The Impact of a 10-Month Synbiotic Intake on eGFR, Uremic Toxins, Oxidative Stress, and Inflammatory Markers in Non-Dialysis Chronic Kidney Disease Patients: A Prospective, Non-Randomized, Placebo-Controlled Study
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Design and Sample Size
2.2. Inclusion and Exclusion Criteria
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- Age ≥ 18 years;
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- Diagnosed CKD stage IV–V not receiving dialysis;
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- Ability to provide informed consent.
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- Inability to provide informed consent;
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- Active inflammatory disease;
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- Use of medications affecting gut microbiota (e.g., antibiotics, chemotherapy, biological agents) within the previous 3 months;
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- Use of phosphate binders, statins, or proton pump inhibitors within 3 months.
2.3. Group Allocation
2.4. Intervention and Compliance Monitoring
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- Synbiotic group (n = 25): One gelatin capsule daily containing 75 mg Lactobacillus acidophilus La-14 (2 × 1011 CFU/g) plus 65 mg fructooligosaccharides, taken one hour after a meal for 10 months.
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- Placebo group (n = 25): One identical gelatin capsule daily containing corn starch, taken one hour after a meal for 10 months.
2.5. Blinding
2.6. Data Collection and Laboratory Analyses
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- eGFR (calculated by the CKD-EPI formula);
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- Serum indoxyl sulfate (IS);
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- Serum p-cresyl sulfate (p-CS);
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- Serum interleukin-6 (IL-6);
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- Serum malondialdehyde (MDA).
2.7. Statistical Analysis
3. Results
3.1. Baseline Demographic and Clinical Characteristics of the Two Subgroups Are Summarized in Table 1, Table 2 and Table 3: There Were No Significant Differences Between Synbiotic and Placebo Arms in Terms of Age, Gender Distribution, CKD Etiology, Comorbidities, or Baseline Biomarker Levels
Variable | Total (n = 50) | Synbiotic (n = 25) | Placebo (n = 25) | p-Value (Between Groups) |
---|---|---|---|---|
Age (years), mean ± SD | 58.1 ± 12.4 | 59.0 ± 12.8 | 57.2 ± 12.0 | 0.62 |
Female, n (%) | 25 (50%) | 13 (52%) | 12 (48%) | 1.00 |
Male, n (%) | 25 (50%) | 12 (48%) | 13 (52%) | 1.00 |
Variable | Total (n = 50) | Synbiotic (n = 25) | Placebo (n = 25) |
---|---|---|---|
CKD Etiology, n (%) | |||
• Chronic glomerulonephritis | 16 (32%) | 8 (32%) | 8 (32%) |
• Hypertensive nephropathy | 13 (26%) | 6 (24%) | 7 (28%) |
• Diabetic nephropathy | 11 (22%) | 6 (24%) | 5 (20%) |
• Chronic tubulointerstitial nephritis | 6 (12%) | 3 (12%) | 3 (12%) |
• ADPKD | 2 (4%) | 1 (4%) | 1 (4%) |
• Other | 2 (4%) | 1 (4%) | 1 (4%) |
Comorbidities, n (%) | |||
• AHT + IHD | 18 (36%) | 10 (40%) | 8 (32%) |
• DM + AHT | 15 (30%) | 7 (28%) | 8 (32%) |
• AHT + CVD | 6 (12%) | 3 (12%) | 3 (12%) |
• AHT only | 8 (16%) | 4 (16%) | 4 (16%) |
• None | 3 (6%) | 1 (4%) | 2 (8%) |
Variable | Total (n = 50) | Synbiotic (n = 25) | Placebo (n = 25) | p-Value (Between Groups) |
---|---|---|---|---|
eGFR (mL/min/1.73 m2), mean ± SD | 16.4 ± 5.8 | 16.5 ± 6.2 | 16.3 ± 5.3 | 0.96 |
IS (ng/L), mean ± SD | 128.3 ± 30.2 | 135.9 ± 39.8 | 120.7 ± 20.6 | 0.07 |
p-CS (pg/mL), mean ± SD | 15.3 ± 10.0 | 15.8 ± 11.2 | 14.8 ± 10.6 | 0.78 |
IL-6 (pg/mL), mean ± SD | 17.7 ± 11.3 | 17.1 ± 13.6 | 18.3 ± 8.2 | 0.81 |
MDA (pg/mL), mean ± SD | 1739.0 ± 706.9 | 1712.1 ± 721.3 | 1765.9 ± 691.5 | 0.86 |
3.2. Changes in eGFR and Uremic Toxins
4. Discussion
- eGFR decline: Over 10 months, the synbiotic group experienced a non-significant decrease in eGFR (Δ = −1.2 ± 2.5 mL/min/1.73 m2; p = 0.12), whereas placebo patients had a statistically significant decline (Δ = −3.5 ± 3.0 mL/min/1.73 m2; p < 0.001). The between-group difference in ΔeGFR was 2.3 mL/min/1.73 m2 (95% CI: 0.5 to 4.1; p = 0.014) but did not remain significant after Bonferroni correction (adjusted p = 0.07).
- Indoxyl sulfate (IS): Synbiotic supplementation led to a significant reduction in serum IS (Δ = −15.4 ± 8.2 ng/L; p = 0.019), while the placebo group saw a non-significant rise (Δ = −3.1 ± 6.5 ng/L; p = 0.52). The between-group difference (−12.3 ng/L; 95% CI: −17.8 to −6.8; p < 0.001) remained significant after Bonferroni correction (adjusted p = 0.005).
- p-Cresyl sulfate (p-CS), IL-6, and MDA: Neither p-CS, IL-6, or MDA changed significantly in either group, and between-group comparisons all fell short of significance (adjusted p > 0.10).
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- eGFR: Our trend toward a slower eGFR decline in synbiotic-treated patients echoes the majority of meta-analyses showing no robust improvement in renal function from biotic supplements in CKD [30,31,32,33,34]. For example, Pisano et al. [30] (n = 345, stages II–V) and Firouzi et al. [31] (n = 376 stage II–V) both concluded that biotics did not meaningfully alter eGFR. McFarlane et al. [32] similarly found no eGFR benefit in three pooled RCTs. SYNERGY II, a 12-month, synbiotic RCT in CKD III–V, actually reported a significant eGFR drop in the intervention arm [29]. In our trial, although the unadjusted between-group p = 0.014 suggests a smaller decline with synbiotic, the effect size (≈2.3 mL/min/1.73 m2) was modest and lost statistical significance after correction, indicating limited clinical relevance.
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- Indoxyl sulfate: The significant IS reduction in our synbiotic group aligns with shorter trials (4–12 weeks) showing lowered IS after prebiotic or synbiotic intake [33,35,36] mainly in hemodialysis patients, but it contrasts with others’ null toxin results [29,32,34]. The magnitude of IS lowering (≈12 ng/L difference) in our CKD IV–V cohort suggests that extended synbiotic dosing can reduce protein-bound toxins even in advanced CKD, provided sufficient duration and adherence.
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- Inflammation (IL-6) and Oxidative Stress (MDA): Our non-significant reductions in IL-6 and MDA are in line with Liu et al. [37] and Yu Z et al. [38] who reported that only prebiotics (rather than synbiotics) achieved a consistent IL-6 drop. Zheng et al. [39] tended to MDA decreases only with longer (>12 weeks) interventions in select subgroups (with lower BMI). In dialysis patients, our prior single-arm 8-week study [35] found significant IL-6 and MDA decreases, suggesting that synbiotics may exert stronger anti-inflammatory/antioxidant effects in hemodialysis patients.
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- Strengths:
- Duration and Stage: Ten months of observation in CKD IV–V is longer than most published synbiotic trials.
- Single-Blind Design with Rigorous Adherence Tracking: Pill counts and diaries ensured that only adherent patients were analyzed.
- Comprehensive Biomarkers: We measured both protein-bound uremic toxins and markers of inflammation/oxidative stress.
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- Limitations:
- Small Sample Size and Power: Only 42 completers (21 per arm) yielded ~80% power to detect large effect sizes (d ≥ 0.8). Consequently, null findings for p-CS, IL-6, and MDA may reflect a type II error rather than a true lack of effect.
- Non-Randomized Allocation and Single-Blinding: Investigators knew group assignments, introducing potential performance bias. Laboratory staff were blinded, but unmeasured behavioral changes cannot be excluded.
- No Microbiome Data: Without stool sequencing or metabolomics, our mechanistic interpretations remain speculative.
- Absence of Pre-Registration: Primary and secondary outcomes were defined a priori in our internal protocol but were not registered, exposing us to possible reporting bias.
- Withdrawals for Non-Compliance and RRT (n = 8): This further reduced sample size and may have introduced attrition bias.
- Single-Center Study: Limits generalizability beyond our local CKD population.
- Larger, randomized, double-blind RCTs in CKD III–V with block randomization to balance key covariates.
- Microbiome and metabolomic profiling to link specific bacterial taxa or metabolic pathways to reductions in uremic toxins.
- Longer follow-up (≥ 12 months) to determine if sustained IS lowering translates into slower progression (e.g., dialysis initiation, cardiovascular events).
- Dose–response and formulation studies comparing different probiotic strains, prebiotic fibers, or synbiotic combinations to identify the most efficacious formula.
- With the inclusion of earlier CKD stages (II–III), it is plausible that synbiotics are more effective when residual kidney function is higher.
5. Conclusions
- Primary Outcomes: Synbiotic intake significantly reduced serum indoxyl sulfate compared with placebo (between-group ΔIS = −12.3 ng/L; adjusted p = 0.005).
- Renal Function: The synbiotic group showed a smaller eGFR decline than placebo (ΔeGFR = −1.2 vs. −3.5 mL/min/1.73 m2), but this difference lost statistical significance after the multiple comparison correction (adjusted p = 0.07) and was not clinically robust.
- Secondary Outcomes: No significant effects were observed on p-cresyl sulfate, interleukin-6, or malondialdehyde.
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
CFU | colony forming units |
CKD | chronic kidney disease |
CRP | C–reactive protein |
Da | Dalton |
eGFR | estimated glomerular filtration rate |
ELISA | enzyme-linked immunosorbent assay |
ESRD | end-stage renal disease |
IFN-γ | interferon gamma |
IL | interleukin 6 |
IL-12 | interleukin 12 |
IL-1β | interleukin-1β |
IS | indoxyl sulfate |
MDA | malondialdehyde |
p-CS | p-cresyl sulfate |
ROS | reactive oxygen species |
RRT | renal replacement therapy |
SCFAs | short-chain fatty acids |
SD | standard deviation |
SEM | standard error of mean |
SuPAR | soluble urokinase-type plasminogen activator receptor |
TNF-α | tumor necrosis factor–alpha |
TWEAK Fn14 | tumor necrosis factor-like weak inducer of apoptosis, fibroblast growth factor-inducible 14 |
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Outcome | Group | Baseline (Mean ± SD) | Month 10 (Mean ± SD) | Change (Mean ± SD) | Within-Group p | Between-Group p (Adjusted) |
---|---|---|---|---|---|---|
eGFR (mL/min/1.73 m2) | Synbiotic | 16.5 ± 6.2 | 15.6 ± 6.7 | −1.2 ± 2.5 | 0.12 | 0.014 (0.07) |
Placebo | 16.3 ± 5.3 | 15.04 ± 5.83 | −3.5 ± 3.0 | <0.001 | ||
IS (ng/L) | Synbiotic | 135.9 ± 39.8 | 113.12 ± 39.52 | −15.4 ± 8.2 | 0.019 | <0.001 (0.005) |
Placebo | 120.7 ± 20.6 | 124.7 ± 19.7 | −3.1 ± 6.5 | 0.52 |
Outcome | Group | Baseline (Mean ± SD) | Month 10 (Mean ± SD) | Change (Mean ± SD) | Within-Group p | Between-Group p (Adjusted) |
---|---|---|---|---|---|---|
p-CS (pg/mL) | Synbiotic | 15.8 ± 11.2 | 15.1 ± 10.6 | −0.6 ± 3.3 | 0.890 | 0.53 (1.00) |
Placebo | 14.8 ± 10.6 | 15.1 ± 10.5 | +0.3 ± 3.1 | 0.901 | ||
IL-6 (pg/mL) | Synbiotic | 17.1 ± 13.6 | 12.4 ± 13.6 | −4.7 ± 7.2 | 0.370 | 0.46 (1.00) |
Placebo | 18.3 ± 8.2 | 17.4 ± 11.7 | −0.96 ± 4.8 | 0.821 | ||
MDA (pg/mL) | Synbiotic | 1712.1 ± 721.3 | 1654.1 ± 743.0 | −58.0 ± 145.0 | 0.833 | 0.72 (1.00) |
Placebo | 1765.9 ± 691.5 | 1768.2 ± 642.7 | +2.3 ± 130.0 | 0.941 |
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Kuskunov, T.; Tilkiyan, E.; Zdravkova, I.; Valova, S.; Boyanov, K.; Bivolarska, A. The Impact of a 10-Month Synbiotic Intake on eGFR, Uremic Toxins, Oxidative Stress, and Inflammatory Markers in Non-Dialysis Chronic Kidney Disease Patients: A Prospective, Non-Randomized, Placebo-Controlled Study. Medicina 2025, 61, 1199. https://doi.org/10.3390/medicina61071199
Kuskunov T, Tilkiyan E, Zdravkova I, Valova S, Boyanov K, Bivolarska A. The Impact of a 10-Month Synbiotic Intake on eGFR, Uremic Toxins, Oxidative Stress, and Inflammatory Markers in Non-Dialysis Chronic Kidney Disease Patients: A Prospective, Non-Randomized, Placebo-Controlled Study. Medicina. 2025; 61(7):1199. https://doi.org/10.3390/medicina61071199
Chicago/Turabian StyleKuskunov, Teodor, Eduard Tilkiyan, Irina Zdravkova, Siyana Valova, Krasimir Boyanov, and Anelia Bivolarska. 2025. "The Impact of a 10-Month Synbiotic Intake on eGFR, Uremic Toxins, Oxidative Stress, and Inflammatory Markers in Non-Dialysis Chronic Kidney Disease Patients: A Prospective, Non-Randomized, Placebo-Controlled Study" Medicina 61, no. 7: 1199. https://doi.org/10.3390/medicina61071199
APA StyleKuskunov, T., Tilkiyan, E., Zdravkova, I., Valova, S., Boyanov, K., & Bivolarska, A. (2025). The Impact of a 10-Month Synbiotic Intake on eGFR, Uremic Toxins, Oxidative Stress, and Inflammatory Markers in Non-Dialysis Chronic Kidney Disease Patients: A Prospective, Non-Randomized, Placebo-Controlled Study. Medicina, 61(7), 1199. https://doi.org/10.3390/medicina61071199