acid; LPD: Low-protein diet; GI: Gastrointestinal; HD: Hemodialysis.