Synbiotics, prebiotics and probiotics for people with chronic kidney disease

Tess E Cooper; Rabia Khalid; Samuel Chan; Jonathan C Craig; Carmel M Hawley; Martin Howell; David W Johnson; Allison Jaure; Armando Teixeira-Pinto; Germaine Wong

doi:10.1002/14651858.CD013631.pub2

. 2023 Oct 23;2023(10):CD013631. doi: 10.1002/14651858.CD013631.pub2

Synbiotics, prebiotics and probiotics for people with chronic kidney disease

Tess E Cooper ^1,^✉, Rabia Khalid ^1,², Samuel Chan ³, Jonathan C Craig ^4,⁵, Carmel M Hawley ³, Martin Howell ^1,², David W Johnson ³, Allison Jaure ^1,², Armando Teixeira-Pinto ^1,², Germaine Wong ^1,^2,⁶

Editor: Cochrane Kidney and Transplant Group

PMCID: PMC10591284 PMID: 37870148

Abstract

Background

Chronic kidney disease (CKD) is a major public health problem affecting 13% of the global population. Prior research has indicated that CKD is associated with gut dysbiosis. Gut dysbiosis may lead to the development and/or progression of CKD, which in turn may in turn lead to gut dysbiosis as a result of uraemic toxins, intestinal wall oedema, metabolic acidosis, prolonged intestinal transit times, polypharmacy (frequent antibiotic exposures) and dietary restrictions used to treat CKD. Interventions such as synbiotics, prebiotics, and probiotics may improve the balance of the gut flora by altering intestinal pH, improving gut microbiota balance and enhancing gut barrier function (i.e. reducing gut permeability).

Objectives

This review aimed to evaluate the benefits and harms of synbiotics, prebiotics, and probiotics for people with CKD.

Search methods

We searched the Cochrane Kidney and Transplant Register of Studies up to 9 October 2023 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov.

Selection criteria

We included randomised controlled trials (RCTs) measuring and reporting the effects of synbiotics, prebiotics, or probiotics in any combination and any formulation given to people with CKD (CKD stages 1 to 5, including dialysis and kidney transplant). Two authors independently assessed the retrieved titles and abstracts and, where necessary, the full text to determine which satisfied the inclusion criteria.

Data collection and analysis

Data extraction was independently carried out by two authors using a standard data extraction form. Summary estimates of effect were obtained using a random‐effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) or standardised mean difference (SMD) and 95% CI for continuous outcomes. The methodological quality of the included studies was assessed using the Cochrane risk of bias tool. Data entry was carried out by one author and cross‐checked by another. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Main results

Forty‐five studies (2266 randomised participants) were included in this review. Study participants were adults (two studies in children) with CKD ranging from stages 1 to 5, with patients receiving and not receiving dialysis, of whom half also had diabetes and hypertension.

No studies investigated the same synbiotic, prebiotic or probiotic of similar strains, doses, or frequencies. Most studies were judged to be low risk for selection bias, performance bias and reporting bias, unclear risk for detection bias and for control of confounding factors, and high risk for attrition and other biases.

Compared to prebiotics, it is uncertain whether synbiotics improve estimated glomerular filtration rate (eGFR) at four weeks (1 study, 34 participants: MD ‐3.80 mL/min/1.73 m², 95% CI ‐17.98 to 10.38), indoxyl sulfate at four weeks (1 study, 42 participants: MD 128.30 ng/mL, 95% CI ‐242.77 to 499.37), change in gastrointestinal (GI) upset (borborymgi) at four weeks (1 study, 34 participants: RR 15.26, 95% CI 0.99 to 236.23), or change in GI upset (Gastrointestinal Symptom Rating Scale) at 12 months (1 study, 56 participants: MD 0.00, 95% CI ‐0.27 to 0.27), because the certainty of the evidence was very low.

Compared to certain strains of prebiotics, it is uncertain whether a different strain of prebiotics improves eGFR at 12 weeks (1 study, 50 participants: MD 0.00 mL/min, 95% CI ‐1.73 to 1.73), indoxyl sulfate at six weeks (2 studies, 64 participants: MD ‐0.20 μg/mL, 95% CI ‐1.01 to 0.61; I² = 0%) or change in any GI upset, intolerance or microbiota composition, because the certainty of the evidence was very low.

Compared to certain strains of probiotics, it is uncertain whether a different strain of probiotic improves eGFR at eight weeks (1 study, 30 participants: MD ‐0.64 mL/min, 95% CI ‐9.51 to 8.23; very low certainty evidence).

Compared to placebo or no treatment, it is uncertain whether synbiotics improve eGFR at six or 12 weeks (2 studies, 98 participants: MD 1.42 mL/min, 95% CI 0.65 to 2.2) or change in any GI upset or intolerance at 12 weeks because the certainty of the evidence was very low.

Compared to placebo or no treatment, it is uncertain whether prebiotics improves indoxyl sulfate at eight weeks (2 studies, 75 participants: SMD ‐0.14 mg/L, 95% CI ‐0.60 to 0.31; very low certainty evidence) or microbiota composition because the certainty of the evidence is very low.

Compared to placebo or no treatment, it is uncertain whether probiotics improve eGFR at eight, 12 or 15 weeks (3 studies, 128 participants: MD 2.73 mL/min, 95% CI ‐2.28 to 7.75; I² = 78%), proteinuria at 12 or 24 weeks (1 study, 60 participants: MD ‐15.60 mg/dL, 95% CI ‐34.30 to 3.10), indoxyl sulfate at 12 or 24 weeks (2 studies, 83 participants: MD ‐4.42 mg/dL, 95% CI ‐9.83 to 1.35; I² = 0%), or any change in GI upset or intolerance because the certainty of the evidence was very low. Probiotics may have little or no effect on albuminuria at 12 or 24 weeks compared to placebo or no treatment (4 studies, 193 participants: MD 0.02 g/dL, 95% CI ‐0.08 to 0.13; I² = 0%; low certainty evidence).

For all comparisons, adverse events were poorly reported and were minimal (flatulence, nausea, diarrhoea, abdominal pain) and non‐serious, and withdrawals were not related to the study treatment.

Authors' conclusions

We found very few studies that adequately test biotic supplementation as alternative treatments for improving kidney function, GI symptoms, dialysis outcomes, allograft function, patient‐reported outcomes, CVD, cancer, reducing uraemic toxins, and adverse effects.

Keywords: Adult; Child; Humans; Dysbiosis; Dysbiosis/complications; Dysbiosis/therapy; Indican; Prebiotics; Probiotics; Probiotics/therapeutic use; Renal Insufficiency, Chronic; Renal Insufficiency, Chronic/complications; Renal Insufficiency, Chronic/therapy; Synbiotics; Uremic Toxins

Plain language summary

Prebiotics (dietary fibre), probiotics (good bacteria) or synbiotics (prebiotics plus probiotics) for people with chronic kidney disease

Key messages

Chronic kidney disease (CKD) is a serious health problem that affects over 850 million people worldwide. People with kidney disease have an unhealthy balance of good and bad bacteria in their guts, called 'gut dysbiosis'. This imbalance arises because of the effects of reduced kidney function (retained toxic waste products, fluid retention causing the gut wall to swell), drugs frequently used in people with CKD (especially antibiotics), and dietary restrictions placed on people with CKD.

Gut dysbiosis can, in turn, cause or worsen CKD because bacteria can produce toxins that cross the bowel wall and damage the kidneys. Gut dysbiosis can also cause stomach problems (like bloating, cramping, constipation and diarrhoea) and reduce quality of life.

To improve the balance of the gut flora, good bacteria can be taken in tablets of high doses of prebiotics and probiotics. Prebiotics, or indigestible plant fibre, can encourage the growth of good bacteria. Synbiotics are a combination of prebiotics and probiotics. Some research suggests that taking high doses of the good bacteria can re‐balance the good bacteria in people's gut, thereby improving bowel symptoms and the conditions that lead to worsening of CKD.

What did we do?

We reviewed all of the evidence on synbiotics, prebiotics and probiotics to see whether they can improve outcomes in people who have CKD (all stages 1 to 5).

What did we find?

We found 45 studies randomising 2266 participants. Half of these looked at participants receiving dialysis (mostly haemodialysis), and the other half not receiving dialysis. Half also had diabetes and hypertension.

We are uncertain whether synbiotics, prebiotics, or probiotics improve bowel outcomes, quality of life, kidney toxin levels or kidney function.

The quality of the evidence that we found is low quality and very low certainty. All studies were conducted using moderate to poor‐quality methods with too few patients.

Summary

Currently, we do not have enough information from trials to know whether synbiotics, prebiotics or probiotics work to improve bowel symptoms, quality of life, kidney toxin levels, or kidney function in people with CKD. Ten studies are currently ongoing; therefore, it is possible that findings may change with the inclusion of these studies in future updates.

The evidence is up to date to 9 October 2023.

Summary of findings

Summary of findings 1. Synbiotic versus another synbiotic for people with chronic kidney disease.

Synbiotic versus another synbiotic for people with chronic kidney disease
Patient or population: people with CKD Setting: hospital or primary care Intervention: synbiotic 2 Comparison: synbiotic 1
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No. of participants (RCTs)	Certainty of the evidence (GRADE)
Outcomes	Risk with synbiotic 1	Risk with synbiotic 2	Relative effect (95% CI)	No. of participants (RCTs)	Certainty of the evidence (GRADE)
eGFR	‐	‐	‐	‐	‐
Albuminuria or proteinuria	‐	‐	‐	‐	‐
Indoxyl sulfate	‐	‐	‐	‐	‐
Change in any GI upset or intolerance	‐	‐	‐	‐	‐
Microbiota composition	‐	‐	‐	‐	‐
Graft function	‐	‐	‐	‐	‐
Graft infection	‐	‐	‐	‐	‐
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; CKD: chronic kidney disease; eGFR: (estimated) glomerular filtration rate; GI: gastrointestinal; RCT: randomised controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Synbiotic versus prebiotic for people with chronic kidney disease
Patient or population: people with CKD Setting: hospital or primary care Intervention: synbiotic Comparison: prebiotic
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No. of participants (RCTs)	Certainty of the evidence (GRADE)
	Risk with prebiotic	Risk with synbiotic
eGFR (mL/min) Follow‐up: 4 weeks	CKD stage 3Ga (transplant)		‐	34 (1)	⊕⊝⊝⊝ very low¹
	The mean eGFR was 3.8 mL/min lower (17.98 lower to 10.38 higher) with synbiotic compared prebiotic
Albuminuria or proteinuria	‐	‐	‐	‐	‐
Indoxyl sulfate (ng/mL) Follow‐up: 4 weeks	CKD stage G5D		‐	42 (1)	⊕⊝⊝⊝ very low¹
	The mean indoxyl sulfate was 128.3 ng/mL higher (242.77 lower to 499.37 higher) with synbiotic compared prebiotic
Change in any GI upset (borborygmi) Follow‐up: 4 weeks	CKD stage 3Ga (transplant)		RR 15.26 (0.99 to 236.23)	34 (1)	⊕⊝⊝⊝ very low¹
	0 per 1,000	0 per 1,000 (0 to 0)
Change in any GI upset (GSRS total index) Follow‐up: 12 months	CKD stage 3 to 4			56 (1)	⊕⊝⊝⊝ very low¹
	The mean change in any GI upset was 0.00 (0.27 lower to 0.27 higher) with synbiotic compared prebiotic
Microbiota composition	‐	‐	‐	‐	‐
Graft function	‐	‐	‐	‐	‐
Graft infection	‐	‐	‐	‐	‐
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; CKD: chronic kidney disease; eGFR: estimated glomerular filtration rate; GI: gastrointestinal; RR: risk ratio; RCT: randomised controlled trial
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Prebiotic versus another prebiotic for people with chronic kidney disease
Patient or population: people with CKD Setting: hospital or primary care Intervention: prebiotic 2 Comparison: prebiotic 1
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No. of participants (RCTs)	Certainty of the evidence (GRADE)
	Risk with prebiotic 1	Risk with prebiotic 2
eGFR (mL/min) Follow‐up: 12 weeks	CKD stage 3 to 5 (non‐dialysis)		‐	50 (1)	⊕⊝⊝⊝ very low¹
	The mean eGFR was 0 mL/min lower (1.73 lower to 1.73 higher) with prebiotic 2 compared to prebiotic 1
Albuminuria or proteinuria	‐	‐	‐	‐	‐
Indoxyl sulfate (μg/mL) Follow‐up: 6 weeks	CKD stage G5D with diabetes		‐	64 (2)	⊕⊝⊝⊝ very low¹
	The mean indoxyl sulfate was 0.2 μg/mL lower (1.01 lower to 0.61 higher) with prebiotic 2 compared to prebiotic 1
Change in any GI upset or intolerance Follow‐up: 4 weeks	CKD stage G5D with diabetes		‐	24 (1)	⊕⊝⊝⊝ very low¹
Burping	The mean burping was 0.17 higher (0.5 lower to 0.84 higher) with prebiotic 2 compared to prebiotic 1
Cramping	The mean cramping was 0.17 lower (0.5 lower to 0.16 higher) with prebiotic 2 compared to prebiotic 1
Distension	The mean distension was 0.33 higher (0.04 lower to 0.7 higher) with prebiotic 2 compared to prebiotic 1
Flatulence	The mean flatulence was 1 higher (0.25 higher to 1.75 higher) with prebiotic 2 compared to prebiotic 1
Nausea	The mean nausea was 0 (0 to 0 ) with prebiotic 2 compared to prebiotic 1
Reflux	The mean reflux was 0 (0.5 lower to 0.5 higher) with prebiotic 2 compared to prebiotic 1
Rumblings	The mean rumblings was 0.5 higher (0.14 lower to 1.14 higher) with prebiotic 2 compared to prebiotic 1
Microbiota composition Follow‐up: 4 weeks	CKD stage G5D with diabetes		‐	24 (1)	‐
Actinobacteria	The mean Actinobacteria was 1.26 lower (4.46 lower to 1.94 higher) with prebiotic 2 compared to prebiotic 1
Bacteriodetes	The mean Bacteriodetes was 3.23 higher (8.24 lower to 14.7 higher) with prebiotic 2 compared to prebiotic 1
Proteobacteria	The mean Proteobacteria was 0.11 higher (1.61 lower to 1.83 higher) with prebiotic 2 compared to prebiotic 1
Firmicutes	The mean Firmicutes was 2.44 lower (14.19 lower to 9.31 higher) with prebiotic 2 compared to prebiotic 1
Synergistetes	The mean Synergistetes was MD 0.25 lower (0.89 lower to 0.39 higher) with prebiotic 2 compared to prebiotic 1
Verrucomicrobia	The mean Verrucomicrobia was 0.96 higher (1.36 lower to 3.28 higher) with prebiotic 2 compared to prebiotic 1
Faecal acetate	The mean faecal acetate was 69.91 lower (203.95 lower to 64.13 higher) with prebiotic 2 compared to prebiotic 1
Faecal propionate	The mean faecal propionate was 19.35 lower (63.87 lower to 25.17 higher) with prebiotic 2 compared to prebiotic 1
Faecal butyrate	The mean faecal butyrate was 11.04 lower (39.57 lower to 17.49 higher) with prebiotic 2 compared to prebiotic 1
Faecal total short‐chain fatty acids	The mean faecal total short‐chain fatty acids were 104.71 lower (293.34 lower to 83.92 higher) with prebiotic 2 compared to prebiotic 1
Faecal total short‐chain fatty acids	The mean faecal total short‐chain fatty acids were 104.71 lower (293.34 lower to 83.92 higher) with prebiotic 2 compared to prebiotic 1
Faecal indoles	The mean faecal indoles were 2.71 higher (69.78 lower to 75.2 higher) with prebiotic 2 compared to prebiotic 1
Faecal P‐cresol	The mean faecal p‐cresol was 28.84 higher (105.07 lower to 162.75 higher) with prebiotic 2 compared to prebiotic 1
Graft function	‐	‐	‐	‐	‐
Graft infection	‐	‐	‐	‐	‐
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CKD: chronic kidney disease; CI: confidence interval; eGFR: estimated glomerular filtration rate; GI: gastrointestinal; RR: risk ratio; RCT: randomised controlled trial
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Prebiotic versus probiotic for people with chronic kidney disease
Patient or population: people with CKD Settings: hospital or primary care Intervention: prebiotic Comparison: probiotic
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (RCTs)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Risk with probiotic	Risk with prebiotic
eGFR	‐	‐	‐	‐	‐
Albuminuria or proteinuria	‐	‐	‐	‐	‐
Indoxyl sulfate	‐	‐	‐	‐	‐
Change in any GI upset or intolerance	‐	‐	‐	‐	‐
Microbiota composition	‐	‐	‐	‐	‐
Graft function	‐	‐	‐	‐	‐
Graft infection	‐	‐	‐	‐	‐
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CKD: chronic kidney disease; CI: confidence interval; eGFR: estimated glomerular filtration rate; GI: gastrointestinal; RCT: randomised controlled trial
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Probiotic versus another probiotic for people with chronic kidney disease
Patient or population: people with CKD Setting: hospital or primary care Intervention: probiotic 2 Comparison: probiotic 1
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No. of participants (RCTs)	Certainty of the evidence (GRADE)
Outcomes	Risk with probiotic 1	Risk with probiotic 2	Relative effect (95% CI)	No. of participants (RCTs)	Certainty of the evidence (GRADE)
eGFR (mL/min) Follow‐up: 8 weeks	CKD stage G3 to G4		‐	30 (1)	⊕⊝⊝⊝ very low¹
eGFR (mL/min) Follow‐up: 8 weeks	The mean eGFR was 0.64 mL/min lower (9.51 lower to 8.23 higher) with probiotic 2 than probiotic 1		‐	30 (1)	⊕⊝⊝⊝ very low¹
Albuminuria or proteinuria	‐	‐	‐	‐	‐
Indoxyl sulfate	‐	‐	‐	‐	‐
Change in any GI upset or intolerance	‐	‐	‐	‐	‐
Microbiota composition	‐	‐	‐	‐	‐
Graft function	‐	‐	‐	‐	‐
Graft infection	‐	‐	‐	‐	‐
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CKD: chronic kidney disease; CI: confidence interval; eGFR: estimated glomerular filtration rate; GI: gastrointestinal; RR: risk ratio; RCT: randomised controlled trial
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Synbiotic versus placebo or no treatment for people with chronic kidney disease
Patient or population: people with CKD Setting: hospital or primary care Intervention: synbiotic Comparison: placebo or no treatment
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No. of participants (RCTs)	Certainty of the evidence (GRADE)
	Risk with placebo or no treatment	Risk with synbiotic
eGFR (mL/min) Follow‐up: 6 or 12 weeks	CKD stage G3b		‐	98 (2)	⊕⊝⊝⊝ very low¹
	The mean eGFR was 1.42 mL/min higher (0.65 higher to 2.2 higher) with synbiotic than placebo or no treatment
Albuminuria or proteinuria	‐	‐	‐	‐	‐
Indoxyl sulfate	‐	‐	‐	‐	‐
Change in any GI upset or intolerance (GSRS) Follow‐up: 12 weeks	CKD stage 3b		‐	23 (1)	⊕⊝⊝⊝ very low¹
Rumbling	The mean rumbling was 0.54 GSRS lower (0.77 lower to 0.31 lower) with synbiotic than placebo or no treatment
Hard stools	The mean hard stools was 0.09 GSRS lower (0.35 lower to 0.17 higher) with synbiotic than placebo or no treatment
Abdominal pain	The mean abdominal pain was 0.22 GSRS higher (0.02 lower to 0.46 higher) with synbiotic than placebo or no treatment
Constipation syndrome	The mean constipation syndrome was 0.17 GSRS lower (0.72 lower to 0.38 higher) with synbiotic than placebo or no treatment
Microbiota composition	‐	‐	‐	‐	‐
Graft function	‐	‐	‐	‐	‐
Graft infection	‐	‐	‐	‐	‐
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CKD: chronic kidney disease; CI: confidence interval; eGFR: estimated glomerular filtration rate; GI: gastrointestinal; RR: risk ratio; RCT: randomised controlled trial
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Prebiotic versus placebo or no treatment for people with chronic kidney disease
Patient or population: people with CKD Setting: hospital or primary care Intervention: prebiotic Comparison: placebo or no treatment
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No. of participants (RCTs)	Certainty of the evidence (GRADE)
	Risk with placebo or no treatment	Risk with prebiotic
eGFR	‐	‐	‐	‐	‐
Albuminuria or proteinuria	‐	‐	‐	‐	‐
Indoxyl sulfate (mg/L) Follow‐up: 8 weeks	CKD stage G5D		‐	75 (2)	⊕⊝⊝⊝ very low¹
	The mean indoxyl sulfate was 0.14 mg/L lower (0.6 lower to 0.31 higher) with prebiotic than placebo or no treatment
Any change in GI upset or intolerance	‐	‐	‐	‐	‐
Microbiota composition Follow‐up: 8 weeks	CKD stage 5GD		‐	44 (1)	⊕⊝⊝⊝ very low¹
Faecalibacterium	The mean Faecalibacterium was 2.37 higher (0.23 higher to 4.51 higher) with prebiotic than placebo or no treatment
Parabacteroides	The mean Parabacteroides was 0.22 higher (0.06 higher to 0.38 higher) with prebiotic than placebo or no treatment
Bifidobacteria	The mean Bifidobacteria was 3.92 lower (9.83 lower to 1.99 higher) with prebiotic than placebo or no treatment
Ruminococcus	The mean Ruminococcus was 3.86 higher (0.32 lower to 8.04 higher) with prebiotic than placebo or no treatment
Prevotella	The mean Prevotella was 0.43 lower (1.45 lower to 0.59 higher) with prebiotic than placebo or no treatment
Graft function	‐	‐	‐	‐	‐
Graft infection	‐	‐	‐	‐	‐
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CKD: chronic kidney disease; CI: confidence interval; eGFR: estimated glomerular filtration rate; GI: gastrointestinal; RR: risk ratio; RCT: randomised controlled trial
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Probiotic versus placebo or no treatment for people with chronic kidney disease
Patient or population: people with CKD Setting: hospital or primary care Intervention: probiotic Comparison: placebo or no treatment
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No. of participants (RCTs)	Certainty of the evidence (GRADE)
	Risk with placebo or no treatment	Risk with probiotic
eGFR (mL/min) Follow‐up: 8, 12 or 15 weeks	CKD stage 1 with type 2 diabetes mellitus		‐	40 (1)	⊕⊝⊝⊝ very low¹
	The mean eGFR was 12.1 mL/min higher (4.19 higher to 20.01 higher) with probiotic than placebo or no treatment
	CKD stage 3A with diabetes and hypertension		‐	28 (1)
	The mean eGFR mL/min was 0.4 higher (4.15 lower to 4.95 higher) with probiotic than placebo or no treatment
	CKD stage G5D with diabetes and hypertension		‐	60 (1)
	The mean eGFR was 0.02 mL/min higher (0.63 lower to 0.67 higher) with probiotic than placebo or no treatment
Albuminuria (g/dL) Follow‐up: 12 or 24 weeks	CKD stage G5D		‐	33 (1)	⊕⊕⊝⊝ low²
	The mean albuminuria was 0 g/dL (0.19 lower to 0.19 higher) with probiotic than placebo or no treatment
	CKD stage G5D with diabetes and hypertension		‐	160 (3)
	The mean albuminuria was 0.03 g/dL higher (0.1 lower to 0.16 higher) with probiotic than placebo or no treatment
Proteinuria (mg/dL) Follow‐up: 12 or 24 weeks	CKD stages 1 to 5 with diabetic nephropathy		‐	60 (1)	⊕⊝⊝⊝ very low¹
	The mean albuminuria was 15.6 g/dL (34.3 lower to 3.1 higher) with probiotic than placebo or no treatment
Indoxyl sulfate (mg/dL) Follow‐up: 12 or 24 weeks	CKD stage G5D		‐	33 (1)	⊕⊝⊝⊝ very low¹
	The mean indoxyl sulfate was 6 mg/dL lower (15.02 lower to 3.02 higher) with probiotic than placebo or no treatment
	CKD stage G5D with diabetes and hypertension		‐	50 (1)	⊕⊝⊝⊝ very low¹
	The mean indoxyl sulfate was 3.14 mg/dL lower (10.26 lower to 3.98 higher) with probiotic than placebo or no treatment
Change in any GI upset or intolerance (abdominal pain/diarrhoea) Follow‐up: 12 weeks	CKD stage G5D		RR 2.13 (0.21 to 21.22)	33 (1)	⊕⊝⊝⊝ very low¹
	59 per 1,000	125 per 1,000 (12 to 1,000)
Change in any GI upset or intolerance (constipation) Follow‐up: 12 weeks	CKD stage G5D		RR 3.18 (0.14 to 72.75)	33 (1)	⊕⊝⊝⊝ very low¹
	0 per 1,000	0 per 1,000 (0 to 0)
Microbiota composition	‐	‐	‐	‐	‐
Graft function	‐	‐	‐	‐	‐
Graft infection	‐	‐	‐	‐	‐
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CKD: chronic kidney disease; CI: confidence interval; eGFR: estimated glomerular filtration rate; GI: gastrointestinal; RR: risk ratio; RCT: randomised controlled trial
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

				Persistent albuminuria categories Description and range
				A1	A2	A3
				Normal to mildly increased	Moderately increased	Severely increased
				ACR^a < 30 mg/g	ACR  30 to 300 mg/g	ACR > 300 mg/g
eGFR^b categories (mL/min/1.73 m²) Description and range	G1	Normal or high^c	≥ 90	1 if CKD	1	2
	G2	Mildly decreased^c	60 to 89	1 if CKD	1	2
	G3a	Mildly to moderately decreased	45 to 59	1	2	3
	G3b	Moderately to severely decreased	30 to 44	2	3	3
	G4	Severely decreased	15 to 29	3	3	4+
	G5	Kidney failure	< 15	4+	4+	4+

Database	Search terms
CENTRAL	synbiotic:ti,ab,kw probiotic:ti,ab,kw prebiotic:ti,ab,kw (bifido or lactobacill):ti,ab,kw bacillus:ti,ab,kw enterococcus:ti,ab,kw escherichia:ti,ab,kw oligosaccharide:ti,ab,kw saccharomyces:ti,ab,kw streptococcus next thermophilus:ti,ab,kw (resistant next starch):ti,ab,kw polydextrose:ti,ab,kw (dietary next (fiber or fibre)):ti,ab,kw "gum arabic":ti,ab,kw "hi‐maize":ti,ab,kw oligosaccharides:ti,ab,kw familact:ti,ab,kw "probinul neutro":ti,ab,kw inulin:ti,ab,kw {OR #1‐#19} (kidney next disease* or renal next disease* or kidney next failure or renal next failure):ti,ab,kw renal next insufficiency:ti,ab,kw dialysis:ti,ab,kw (hemodialysis or hemofiltration or hemodiafiltration):ti,ab,kw "renal replacement therapy":ti,ab,kw (ESRF or ESKF or ESRD or ESKD):ti,ab,kw (CKF or CKD or CRF or CRD):ti,ab,kw (CAPD or CCPD or APD):ti,ab,kw (predialysis or "pre‐dialysis"):ti,ab,kw ((kidney or renal) next (transplant or graft*)):ti,ab,kw {OR #21‐#30 #20 and #31 in Trials
MEDLINE	Synbiotics/ Probiotics/ Prebiotics/ synbiotic.tw. probiotic.tw. prebiotic.tw. or/1‐6 Bifidobacterium bifidum/ exp Lactobacillus/ Streptococcus Thermophilus/ exp Saccharomyces/ exp Bacillus/ exp Enterococcus/ Oligosaccharides/ Escherichia/ (bifido or lactobacill).tw. streptococcus thermophilus.tw. saccharomyces.tw. bacillus.tw. enterococcus.tw. eschericia.tw. Dietary Fiber/ Gum Arabic/ (dietary fiber or dietary fibre).tw. resistant starch.tw. polydextrose.tw. gum arabic.tw. hi‐maize.tw. oligosaccharides.tw. familact.tw. probinul neutro.tw. Inulin/ 33 inulin.tw. or/8‐33 or/7,34 exp Kidney Diseases/ exp Renal Replacement Therapy/ dialysis.tw. (hemodialysis or haemodialysis).tw. (hemofiltration or haemofiltration).tw. (hemodiafiltration or haemodiafiltration).tw. (kidney disease or renal disease* or kidney failure or renal failure).tw. (ESRF or ESKF or ESRD or ESKD).tw. (CKF or CKD or CRF or CRD).tw. (CAPD or CCPD or APD).tw. (predialysis or pre‐dialysis).tw. (diabet* adj5 (kidney or renal)).tw. DKD.tw. (glomerulo* or glomerular).tw. (nephritis or nephrotic).tw. (PKD or ADPKD).tw. ((kidney or renal) adj1 (transplant* or graft*)).tw. or/36‐52 and/35,53
EMBASE	synbiotic agent/ prebiotic agent/ exp probiotic agent/ synbiotic.tw. probiotic.tw. prebiotic.tw. or/1‐6 bifidobacterium bifidum/ exp Lactobacillus/ exp bacillus/ exp enterococcus/ escherichia/ oligosaccharide/ exp saccharomyces/ streptococcus thermophilus/ (bifido or lactobacill).tw. bacillus.tw. enterococcus.tw. escherichia.tw. oligosaccharide.tw. saccharomyces.tw. streptococcus thermophilus.tw. dietary fiber/ gum arabic/ gum arabic.tw. (dietary adj (fiber or fibre)).tw. resistant starch.tw. polydextrose.tw. hi‐maize.tw. familact.tw. probinul neutro.tw. Inulin/ inulin.tw. or/8‐33 or/7,34 exp renal replacement therapy/ kidney disease/ chronic kidney disease/ kidney failure/ chronic kidney failure/ mild renal impairment/ stage 1 kidney disease/ moderate renal impairment/ severe renal impairment/ end stage renal disease/ renal replacement therapy‐dependent renal disease/ diabetic nephropathy/ (hemodialysis or haemodialysis).tw. (hemofiltration or haemofiltration).tw. (hemodiafiltration or haemodiafiltration).tw. dialysis.tw. (CAPD or CCPD or APD).tw. (kidney disease* or renal disease* or kidney failure or renal failure).tw. (CKF or CKD or CRF or CRD).tw. (ESRF or ESKF or ESRD or ESKD).tw. (predialysis or pre‐dialysis).tw. exp kidney transplantation/ ((kidney or renal) adj1 (transplant* or graft*)).tw. or/36‐58 and/35,59

Potential source of bias	Assessment criteria
Random sequence generation Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence	Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimisation (minimisation may be implemented without a random element, and this is considered to be equivalent to being random).
	High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
	Unclear: Insufficient information about the sequence generation process to permit judgement.
Allocation concealment Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment	Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web‐based, and pharmacy‐controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
	High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non‐opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
	Unclear: Randomisation stated but no information on method used is available.
Blinding of participants and personnel Performance bias due to knowledge of the allocated interventions by participants and personnel during the study	Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Blinding of outcome assessment Detection bias due to knowledge of the allocated interventions by outcome assessors.	Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Incomplete outcome data Attrition bias due to amount, nature or handling of incomplete outcome data.	Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
	High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
	Unclear: Insufficient information to permit judgement
Selective reporting Reporting bias due to selective outcome reporting	Low risk of bias: The study protocol is available and all of the study’s pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).
	High risk of bias: Not all of the study’s pre‐specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. sub‐scales) that were not pre‐specified; one or more reported primary outcomes were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
	Unclear: Insufficient information to permit judgement
Other bias Bias due to problems not covered elsewhere in the table	Low risk of bias: The study appears to be free of other sources of bias.
	High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data‐dependent process (including a formal‐stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
	Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Study ID	Synbiotic	Prebiotic	Probiotic	Placebo	No treatment/the control starch etc.	Notes from study
Abbasi 2017	‐	‐	Any AE: 4/22 (flatulence: 4) Withdrawal due to AE: 0	‐	Any AE: 5/22 (flatulence: 5) Withdrawal due to AE: 0	Also some minor complaints about the specific taste of soy milk at start. The numbers are not clear
Biruete 2017	‐	Any AE: not reported Withdrawal due to AE: not reported	‐	‐	‐	None reported
Bliss 1992	‐	Gum Arabic Any AE: 8/20 (flatulence: 8) Withdrawal due to AE: unclear Pectin Any AE: 0/20 Withdrawal due to AE: unclear	‐	‐	‐	‐
Borges 2018	‐	‐	Any AE: 5/23 (abdominal pain/diarrhoea: 2; constipation: 1; precordial pain: 2) Withdrawal due to AE: 5	Any AE: 1/23 (abdominal pain: 1; death: 2 (not related to study)) Withdrawal due to AE: 1	‐	‐
Cosola 2021	Any AE: 0/13 Withdrawal due to AE: 0/13	‐	‐	Any AE: 0/13 Withdrawal due to AE: 0/13	‐	‐
de Andrade 2021	‐	Any AE: 0/43 Withdrawal due to AE: 0/43	‐	Any AE: 0/43 Withdrawal due to AE: 0/43	‐	‐
de Araujo 2022	‐	‐	Any AE: 2/40 (abdominal pain/diarrhoea: 2) Withdrawal due to AE: 2	Any AE: 0/40 Withdrawal due to AE: 0/40	‐	‐
Dehghani 2016	Any AE: 4/denominator not clear Withdrawal due to AE: 4	‐	‐	Any AE: 3/denominator not clear Withdrawal due to AE: 3	‐	‐
Ebrahim 2022	‐	Any AE: 0/30 Withdrawals due to AE: 0	‐	‐	Any AE: 0/30 Withdrawals due to AE: 0	‐
Eidi 2018	‐	‐	Any AE: 2/30 (abdominal ascites (acute): 1; vertigo: 1) Withdrawal due to AE: 2/30	Any AE: 0/29 Withdrawal due to AE: 0/29	‐	‐
Elamin 2017	‐	Any AE: unclear/36 Withdrawal due to AE: unclear/36	‐	‐	‐	Quote: "GA supplements were well tolerated with no significant gastrointestinal side effects (Table 4). One patient discontinued the supplements after one dose because she did not like the texture of the solution." Comment: these were reported as a mean across the entire 3 prebiotic groups
Esgalhado 2018	‐	Any AE: unclear/19 (unclear deaths but not related to study drugs) Withdrawal due to AE: unclear	‐	Any AE: unclear/19 (unclear deaths but not related to study drugs) Withdrawal due to AE: unclear	‐	Withdrawals and dropout reasons are unclear whether attributed to study drug or other reasons
Guida 2014	Any AE: 0/18 Withdrawal due to AE: 0/18	Any AE: 0/12 Withdrawal due to AE: 0/12	‐	‐	‐	‐
Guida 2017	Any AE: 13/22 Withdrawal due to AE: 0/22	Any AE: 0/12 Withdrawal due to AE: 0/12	‐	‐	‐	Quote: "Treatment with synbiotics was well tolerated with no relevant gastrointestinal adverse effect; borborygmi were reported as occasional by most patients (60%), whereas abdominal pain was virtually absent in both groups."
He 2022	‐	Oligosaccharide Any AE: 0/33 Withdrawal due to AE: 0/33 Maltodextrin Any AE: 1/33 (peritonitis: 1) Withdrawal due to AE: 1/33 (peritonitis: 1)	‐	‐	‐	‐
Haghighat 2019	Any AE: 1/50 (headache: 1) Withdrawal due to AE: 0	Any AE: 3/25 (headache: 1; fatigue: 1; breathing problems: 1) Withdrawal due to AE: 0	‐	‐	‐	These adverse events in this study were judged by the authors to be unrelated to study interventions
Khosroshahi 2018	‐	Any AE: 5/25 (epigastric pain and vomiting: 1; distention: 2; nausea: 2) Withdrawal due to AE: 1 (epigastric pain and vomiting: 1)	‐	Any AE: 2/25 (dyspepsia: 1; nausea: 1) Withdrawal due to AE: 0	‐
Kooshki 2019	Any AE: not reported/25 Withdrawal due to AE: not reported	‐	‐	Any AE: not reported/25 Withdrawal due to AE: not reported	‐	‐
Li 2020	‐	Inulin Any AE: 2/19 (peritonitis: 2) Withdrawals due to AE: 2 Maltodextrin Any AE: 3/20 (peritonitis: 2; death: 1 (not related to study drug)) Withdrawal due to AE: 3	‐	‐	‐	Data are not entered into meta‐analysis as these are from both phases of cross‐over
Lim 2021	‐	‐	Any AE: 2/28 (infection: 2) Withdrawal due to AE: 2/28 (hospitalisation due to infection: 2)	Any AE: 0/28 Withdrawal due to AE: 0/28	‐	One death in each arm but not related to study treatment Quote: "No significant gastrointestinal side effects were reported or recorded throughout the study in either group."
Liu 2020	‐	‐	Any AE: unclear/25 Withdrawal due to AE: unclear/25	Any AE: unclear/25 Withdrawal due to AE: unclear/25	Three from probiotics and 2 from placebo discontinued but reasons not provided and unclear whether related to adverse effects from study intervention or simply lost.
Lopes 2018	Any AE: 14/49 (abdominal discomfort: 3; did not fit the food: 5; difficulty consuming product at home: 2; hospitalisation and death (unclear whether related to study): 4) Withdrawal due to AE: 10 (abdominal discomfort: 3; did not fit the food: 5; difficulty consuming product at home: 2)	Any AE: 13/50 (abdominal discomfort: 4; did not fit the food: 5; difficulty consuming product at home: 4) Withdrawal due to AE: 13 (abdominal discomfort: 4; did not fit the food: 5; difficulty consuming product at home: 4)	‐	‐	‐	‐
Lydia 2022	Any AE: 9/30 (diarrhoea: 6; nausea: 2; bloating: 1) Withdrawal due to AE: 2/30 (diarrhoea: 2)	‐	‐	Any AE: 7/30 (diarrhoea: 2; nausea: 3; stomach ache/heartburn: 2) Withdrawal due to AE: 0/30	‐	‐
Mafi 2018	‐	‐	Any AE: not reported/30 Withdrawal due to AE: 0/30	Any AE: not reported/30 ThreeWithdrawal due to AE: 0/30	‐	Three withdrawals from each group due to personal reasons and not related to the study drug
Mazruei Arani 2019	‐	‐	Any AE: not reported/30 Withdrawals due to AE: not reported/30	Any AE: not reported/30 Withdrawals due to AE: not reported/30	‐	Two withdrawals from probiotic group, 1 withdrawal from placebo group. Reasons not provided and unclear whether related to study or not
Meng 2019	‐	Any AE: 1/37: AE not specified Withdrawal due to AE: 1/37	‐	‐	Any AE: 0/38 Withdrawal due to AE: 0/38	‐
Miraghajani 2017	‐	‐	Any AE: not reported/24 Withdrawals due to AE: 0/24	‐	Any AE: not reported/24 Withdrawals due to AE: 0/24
Miranda Alatriste 2014	‐	‐	Lower dose Any AE: 0/15 Withdrawal due to AE: 0/16 Higher dose Any AE: 0/15 Withdrawal due to AE: 0/16	‐	‐	One hospitalised with urinary tract infection in low dose probiotic group, but not specified whether this was related to study drug One participant did not tolerate the drink, but this was during inclusion criteria and pre‐randomisation
Mirzaeian 2020	Any AE: 0/24 Withdrawal due to AE: 0/24	Any AE: 0/24 Withdrawal due to AE: 0/24	‐	‐	‐	One death in each arm; however, not related to the study intervention
Natarajan 2014	‐	Any AE: unclear/28 Withdrawal due to AE: unclear/28	Any AE: 2/28 Withdrawal due to AE: 2/28 (nausea and vomiting: 2)	‐	‐	Cross‐over numbers and denominators are unclear One death not related to study intervention: myocardial infarction at home from underlying cardiovascular conditions
Pan 2021	‐	Any AE: 0/58 Withdrawals due to AE: 0/58	Any AE: 0/58 Withdrawals due to AE: 0/58	‐	‐	Other lost to follow‐up not related to study treatment
PREBIOTIC 2022	‐	Any AE: 15/27 (UTI: 9; skin: 2; GI: 1; other: 3) Serious AE: 9/27 (hospitalised due to GI issue: 4; hospitalised due to skin issue: 2; hospitalised due to other: 3) Withdrawals due to AE: unclear/27	‐	Any AE: 14/27 (bloodstream infection: 1; respiratory infection: 1; UTI: 6; skin issue: 3; cardiovascular: 1; GI: 2) Serious AE: 1/27 (hospitalised due to UTI: 1) Withdrawals due to AE: unclear/27	‐	Withdrawals due to adverse events are unclear. There appear to be several discontinued participants in both arms. Reasons not linked to whether these are due to adverse events or practicalities of the feasibility trial. ITT analysis was undertaken
ProbiotiCKD 2019	‐	‐	Any AE: 0/14 Withdrawal due to AE: 0/14	Any AE: 0/14 Withdrawal due to AE: 0/14	‐	‐
Poesen 2016	‐	Rabinoxylan Any AE: 1/40 (nausea) Withdrawal due to AE: 1/40 Maltodextrin Any AE: 0/40 Withdrawal due to AE: 0/40	‐	‐	‐	‐
Ranganathan 2009	‐	‐	Any AE: 0/16 Withdrawal due to AE: 0/16	Any AE: 0/16 Withdrawal due to AE: 0/16	‐	Three were withdrawn not due to adverse effects from study treatment The serious AE,MI, was not clear which group
Ramos 2019	‐	Fructo‐oligosaccharide Any AE: 0/24 Withdrawal due to AE: 0 Maltodextrin Any AE: 0/26 Withdrawal due to AE: 0	‐	‐	‐	The discontinued patients were not due to GI symptoms or due to the need of antibiotics
Shariaty 2017	‐	‐	Any AE: not reported/18 Withdrawals due to AE: not reported	Any AE: not reported/18 Withdrawals due to AE: not reported	‐	No adverse events reported, possible none
Sirich 2014	‐	Any AE: 0/28 Withdrawal due to AE: 2/28	‐	‐	Any AE: 2/28 (bloating: 1; loose stools: 1) Withdrawal due to AE: 2/28 (bloating: 1; loose stools: 1)	‐
Soleimani 2017	‐	‐	Any AE: 0/30 Withdrawals due to AE: 0	Any AE: 0/30 Withdrawals due to AE: 0	‐	‐

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Patient‐reported outcomes: HRQoL at 12 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
1.1.1 CKD stage G5D with diabetes and hypertension	1	46	Mean Difference (IV, Random, 95% CI)	1.98 [‐11.12, 15.08]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Kidney function: eGFR at 4 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.1.1 CKD stage 3Ga (transplant)	1	34	Mean Difference (IV, Random, 95% CI)	‐3.80 [‐17.98, 10.38]
2.2 Kidney function: serum creatinine at 8 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.2.1 CKD stage G5D	1	42	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐1.50, 1.10]
2.3 Uraemic toxins: urea at 4 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.3.1 CKD stage G5D	1	42	Mean Difference (IV, Random, 95% CI)	‐2.10 [‐13.93, 9.73]
2.4 Uraemic toxins: indoxyl sulfate at 4 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.4.1 CKD stage G5D	1	42	Mean Difference (IV, Random, 95% CI)	128.30 [‐242.77, 499.37]
2.5 Uraemic toxins: p‐cresol sulfate at 4 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.5.1 CKD stage 3Ga (transplant)	1	34	Mean Difference (IV, Random, 95% CI)	‐2.10 [‐3.92, ‐0.28]
2.6 GI function: change in any GI upset or intolerance (prevalence of borborygmi) at 4 weeks	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.6.1 CKD stage 3Ga (transplant)	1	34	Risk Ratio (M‐H, Random, 95% CI)	15.26 [0.99, 236.23]
2.7 GI function: change in any GI upset or intolerance (GSRS Total Index at 12 months)	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.7.1 CKD Stage 3 to 4	1	56	Mean Difference (IV, Random, 95% CI)	0.00 [‐0.27, 0.27]
2.8 GI function: faecal pH at 7 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.8.1 CKD stage G5D	1	58	Mean Difference (IV, Random, 95% CI)	‐0.63 [‐1.13, ‐0.13]
2.9 GI function: faecal characteristics (Bristol Stool Chart) at 4 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.9.1 CKD stage 3Ga (transplant)	1	34	Mean Difference (IV, Random, 95% CI)	‐0.50 [‐1.15, 0.15]
2.10 GI function: faecal characteristics (Bristol Stool Chart) at 12 months	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.10.1 CKD stage 3 to 4	1	56	Mean Difference (IV, Random, 95% CI)	0.50 [‐0.18, 1.18]
2.11 Patient‐reported outcomes: HRQoL at 24 weeks	2		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.11.1 CKD stage G5D with diabetes and hypertension	2	65	Mean Difference (IV, Random, 95% CI)	6.38 [‐4.88, 17.64]
2.12 Adverse events: any adverse event	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.12.1 CKD stage G3a (transplant)	2	64	Risk Ratio (M‐H, Random, 95% CI)	15.26 [0.99, 236.23]
2.12.2 CKD stage 3 to 4	1	68	Risk Ratio (M‐H, Random, 95% CI)	1.48 [0.65, 3.36]
2.12.3 CKD stage 5GD	2	147	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.58, 2.09]
2.13 Withdrawals due to adverse events	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.13.1 CKD stage 3Ga (transplant)	2	64	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
2.13.2 CKD stage G5D	2	147	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.38, 1.62]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Kidney function: eGFR at 12 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.1.1 CKD stage 3 to 5 (non‐dialysis)	1	50	Mean Difference (IV, Random, 95% CI)	0.00 [‐1.73, 1.73]
3.2 Uraemic toxins: indoxyl sulfate at 6 weeks	2		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.2.1 CKD stage G5D with diabetes	2	64	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐1.01, 0.61]
3.3 Uraemic toxins: p‐cresol sulfate at 6 weeks	2		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only
3.3.1 CKD stage G5D with diabetes	2	64	Std. Mean Difference (IV, Random, 95% CI)	‐0.04 [‐0.53, 0.45]
3.4 GI function: change in any GI upset or intolerance (burping) at 4 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.4.1 CKD stage G5D with diabetes	1	24	Mean Difference (IV, Random, 95% CI)	0.17 [‐0.50, 0.84]
3.5 GI function: change in any GI upset or intolerance (cramping) at 4 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.5.1 CKD stage G5D with diabetes	1	24	Mean Difference (IV, Random, 95% CI)	‐0.17 [‐0.50, 0.16]
3.6 GI function: change in any GI upset or intolerance (distension) at 4 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.6.1 CKD stage G5D with diabetes	1	24	Mean Difference (IV, Random, 95% CI)	0.33 [‐0.04, 0.70]
3.7 GI function: change in any GI upset or intolerance (flatulence) at 4 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.7.1 CKD stage G5D with diabetes	1	24	Mean Difference (IV, Random, 95% CI)	1.00 [0.25, 1.75]
3.8 GI function: change in any GI upset or intolerance (nausea) at 4 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.8.1 CKD stage G5D with diabetes	1	24	Mean Difference (IV, Random, 95% CI)	0.00 [‐0.00, 0.00]
3.9 GI function: change in any GI upset or intolerance (reflux) at 4 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.9.1 CKD stage G5D with diabetes	1	24	Mean Difference (IV, Random, 95% CI)	0.00 [‐0.50, 0.50]
3.10 GI function: change in any GI upset or intolerance (rumblings) at 4 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.10.1 CKD stage G5D with diabetes	1	24	Mean Difference (IV, Random, 95% CI)	0.50 [‐0.14, 1.14]
3.11 GI function: microbiota composition (Actinobacteria) at 4 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.11.1 CKD stage G5D with diabetes	1	24	Mean Difference (IV, Random, 95% CI)	‐1.26 [‐4.46, 1.94]
3.12 GI function: microbiota composition (Bacteriodetes) at 4 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.12.1 CKD stage G5D with diabetes	1	24	Mean Difference (IV, Random, 95% CI)	3.23 [‐8.24, 14.70]
3.13 GI function: microbiota composition (Proteobacteria) at 4 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.13.1 CKD stage G5D with diabetes	1	24	Mean Difference (IV, Random, 95% CI)	0.11 [‐1.61, 1.83]
3.14 GI function: microbiota composition (Firmicutes) at 4 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.14.1 CKD stage G5D with diabetes	1	24	Mean Difference (IV, Random, 95% CI)	‐2.44 [‐14.19, 9.31]
3.15 GI function: microbiota composition (Synergistetes) at 4 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.15.1 CKD stage G5D with diabetes	1	24	Mean Difference (IV, Random, 95% CI)	‐0.25 [‐0.89, 0.39]
3.16 GI function: microbiota composition (Verrucomicrobia) at 4 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.16.1 CKD stage G5D with diabetes	1	24	Mean Difference (IV, Random, 95% CI)	0.96 [‐1.36, 3.28]
3.17 GI function: microbiota composition (faecal acetate) at 4 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.17.1 CKD stage G5D with diabetes	1	24	Mean Difference (IV, Random, 95% CI)	‐69.91 [‐203.95, 64.13]
3.18 GI function: microbiota composition (faecal propionate) at 4 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.18.1 CKD stage G5D with diabetes	1	24	Mean Difference (IV, Random, 95% CI)	‐19.35 [‐63.87, 25.17]
3.19 GI function: microbiota composition (faecal butyrate) at 4 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.19.1 CKD stage G5D with diabetes	1	24	Mean Difference (IV, Random, 95% CI)	‐11.04 [‐39.57, 17.49]
3.20 GI function: microbiota composition (faecal total short‐chain fatty acids) at 4 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.20.1 CKD stage G5D with diabetes	1	24	Mean Difference (IV, Random, 95% CI)	‐104.71 [‐293.34, 83.92]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Dialysis outcomes: peritonitis at 24 weeks	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
4.1.1 CKD stage G5D with diabetes and hypertension	1	47	Risk Ratio (M‐H, Random, 95% CI)	Not estimable

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Kidney function: GFR at 8 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
5.1.1 CKD stage G3 to G4	1	30	Mean Difference (IV, Random, 95% CI)	‐0.64 [‐9.51, 8.23]
5.2 Kidney function: serum creatinine at 8 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
5.2.1 CKD stage G3 to G4	1	30	Mean Difference (IV, Random, 95% CI)	‐0.13 [‐0.89, 0.63]
5.3 Uraemic toxins: urea at 8 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
5.3.1 CKD stage G3 to G4	1	30	Mean Difference (IV, Random, 95% CI)	4.57 [‐9.52, 18.66]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Kidney function: eGFR at 6 or 12 weeks	2		Mean Difference (IV, Random, 95% CI)	Subtotals only
6.1.1 CKD stage G3b	2	98	Mean Difference (IV, Random, 95% CI)	1.42 [0.65, 2.20]
6.2 Kidney function: SrCr at 6 or 12 weeks	2	98	Mean Difference (IV, Random, 95% CI)	‐0.57 [‐1.08, ‐0.07]
6.2.1 CKD stage G3b	2	98	Mean Difference (IV, Random, 95% CI)	‐0.57 [‐1.08, ‐0.07]
6.3 Uraemic toxins: urea at 6 or 12 weeks	2	117	Mean Difference (IV, Random, 95% CI)	3.34 [‐15.65, 22.32]
6.3.1 CKD stage G3b	1	75	Mean Difference (IV, Random, 95% CI)	‐3.48 [‐14.50, 7.54]
6.3.2 CKD stage G5D with diabetes and hypertension	1	42	Mean Difference (IV, Random, 95% CI)	17.10 [‐8.80, 43.00]
6.4 GI function: GSRS Item 6 (rumbling) at 12 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
6.4.1 CKD stage 3b	1	23	Mean Difference (IV, Random, 95% CI)	‐0.54 [‐0.77, ‐0.31]
6.5 GI function: GSRS Item 13 (hard stools) at 12 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
6.5.1 CKD stage 3b	1	23	Mean Difference (IV, Random, 95% CI)	‐0.09 [‐0.35, 0.17]
6.6 GI function: abdominal pain at 12 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
6.6.1 CKD stage 3b	1	23	Mean Difference (IV, Random, 95% CI)	0.22 [‐0.02, 0.46]
6.7 GI function: constipation syndrome at 12 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
6.7.1 CKD stage 3b	1	23	Mean Difference (IV, Random, 95% CI)	‐0.17 [‐0.72, 0.38]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Kidney function: serum creatinine at 8 or 12 weeks	3	145	Mean Difference (IV, Random, 95% CI)	0.52 [‐2.39, 3.44]
7.1.1 CKD stage A2 with diabetic nephropathy	1	70	Mean Difference (IV, Random, 95% CI)	4.70 [0.47, 8.93]
7.1.2 CKD stage G5D	2	75	Mean Difference (IV, Random, 95% CI)	‐0.75 [‐3.16, 1.66]
7.2 Uraemic toxins: urea at 12 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
7.2.1 CKD stage A2 with diabetic nephropathy	1	70	Mean Difference (IV, Random, 95% CI)	‐0.40 [‐0.86, 0.06]
7.3 Uraemic toxins: indoxyl sulfate at 8 weeks	2		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only
7.3.1 CKD stage G5D	2	75	Std. Mean Difference (IV, Random, 95% CI)	‐0.14 [‐0.60, 0.31]
7.4 Uraemic toxins: p‐cresyl sulfate at 8 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
7.4.1 CKD stage G5D	1	44	Mean Difference (IV, Random, 95% CI)	‐1.68 [‐14.30, 10.94]
7.5 GI function: microbiota composition (Facealibacterium) at 8 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
7.5.1 CKD stage 5GD	1	44	Mean Difference (IV, Random, 95% CI)	2.37 [0.23, 4.51]
7.6 GI function: microbiota composition (Parabacteroides) at 8 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
7.6.1 CKD stage 5GD	1	44	Mean Difference (IV, Random, 95% CI)	0.22 [0.06, 0.38]
7.7 GI function: microbiota composition (Bifidobacteria) at 8 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
7.7.1 CKD stage 5GD	1	44	Mean Difference (IV, Random, 95% CI)	‐3.92 [‐9.83, 1.99]
7.8 GI function: microbiota composition (Ruminococcus) at 8 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
7.8.1 CKD stage 5GD	1	44	Mean Difference (IV, Random, 95% CI)	3.86 [‐0.32, 8.04]
7.9 GI function: microbiota composition (Prevotella) at 8 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
7.9.1 CKD stage 5GD	1	44	Mean Difference (IV, Random, 95% CI)	‐0.43 [‐1.45, 0.59]
7.10 Adverse events: any adverse event (number of participants)	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
7.10.1 CKD stage G5D	1	50	Risk Ratio (M‐H, Random, 95% CI)	2.50 [0.53, 11.70]
7.11 Withdrawals due to adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
7.11.1 CKD stage G5D	1	50	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.13, 70.30]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Kidney function: GFR at 8, 12 or 15 weeks	3	128	Mean Difference (IV, Random, 95% CI)	2.73 [‐2.28, 7.75]
8.1.1 CKD stage 1 and type 2 diabetes	1	40	Mean Difference (IV, Random, 95% CI)	12.10 [4.19, 20.01]
8.1.2 CKD stage 3A with diabetes and hypertension	1	28	Mean Difference (IV, Random, 95% CI)	0.40 [‐4.15, 4.95]
8.1.3 CKD stage G5D with diabetes and hypertension	1	60	Mean Difference (IV, Random, 95% CI)	0.02 [‐0.63, 0.67]
8.2 Kidney function: serum creatinine at 8, 12 or 24 weeks	6	303	Mean Difference (IV, Random, 95% CI)	‐0.51 [‐1.06, 0.04]
8.2.1 CKD stage G5D	1	33	Mean Difference (IV, Random, 95% CI)	‐0.70 [‐4.48, 3.08]
8.2.2 Diabetic nephropathy all CKD stages	2	120	Mean Difference (IV, Random, 95% CI)	‐1.19 [‐2.96, 0.57]
8.2.3 CKD stage G5D with diabetes and hypertension	2	110	Mean Difference (IV, Random, 95% CI)	0.08 [‐0.48, 0.64]
8.2.4 CKD stage 1 and type 2 diabetes	1	40	Mean Difference (IV, Random, 95% CI)	‐0.17 [‐0.26, ‐0.08]
8.3 Kidney function: albuminuria at 12 or 24 weeks	4	193	Mean Difference (IV, Random, 95% CI)	0.02 [‐0.08, 0.13]
8.3.1 CKD stage G5D	1	33	Mean Difference (IV, Random, 95% CI)	0.00 [‐0.19, 0.19]
8.3.2 CKD stage G5D with diabetes and hypertension	3	160	Mean Difference (IV, Random, 95% CI)	0.03 [‐0.10, 0.16]
8.4 Kidney function: proteinuria at 12 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
8.4.1 Diabetic nephropathy all CKD stages	1	60	Mean Difference (IV, Random, 95% CI)	‐15.60 [‐34.30, 3.10]
8.5 Uraemic toxins: urea at 12 or 24 weeks	5	263	Mean Difference (IV, Random, 95% CI)	‐1.11 [‐2.58, 0.35]
8.5.1 CKD stage G5D	1	33	Mean Difference (IV, Random, 95% CI)	1.80 [‐9.59, 13.19]
8.5.2 Diabetic nephropathy all CKD stages	2	120	Mean Difference (IV, Random, 95% CI)	‐1.90 [‐5.06, 1.26]
8.5.3 CKD stage G5D with diabetes and hypertension	2	110	Mean Difference (IV, Random, 95% CI)	0.06 [‐5.61, 5.72]
8.6 Uraemic toxins: indoxyl sulfate at 12 or 24 weeks	2	83	Mean Difference (IV, Random, 95% CI)	‐4.24 [‐9.83, 1.35]
8.6.1 CKD stage G5D	1	33	Mean Difference (IV, Random, 95% CI)	‐6.00 [‐15.02, 3.02]
8.6.2 CKD stage G5D with diabetes and hypertension	1	50	Mean Difference (IV, Random, 95% CI)	‐3.14 [‐10.26, 3.98]
8.7 Uraemic toxins: p‐cresyl sulfate at 4, 12 or 24 weeks	3	125	Mean Difference (IV, Random, 95% CI)	‐2.12 [‐5.19, 0.95]
8.7.1 CKD stage G5D	2	75	Mean Difference (IV, Random, 95% CI)	‐1.27 [‐2.31, ‐0.24]
8.7.2 CKD stage G5D with diabetes and hypertension	1	50	Mean Difference (IV, Random, 95% CI)	‐6.21 [‐13.92, 1.50]
8.8 Uraemic toxins: indole‐3‐acetic acid acid at 12 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
8.8.1 CKD stage G5D	1	33	Mean Difference (IV, Random, 95% CI)	‐288.10 [‐464.41, ‐111.79]
8.9 GI function: any GI upset or intolerance (abdominal pain/diarrhoea) at 12 weeks	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
8.9.1 CKD stage G5D	1	33	Risk Ratio (M‐H, Random, 95% CI)	2.12 [0.21, 21.22]
8.10 GI function: any GI upset or intolerance (constipation) at 12 weeks	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
8.10.1 CKD stage G5D	1	33	Risk Ratio (M‐H, Random, 95% CI)	3.18 [0.14, 72.75]
8.11 GI function: faecal pH at 12 weeks	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
8.11.1 CKD stage G5D	1	20	Mean Difference (IV, Random, 95% CI)	‐0.30 [‐0.83, 0.23]
8.12 Adverse events: any adverse event (number of participants)	4	205	Risk Ratio (M‐H, Random, 95% CI)	1.96 [0.63, 6.12]
8.12.1 CKD stage 1 and type 2 diabetes	1	44	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.25, 2.59]
8.12.2 CKD stage G5D	2	105	Risk Ratio (M‐H, Random, 95% CI)	4.95 [0.90, 27.12]
8.12.3 CKD stage G5D with diabetes and hypertension	1	56	Risk Ratio (M‐H, Random, 95% CI)	5.00 [0.25, 99.67]
8.13 Withdrawals due to adverse events	4	205	Risk Ratio (M‐H, Random, 95% CI)	4.96 [1.13, 21.77]
8.13.1 CKD stage G5D	2	105	Risk Ratio (M‐H, Random, 95% CI)	4.95 [0.90, 27.12]
8.13.2 CKD stage G5D with diabetes and hypertension	1	56	Risk Ratio (M‐H, Random, 95% CI)	5.00 [0.25, 99.67]
8.13.3 CKD stage 1 and type 2 diabetes	1	44	Risk Ratio (M‐H, Random, 95% CI)	Not estimable

*Study characteristics*
Methods	Study design Parallel, 2‐arm, double‐blind RCT Time frame Treatment: 8 weeks Follow‐up: none past treatment
Participants	Study characteristics Country: Iran Setting: single centre Inclusion criteria: ≥ 25 years; CKD; microalbuminuria and GFR > 60 mL/min; type 2 DN Exclusion criteria: history of inflammatory bowel disease, infection; liver disease; smoking, rheumatoid arthritis; alcoholism; recent antibiotic therapy; taking multivitamins or omega 3 within 1 month prior to study Baseline characteristics Number (randomised/analysed): intervention group (22/20); control group (22/20) Mean age ± SD (years): intervention group (56.9 ± 8.1); control group (53.6 ± 7.19) Sex (M/F): 19/21 CKD stage: 1 to 2 Kidney measurements eGFR (mL/min/1.73 m²): intervention group (71.5 ± 9.5); control group (72.1 ± 9.11) SCr (mg/dL): intervention group (1.01 ± 0.11); control group (1.03 ± 0.16) Comorbidities: diabetic nephropathy; type 2 DM GI status: none reported
Interventions	Intervention group Probiotics: soy milk + Lactobacillusplantarum A7 2 x 10⁷ CFU/mL, 200 mL/day Time: 8 weeks Control group No treatment: soy milk standard, 200 mL/day Time: 8 weeks
Outcomes	Outcomes reported by this study at 8 weeks SCr Proteinuria IL‐18 Serum sialic acid TNF‐α High‐sensitivity CRP GFR Serum cholesterol Serum triglyceride LDL HDL Physical activity (MET) Serum sodium Serum potassium Fasting blood sugar Serum genistein
Notes	Baseline differences between groups Possible differences in lipid panel, SCr, serum phosphorus, and serum genistein at baseline Publication type Full‐text article
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was done by the use of computer‐generated random numbers"
Allocation concealment (selection bias)	Low risk	Quote: "Randomization and allocation were concealed from the researcher and volunteers till the analyses were finalised"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The bottles and soy milk were provided by the same soy milk factory. Bottles were identical in shape and probiotics soy milk was indistinguishable in colour, smell, and taste from conventional soy milk" Quote: "At each study visit, participants received sufficient bottles for a 3‐day period until the next visit, in a double‐blinded design"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "All the tests were performed in a blinded fashion, in pairs (before and after the intervention) at the same time, in the same analytic run, and in random order to reduce systematic error and inter‐assay variability"
Incomplete outcome data (attrition bias) All outcomes	High risk	All participants were accounted for with reasons for withdrawals provided Attrition: 9% ITT analysis not undertaken
Selective reporting (reporting bias)	High risk	Trial registration or a priori published protocol: Iranian Registry of Clinical Trials IRCT20161027479N2. Missing outcome data for several planned outcomes from the trial registration, including proteinuria and TNF‐alpha
Control for confounding factors	Low risk	Pre‐treatment period: 2‐week run‐in phase: participants asked to avoid fermented or probiotic food, avoid consumption of any dietary supplements, report changes in medications Study period: All participants consumed a diet containing 0.8 g/kg protein, 2000 mg sodium, 2000 mg potassium, 1500 mg phosphorus. Obtained using 24‐hour recall food diary
Other bias	Unclear risk	Conflicts declared: "None declared" Funding declared: Isfahan University of Medical Sciences

*Study characteristics*
Methods	Study design Cross‐over, 2‐arm, multicentre, double‐blind, placebo‐controlled RCT Time frame Treatment: 4 weeks Follow‐up: none past treatment
Participants	Study characteristics Countries: Belgium, USA Setting: multicentre (2 sites) Inclusion criteria: ≥ 18 years; HD, 3 times/week for at least 3 months; able to provide 4 faecal samples Exclusion criteria: previous major GI disease or intestinal resection; antibiotic treatment 1 month prior; sustained hypercalcemia; currently taking probiotics or prebiotics Baseline characteristics Number (randomised/analysed): 13/12 Mean age ± SD: 55 ± 10 years Sex (M/F): 6/6 CKD stage: G5D Kidney measurements Mean serum albumin ± SD: 3.27 ± 0.25 g/dL Comorbidities: diabetes (46%)
Interventions	Intervention group Prebiotic: inulin (females 10 g/day, males 15 g/day) in powder form sachet Time: 4 weeks Control group Prebiotic: maltodextrin (females 6 g/day, males 9 g/day) in powder form sachet Time: 4 weeks Washout period 4 weeks
Outcomes	Outcomes reported by this study at 4 weeks Faecal characteristics (Bristol Stool Chart) Faecal microbiota (DNA extraction) Faecal dry matter, SCFAs, phenols, indoles Blood sample collection (plasma metabolites) Dietary intake (48‐hour recall food diary)
Notes	Baseline differences between groups None Publication type Full‐text article
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Participants were randomized using a simple randomization technique (coin toss)"
Allocation concealment (selection bias)	Low risk	Quote: "Randomization was performed by a research coordinator so that both researchers and participants were blinded to the treatment allocation"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Randomization was performed by a research coordinator so that both researchers and participants were blinded to the treatment allocation"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not explicitly clear that the outcome assessors are part of the double‐blinding
Incomplete outcome data (attrition bias) All outcomes	High risk	All participants were accounted for with reasons for withdrawals provided One death not related to study drug Attrition = 8% ITT analysis not undertaken
Selective reporting (reporting bias)	Low risk	Trial registration or a priori published protocol: NCT02718885
Control for confounding factors	Unclear risk	Pre‐treatment period: no run‐in phase length of time was mentioned. However, patients were excluded if they had been taking antibiotics 1 month prior and could not be currently taking prebiotics or probiotics (length of time unstated) Study period: not reported
Other bias	High risk	Conflicts declared: "Beneo GmbH donated Orafti Synergy, but had no input in the study design, data analyses, or manuscript preparation. AB was supported by a Predoctoral Fellowship from CONACyT (Mexico’s Council of Science and Technology), a postdoctoral fellowship NIH‐T32 DK120524, has received honoraria from AMGEN, research grants from Keryx Pharmaceuticals for work unrelated to the present manuscript, and is part of the AUGmeNt workgroup from the Academy of Nutrition and Dietetics. BMK has received consulting fees, research grants, and is a member of the AUGmeNt workgroup from the Academy of Nutrition and Dietetics. KRW has received funding from the National Institutes of Health and the Renal Research Institute." Funding declared: "This work was supported by a research grant from the Renal Research Institute (C2930) and the Division of Nutritional Sciences at the University of Illinois (USDA Vision 20/20 research program award)"

*Study characteristics*
Methods	Study design Cross‐over, 2‐arm, single‐blind RCT Time frame Treatment: 4 weeks Follow‐up: none past treatment
Participants	Study characteristics Country: USA Setting: single centre Inclusion criteria: ≥ 18 years; treated with low protein diet for a minimum 4 months prior Exclusion criteria: on dialysis; liver disease; kidney transplant; pregnant or lactating; active GI bleeding Baseline characteristics Number (randomised/analysed): 20/16 Age range: 20 to 72 years Sex (M/F): 13/7 CKD stage: 1 to 3 Kidney measurements Mean SCr ± SEM: 0.39 ± 0.07 mol/L Comorbidities: diabetic nephropathy (4); arterial nephrosclerosis (4); glomerular disease (3); amyloid nephropathy (1); FSGS (1); obstructive uropathy (1); polycystic kidney disease (1); scleroderma (1)
Interventions	Intervention group Prebiotic: gum Arabic 25 g mixture in 150 mL juice twice/day (total 50 g gum Arabic) Time: 4 weeks Control group Prebiotic: placebo mixture of pectin 0.5 g in 150 mL juice twice/day (total 1 g pectin) Time: 4 weeks
Outcomes	Outcomes reported by this study at 4 weeks Stool fractionation (stool weight and faecal bacterial mass), each 5 days, wet weight and dry weight Nitrogen analyses (nitrogen excretion and serum urea nitrogen) Nutritional assessment and dietary intake (food diary) Adverse events
Notes	Baseline differences between groups None Publication type Full‐text article
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Subjects were randomly divided into two groups during dietary period 1" Insufficient information provided regarding methodology used to undertake randomisation, unable to form judgement
Allocation concealment (selection bias)	Unclear risk	No information provided regarding concealment of the allocation
Blinding of participants and personnel (performance bias) All outcomes	High risk	"The investigator provided subjects in both groups with the juice mixtures and the subjects were not informed of their content" Single‐blind study
Blinding of outcome assessment (detection bias) All outcomes	High risk	Single‐blind study
Incomplete outcome data (attrition bias) All outcomes	High risk	No missing outcome data; however no details about which arm non‐completers were from Denominators for each group between cross‐over period are unclear Attrition = 20% ITT analysis not undertaken
Selective reporting (reporting bias)	Unclear risk	Trial registration: not reported
Control for confounding factors	Low risk	Pre‐treatment period: low protein diet 4 months prior Study period: continued low‐protein diet
Other bias	High risk	Conflicts declared: "Supported in part by an individual National Research Award (NR06335), the American Nurses' Foundation 1989 Bristol Myers Fund Scholar Award (to DZB), and the 1989 American Nurses' Foundation/Sigma Theta Tau International Scholar Award (to DZB). Welch's brand frozen fruit juice concentrates and Glad‐Lock freezer bags were generously provided by Welch's Foods, Inc (Westfied, NY) and by First Brands Corporation (Danbury, CT), respectively. The price of Nutriloid Gum Arabic Spray Dry Powder was discounted by TIC Gums, Inc (Belcamp, MD)." Funding declared: not reported

*Study characteristics*
Methods	Study design Parallel, 2‐arm, single‐blind, placebo‐controlled RCT Time frame Treatment: 8 weeks Follow‐up: 12 weeks (4 weeks past end of treatment)
Participants	Study characteristics Country: Italy Setting: single centre (outpatient) Inclusion criteria: 30 to 65 years; CKD stage 3b to 5, non‐dialysis; BMI 18.5 to 29.9; controlled diet Exclusion criteria: type 2 DM; use of antibiotics or probiotics up to 30 days prior to recruitment; chronic GI disorders; systemic inflammatory diseases; suspicion or clinical diagnosis of malignancy; chronic liver disease; treatment with corticosteroids or immunosuppressive drugs; previous acute CVD (MI, stroke); psychiatric conditions reducing the compliance to treatment protocols Baseline characteristics Number: intervention group (13); control group (10) Mean age ± SD (years): intervention group (51 ± 4.3); control group (51.5 ± 2.8) Sex (M/F): intervention group (7/6); control group (7/3) CKD stage: 3 Kidney measurements Mean eGFR ± SD (mL/min): intervention group (31.5 ± 2.8); control group (23.9 ± 3.6) Mean SCr ± SD (mg/dL): intervention group (2.3 ± 0.2); control group (3.2 ± 0.4) Mean serum albumin ± SD (g/dL): intervention group (3.9 ± 0.1); control group (3.9 ± 0.1) Comorbidities: not reported GI status: not reported
Interventions	Intervention group Synbiotic: Lactobacillus casei LC4P1 2.4 x 10⁹, Bifidobacterium animalis BLC1 2.4 x 10⁹, fructo‐oligosaccharides 2.5 g, inulin 2.5 g, and natural antioxidants (a mix of quercetin 0.064 g, reservatrol 0.023 g and proanthocyanidins 0.013 g) Time: 8 weeks Control Group Placebo: not reported Time: 8 weeks
Outcomes	Outcomes reported by this study at 8 weeks P‐cresyl sulfate Indoxyl sulfate Intestinal permeability GI symptoms (reported in separate paper) BMI eGFR SCr Serum albumin Azotaemia Serum calcium Serum phosphorus Serum potassium Serum sodium CaxP Total serum proteins CRP Urinary creatinine Urinary proteins
Notes	Baseline differences between groups None Publication type Full‐text article
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The randomization was performed by an independent researcher by means of software, using gender as a blocking factor"
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: "The powder formulations were anonymously labelled and were undistinguishable for the patients" Single‐blind study
Blinding of outcome assessment (detection bias) All outcomes	High risk	Single‐blind study
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants were accounted for with reasons for withdrawals provided Attrition = 0% (in CKD participants) ITT analysis undertaken in CKD participants
Selective reporting (reporting bias)	High risk	Trial registration or a priori published protocol: NCT03815786 Outcomes: "TMAO was not evaluated due to technical problems during the execution of the analysis"
Control for confounding factors	Unclear risk	Pre‐treatment period: Unclear, "controlled diet" Study period: Unclear
Other bias	Unclear risk	Conflicts declared: "S.F. is the Chief Executive Officer of Research Center « Sergio Fontana 1900–1982» (Farmalabor); F.M.L.F. is the research and development manager of the Research Center « Sergio Fontana 1900–1982» (Farmalabor). The other authors declare no conflict of interest." Funding declared: "This study has been funded from the XUANRO4‐NATURE‐Nuovo Approccio Per la Riduzione Delle Tossine Uremiche Renali, REGIONE PUGLIA‐FSC 2007–2013 Ricerca. Intervento 'Cluster Tecnologici Regionali' "

*Study characteristics*
Methods	Study design Cross‐over, 2‐arm, double‐blind, placebo‐controlled RCT Time frame Treatment: 4 weeks Follow‐up: none past treatment
Participants	Study characteristics Country: Brazil Setting: single centre (outpatient clinic) Inclusion criteria: 18 to 80 years; APD, dialysis vintage of at least 3 months; adherent to dialysis treatment Exclusion criteria: currently using prebiotics, probiotics, synbiotics, and antibiotics one month before the beginning of the study; the presence of inflammatory bowel diseases, stomach, or bowel resection; liver cirrhosis; cancer; HIV; peritonitis in the last month; pregnancy; breastfeeding; presenting any GI intolerance after dose adjustments; hospitalised; started antibiotics; underwent kidney transplant once starting study Baseline characteristics Number (randomised/analysed): 43/26 Mean age ± SD: 55 ± 12 years Sex (M/F): 23/43 CKD stage: 1 to 5, including G5D Kidney measurements Median SCr (IQR) (mg/dL): 8.3 (6.5 to 11.8) Mean albumin± SD (g/dL): 3.9 ± 0.34 Comorbidities: diabetes (85%); diabetic nephropathy (19%); hypertensive nephropathy (4%); GN (8%); polycystic kidney disease (15%) GI status: median (IQR) GSRS score 29 (24–41)
Interventions	Intervention group Prebiotic: unripe banana flour (48% resistant starch) 21 g/day. Dose escalation to double/day, after 3 days in the absence of adverse effects Time: 4 weeks Washout 4 weeks Control group Placebo: waxy corn starch 12 g/day. Dose escalation to double/day, after 3 days in the absence of adverse effects Time: 4 weeks
Outcomes	Outcomes reported by this study at 12 weeks Indoxyl sulfate p‐cresyl sulfate Indoxyl 3‐acetic acid High‐sensitivity CRP IL‐6 IL‐10 TNF‐alpha Serum lipopolysaccharide LPS Dietary intake
Notes	Baseline differences between groups None Publication type Full‐text article Available data No available data for meta‐analyses: first phase of crossover not reported as separate data
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The participants were assigned to sequential treatment with UBF and placebo, or vice versa, after a blocked randomization procedure using a random block of 4 participants in a 1:1 ratio."
Allocation concealment (selection bias)	Low risk	Quote: "Supplements were packaged in identical sachets and identified by the numbers 225 and 653 in a handling pharmacy, under the responsibility of a pharmacist (Magister Pharmacy, Sao Paulo, Brazil)" Quote: "The list was handed over to another independent researcher who was responsible for separating and allocating supplements to participants"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Supplements were packaged in identical sachets and identified by the numbers 225 and 653 in a handling pharmacy, under the responsibility of a pharmacist (Magister Pharmacy, Sao Paulo, Brazil)" Quote: "The list was handed over to another independent researcher who was responsible for separating and allocating supplements to participants"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	High risk	All participants were accounted for with reasons for withdrawals provided Attrition = 40% Reasons for withdrawals not of major concern related to study treatment ITT analysis not undertaken
Selective reporting (reporting bias)	Low risk	Trial registration or a priori published protocol: Brazilian Clinical Trials Registry (www.ensaiosclinicos.gov.br, IDnumber: RBR‐4xxwwj
Control for confounding factors	Unclear risk	Pre‐treatment period: "The majority of patients had been previously advised by a renal dietician, according to the nutritional guidelines for patients undergoing peritoneal dialysis" Study period: "During each intervention, the participants were advised to maintain a stable dietary pattern and not to take prebiotics, probiotics, or synbiotics. If necessary, dietary adjustments were advised or reinforced during the follow‐up"
Other bias	High risk	Conflicts declared: "The authors declare no conflict of interest" Funding declared: "L.S.d.A., F.A.H.S., N.B.F.P., R.R.T., J.D.d.L. received a scholarship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). SD. Rodrigues receives a scholarship from CAPES—Fundação Araucária and L.C. receives a scholarship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (#302765/2017‐4). The production and analysis of UBF were supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (#13/07914‐8 (FoRC)). Support for this research was provided by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (#2018/12122‐7)"

PERMALINK

Synbiotics, prebiotics and probiotics for people with chronic kidney disease

Tess E Cooper

Rabia Khalid

Samuel Chan

Jonathan C Craig

Carmel M Hawley

Martin Howell

David W Johnson

Allison Jaure

Armando Teixeira-Pinto

Germaine Wong

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Summary of findings 1. Synbiotic versus another synbiotic for people with chronic kidney disease.

Summary of findings 2. Synbiotic versus prebiotic for people with chronic kidney disease.

Summary of findings 3. Prebiotic versus another prebiotic for people with chronic kidney disease.

Summary of findings 4. Prebiotic versus probiotic for people with chronic kidney disease.

Summary of findings 5. Probiotic versus another probiotic for people with chronic kidney disease.

Summary of findings 6. Synbiotic versus placebo or no treatment for people with chronic kidney disease.

Summary of findings 7. Prebiotic versus placebo or no treatment for people with chronic kidney disease.

Summary of findings 8. Probiotic versus placebo or no treatment for people with chronic kidney disease.

Background

Description of the condition

Chronic kidney disease

The gut microbiome

Description of the intervention

Prebiotics

Probiotics

Synbiotics

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Inclusion criteria

Exclusion criteria

Types of interventions

Comparison pairs for analysis

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Results

Description of studies

Results of the search

1.

Included studies

Comparisons

Excluded studies

Ongoing studies and studies awaiting classification

Risk of bias in included studies

2.

Allocation

Random sequence generation

*Study characteristics*
Methods	Study design Parallel, 2‐arm, single‐centre, triple‐blind, placebo‐controlled RCT Time frame Treatment: 4 weeks Follow‐up: none past 4 weeks treatment
Participants	Study characteristics Country: Iran Setting: single centre (hospital dialysis ward) Inclusion criteria: ≥ 20 years ; kidney failure undergoing chronic maintenance HD for at least 3 months; may have diabetic nephropathy, hypertensive nephropathy, nephrotic syndrome, GN Exclusion criteria: history of smoking; PD or previous kidney transplant; lactation or pregnancy; drug history including antibiotics, prebiotics, probiotics, herbal drugs, psychedelic drugs Baseline characteristics Number (randomised/analysed): intervention group (30/21); control group (29/21) Mean age ± SD (years): intervention group (57.05 ± 13.95); control group (59.67 ± 15.04) Sex (M/F): intervention group (15/6); control group (17/4) CKD stage: G5D Kidney measurements Albumin (g/dL): intervention group (4.17 ± .57); control group (4.32 ±.80) SCr (mg/dL): intervention group (8.67 ± 1.92); control group (8.28 ± 3.04) Uric acid (mg/dL): intervention group (6.83 ± 1.24); control group (7.11 ± 1.47) Other CKD biomarkers: hypertensive nephropathy most common cause of kidney failure Comorbidities Diabetes: intervention group (23.8%); control group (38.1%) Hypertension: intervention group (42.9%); control group (38.1%) GN: intervention group (0%); control group (4.8%) GI status: dietary fibre intake (g/day): intervention group (11.33 ± 7.33); control group (11.50 ± 6.61)
Interventions	Intervention group Probiotic: 1 capsule/day containing 1.6 x 10⁷ CFU of LactobacillusRhamnosus from yogurt and cheese of different farms located in the suburbs Heris after meal Time: 28 days Control group Placebo: 1 capsule/day infant formula after a meal Time: 28 days
Outcomes	Outcomes reported by this study at 4 weeks Serum phenol Serum p‐cresol Anthropometric measurements: weight using calibrated Seca scale with a precision of 0.1 kg Energy intake: 3 days food recall was used and analysed with Nutritionist 4 software FGIDs: symptoms in the oesophagus, stomach and intestines, using 93 items questionnaire based on ROM III Anthropometric measurements, BMI Macronutrient intake: proteins, fats and carbohydrates, 3 days food recall was used and analysed with Nutritionist 4 software FGIDs: symptoms in the gall bladder and pancreas, rectum and anal canal, using 93 items questionnaire based on ROM III Intestinal (stool) microbiome, bacteroidetes: real‐time PCR of DNA extracted from stool sample
Notes	Baseline differences between groups None Publication type Full‐text article
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Triple ‐blind randomized placebo‐controlled trial with an allocation ratio of (1:1)" Quote: "The eligible participants were randomly assigned to Lactobacillus Rhamnosus as probiotics or placebo groups by a randomization procedure and subject were matched in each arms regarding to age, sex and history of haemodialysis duration."
Allocation concealment (selection bias)	Unclear risk	No information regarding the concealment of allocation to treatment groups. Insufficient information provided within abstract to permit judgement.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Study states to be triple‐blind however no information regarding the methods use to keep participants or study personnel blinded treatment groups Insufficient information provided within abstract to permit judgement
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Study states to be triple‐blind however no information regarding the methods use to keep outcome assessors blinded treatment groups. Insufficient information provided within abstract to permit judgement.
Incomplete outcome data (attrition bias) All outcomes	High risk	All participants were accounted for with reasons for withdrawals provided Attrition = unclear ITT analysis unclear Serious issues regarding ITT population, number of participants received intervention, whether ITT analysis was correctly performed. Numbers do not match.
Selective reporting (reporting bias)	Unclear risk	Trial registration or a priori published protocol: IRCT201504182017N21. Study registration planned a 4‐arm trial: (1) Probiotic; Lactobacillus rhamnosus (16 Billion CFU) one capsule per day for 28 days; (2) Prebiotic; Inulin (10 grams) one sachet per day for 28 days; (3) Synbiotic; Lactobacillus Rhamnosus (16 Billion CFU, one capsule) with Inulin (10 grams, one sachet) per day for 28 days; (4) Corn starch (10 grams, one sachet) with Infant formula (one capsule) per day, for 28 days. Query on why this was not undertaken Lack of clinically important or relevant outcomes: no issue
Control for confounding factors	Unclear risk	Pre‐treatment period: Nothing reported Study period: "All the participants were asked not to change their usual dietary intakes, recommended vitamin or minerals supplements, physical activity, medication or traditional medicine as adjuvant therapy over the course of the study." "Food intake was assessed using three 24‐h dietary recalls undertaken on separate days (one haemodialysis weekday, one non‐haemodialysis weekday and one non‐haemodialysis weekend day) using a visual aid photo album of real foods before and after treatment. Energy and nutrient intake were analyzed using Nutritionist IV (Axxya Systems, Stafford, TX)."
Other bias	Low risk	Conflicts declared "Authors of this study declare no conflict of interest" Funding declared "No sources of funding"

*Study characteristics*
Methods	Study design Parallel, 3‐arm, open‐label RCT Time frame Treatment: 4 weeks Follow‐up: none past treatment
Participants	Study characteristics Country: Saudi Arabia Setting: single centre (Nephrology clinic) Inclusion criteria: ≥ 18 years; CKD stages 3B or 4 Exclusion criteria: malignancy; liver disease; intestinal resection; inflammatory bowel disease; recent antibiotic therapy; recent gum Arabic use Baseline characteristics Number (randomised/analysed): intervention group 1 (12/12); intervention group 2 (12/9); intervention group 3 (12/9) Mean age ± SD (years): intervention group 1 (48 ± 12); intervention group 2 (52 ± 18); intervention group 3 50 ± 17) Sex (M/F): intervention group 1 (8/4); intervention group 2 (6/3); intervention group 3 (6/3) CKD stage: 3B (15); 4 (15) Kidney measurements eGFR (mL/min/1.73m²): intervention group 1 (26 ± 10); intervention group 2 (33 ± 11); intervention group 3 (29 ± 9) BUN (mmol/L): intervention group 1 (14 ± 6); intervention group 2 (12 ± 5); intervention group 3 (14 ± 4) Comorbidities: Immunosuppression for lupus nephritis and glomerular disease: intervention group (33.3%); intervention group 2 (22.2%); intervention group 3 (22.2%) GI status: not reported
Interventions	Intervention group 1 Prebiotic: gum Arabic 10 g instantly soluble granules in glass of water or juice, once/day Time: 4 weeks Intervention group 2 Prebiotic: gum Arabic 20 g instantly soluble granules in glass of water or juice, once/day Time: 4 weeks Intervention group 3 Prebiotic: gum Arabic 40 g instantly soluble granules in glass of water or juice, once/day Time: 4 weeks
Outcomes	All outcomes reported by this study at 4 weeks GFR Creatinine BUN Sodium Potassium Bicarbonate Uric acid Calcium Phosphorus Magnesium PTH Hb Indoxyl sulfate Urine volume Creatinine excretion Urea excretion Protein excretion CrCl Urea clearance Serum CRP Serum IL‐1 Serum IL‐2 Serum IL‐4 Serum IL‐5 Serum IL‐6 Serum IL‐10 Serum IL‐12 Serum IL‐13 Serum IFN Serum TNF Urinary TGF GI symptoms: abdominal pain; abdominal distention; flatulence; nausea; diarrhoea; constipation
Notes	Baseline differences between groups None Publication type Full‐text article/abstract
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "According to recruitment order, we divided patients into three equal groups using computer‐generated random number lists"
Allocation concealment (selection bias)	Unclear risk	No information regarding the concealment of allocation to treatment groups
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	High risk	Open‐label study
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	All participants were accounted for with reasons for withdrawals provided Attrition = 25% ITT analysis not undertaken
Selective reporting (reporting bias)	Unclear risk	Trial registration or a priori published protocol: not reported
Control for confounding factors	Unclear risk	Pre‐treatment period: not reported Study period: not reported
Other bias	Unclear risk	Conflicts declared: "The authors declared no conflicts of interest" Funding declared: "This clinical trial was funded by a generous grant from King Abdul‐Aziz City for Science and Technology (KACST) in Saudi Arabia (no. 35‐300). The authors would like to acknowledge their gratitude to Professor Yacine Badjah and the Chair of Advanced Materials Research at King Saud University in Riyadh for their kind assistance in performing the liquid chromatography assay."

*Study characteristics*
Methods	Study design Parallel, 3‐arm, double‐blind, placebo‐controlled RCT Time frame Treatment: 12 weeks Follow‐up 24 weeks
Participants	Study characteristics Country: Iran Setting: single centre (Dialysis centre) Inclusion criteria: 30 to 65 years; undergoing HD for at least 3 months prior, have arteriovenous fistula Exclusion criteria: kidney transplant recipient; kidney transplant candidate likely to receive; inflammatory and infectious diseases; malignancy; chronic liver disease; use of a central catheter for HD access; amputated limbs; pregnancy; using steroidal and/or nonsteroidal anti‐inflammatory drugs and antibiotics, antioxidant, and/or anti‐inflammatory supplements (e.g., vitamin E, vitamin C, and omega‐3 fatty acids), pre‐, pro‐, and synbiotic and other forms of probiotics (including probiotic yogurt, kefir, and other fermented foods) within 3 months of study commencement Baseline characteristics Number (randomised/analysed): intervention group 1 (25/23); intervention group 2 (25/23); control group (25/19) Mean age ± SD (years): intervention group 1 (48.04 ± 10.11); intervention group 2 (46.21 ± 11.49); control group (45.47 ± 10.76) Sex (M/F): intervention group 1 (12/11); intervention group 2 (12/11); control group (10/9) CKD stage: G5D Kidney measurements SCr ± SD (mg/dL): intervention group 1 (7.11 ± 2.84); intervention group 2 (60.2 ± 2.40); control group (6.33 ± 3.36) Albumin ± SD (g/dL): intervention group 1 (4.03 ± 0.55); intervention group 2 (4.02 ± 0.52); control group (4.19 ± 0.49) Comorbidities Diabetes: intervention group 1 (69.6%); intervention group 2 (65.2%); control group (63.2%) Hypertension: intervention group 1 (78.3%); intervention group 2 (82.6%); control group (63.2%) GI status GSRS ± SD: intervention group 1 (10.95 ± 3.67); intervention group 2 (11.13 ± 2.76); control group (11.26 ± 3.31)
Interventions	Intervention group 1 Synbiotic 1 Prebiotics: 5 g fructo‐oligosaccharides, 5 g galacto‐oligosaccharides, 5 g inulin Probiotics: 5 g of probiotic powder (Lactobacillusacidophilus T16, Bifodobacteriumbifidum BIA‐6, Bifidobacteriumlactis BIA‐6, and Bifidobacteriumlongum LAF‐5, all 2.7 x 10⁷ CFU Time: 12 weeks Intervention group 2 Synbiotic 2 Prebiotics: 15 g of maltodextrin powder sachets Probiotics: 5 g of probiotic powder (Lactobacillusacidophilus T16, Bifodobacteriumbifidum BIA‐6, Bifidobacteriumlactis BIA‐6, and Bifidobacteriumlongum LAF‐5, all 2.7 x 10⁷ CFU Time: 12 weeks Control group Prebiotic: 20 g of maltodextrin powder as the 'placebo' in sachets but was in fact prebiotic Time: 12 weeks Co‐interventions or additional treatments EPO and IV iron as a regular treatment in accordance with regional HD guidelines
Outcomes	All outcomes recorded at 12 weeks Soluble intercellular adhesion molecule type 1s Soluble vascular cell adhesion molecule type Cytokeratin Uric acid Phosphorus BUN SCr Phosphate Calcium Albumin Brain‐derived neurotrophic factor Hospital anxiety and depression score Energy intake (macros and micros) High‐sensitivity CRP IL‐6 Anti‐HSP70 Endotoxin Beck anxiety and depression indexes HRQoL Treatment adherence (phone call and stool sample tests)
Notes	Baseline differences between groups None Publication type Full‐text article
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A research assistant from Tak Gen Zist Pharmaceutical Company, who was not otherwise involved in the study, performed the randomization. Patients were randomly assigned to one of three study groups following a block randomization procedure with stratified patients in each block based on sex and age. Randomization assignment was carried out using computer‐generated random numbers."
Allocation concealment (selection bias)	Low risk	Quote: "Supplement packaging was done in Tak Gen Zist Pharmaceutical Company" Quote: "A nutritionist at the haemodialysis centre, who was not a member of the core study team and not aware of random sequences, conducted the randomized allocation sequence, enrolling participants and allocating them to interventions. Randomization and allocation were hidden from the researchers and patients until the final analyses were completed."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Randomization and allocation were hidden from the researchers and patients until the final analyses were completed. Sachets (synbiotic, probiotic and placebo) were pre‐packaged according to the randomization code by Tak Gen Zist Pharmaceutical Company, Tehran, Iran."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Randomization and allocation were hidden from the researchers and patients until the final analyses were completed. Sachets (synbiotic, probiotic and placebo) were pre‐packaged according to the randomization code by Tak Gen Zist Pharmaceutical Company, Tehran, Iran."
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants were accounted for with reasons for withdrawals provided Attrition = 13% ITT not undertaken; analysis based on completers N = 65
Selective reporting (reporting bias)	Low risk	Trial registration or a priori published protocol: IRCT2017041233393N1
Control for confounding factors	Low risk	Pre‐treatment period: 3 months prior: no steroidal and/or nonsteroidal anti‐inflammatory drugs and antibiotics, antioxidant, and/or anti‐inflammatory supplements (e.g., vitamin E, vitamin C, and omega‐3 fatty acids), pre‐, pro‐, and synbiotic and other forms of probiotics (including probiotic yogurt, kefir, and other fermented foods) Study period: "Throughout the intervention, patients were requested to maintain stable dietary intakes, physical activity, medications, and not to consume any supplements other than the one provided to them by this trial"
Other bias	High risk	Conflicts declared: "The authors declare that they have no conflicts of interest" Funding declared: Packaging provided by industry; "Supplement packaging was done in Tak Gen Zist Pharmaceutical Company"; "This study was supported by grants from Vice Chancellor of Research, Ahvaz University of Medical Sciences (Ahvaz, Iran)"

*Study characteristics*
Methods	Study design Parallel, 2‐arm, , double‐blind, placebo‐controlled RCT Study duration 24 weeks treatment Follow‐up: none past 24 weeks treatment
Participants	Study characteristics Country: China Setting: single‐centre (Dialysis centre) Inclusion criteria: ≥ 20 years; receiving stable HD 3 times/week for at least 6 months Exclusion criteria: inflammatory diseases; cancer, autoimmune disease; decompensated liver cirrhosis; use of a central catheter for HD access; amputated limbs; pregnancy; had used catabolic drugs; antioxidant vitamin supplements, prebiotics, probiotics, synbiotics, and antibiotics in the last 3 months before starting study Baseline characteristics Number (randomised/analysed): intervention group (28/25); control group (28/25) Mean age ± SD (years): intervention group (61.50 ± 10.30); control group (56.28 ± 12.36) Sex (M/F): intervention group (10/15); control group (10/15) CKD stage: G5D Kidney measurements Mean SCr ± SD (mg/dL): intervention group (11.22 ± 2.21); control group (10.50 ± 1.91) Mean albumin ± SD (g/dL): intervention group (4.12 ± 0.23); control group (4.14 ± 0.27) Comorbidities: hypertension (33); diabetes (25); atherosclerotic vascular disease (18) GI status: not reported
Interventions	Intervention group Probiotic: Lactococcuslactis subspecies 6 g (Lactis LL358, Lactobaccillussalivarius LS159, and Lactobaccilluspentosus LPE588), 100 billion; 1 x 10¹¹ CFU, 2 sachets/day Time: 24 weeks Control group Placebo: powder sachet, 2 sachets/day Time: 24 weeks
Outcomes	Outcomes reported by this study at 24 weeks Triglycerides HDL cholesterol Indoxyl sulfate P‐cresyl sulfate CRP IL‐6 TNF‐alpha Ferritin Lipopolysaccharide binding protein Soluble CD14 HRQoL Urea Creatinine Uric Acid Albumin Phosphorus Total CO₂ Glucose Total cholesterol Anthropometric parameters
Notes	Baseline differences between groups None Publication type Full‐text article
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization assignment was performed by the use of computer‐generated block randomization, and the block size was 4"
Allocation concealment (selection bias)	Low risk	Quote: "Professor Hsueh Fang Wang generated the randomization sequence. Participants, other research staff, and outcome assessors were all blinded to the group assignment process" Quote: "To maintain the conditions of a double‐blind parallel study, the statistician was not aware of the allocation of participants to each intervention. Code breaking was performed after the analysis was completed"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The sachets with probiotics or placebo were indistinguishable in appearance" Quote: "To maintain the conditions of a double‐blind parallel study, the statistician was not aware of the allocation of participants to each intervention. Code breaking was performed after the analysis was completed"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Participants, other research staff, and outcome assessors were all blinded to the group assignment process"
Incomplete outcome data (attrition bias) All outcomes	High risk	All participants were accounted for with reasons for withdrawals provided Attrition = 11% ITT analysis not undertaken
Selective reporting (reporting bias)	Low risk	Trial registration or a priori published protocol: NCT03066921
Control for confounding factors	Unclear risk	Pre‐treatment period: not reported Study period: "Participants’ diet, dialysis schedule, and the medications they used did not change during the study. A food frequency questionnaire was used to confirm unchanged diet habits"
Other bias	High risk	Conflicts declared: "The authors declare that they have no relevant financial interests" Funding declared: "This study was supported by the Ministry of Science and Technology (grant no. MOST 104‐2622‐E‐241‐001‐CC3). The authors are thankful to the New Bellus Enterprise Co., Ltd. (Tainan, Taiwan) for providing us with a sample of Lactobacillus and for sponsoring our study" Industry funding

*Study characteristics*
Methods	Study design Parallel, 2‐arm, open‐label RCT Time frame 2016 to 2017 Treatment: 12 weeks Follow‐up: none past treatment
Participants	Study characteristics Country: China Setting: single centre (Hospital) Inclusion criteria: ≥ 18 years; early type 2 diabetic nephropathy defined as UACR 2.5 to 20 mg/mmol (men) or 3.5 to 20 mg/mmol (women) Exclusion criteria: did not have type 2 diabetes, macroalbuminuria or overt proteinuria; recent infectious diseases; surgery; malignancy; liver cirrhosis Baseline characteristics Number (randomised/analysed): intervention group (37/34); control group (38/36) Mean age ± SD (years): intervention group (62.85 ± 9.3); control group (61 ± 9.5) Sex (M/F): intervention group (18/16); control group (21/15) CKD stage: A2 Kidney measurements Mean SCr ± SD (μmol/L): intervention group (62.4 ± 16.7); control group (63.1 ± 16.1) Mean albumin ± SD (g/L): intervention group (45.9 ± 3.0); control group (46.3 ± 3.3) Comorbidities: diabetes (75); hypertension (48); cerebral apoplexy (5); coronary heart disease (26) GI status: not reported
Interventions	Intervention group Prebiotics: high‐resistant starch, low‐protein flour, 50 g instead of a common staple of equal quality at lunch and dinner each day. The lack of protein is supplemented with high‐quality protein eggs, poultry meat, and dairy products. According to the previous measurement result, the total daily intake was 17.41 g/day Time: 12 weeks Control group No treatment: patients followed protein restriction diet daily with a common staple per day Time: 12 weeks Co‐interventions or additional treatments "During the 12‐week intervention, all patients with DN received low‐salt, low‐fat, and low‐protein dietary pattern and were given basic treatment such as glucose‐lowering, lipid‐lowering, and blood pressure–lowering treatment. But, patients were requested not to change their medicine and insulin treatment programs arbitrarily. All participants received dietary guidance from dietitians and completed 3‐day food records."
Outcomes	Outcomes reported by this study at 12 weeks Fasting blood glucose HbA1c Cholesterol Triglycerides Albumin Prealbumin Serum uric acid Beta2‐microglobulin BUN Creatinine UACR Superoxide dismutase Malondialdehyde IL‐6 TNF‐alpha
Notes	Baseline differences between groups None Publication type Full‐text article
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The patients were randomly divided into intervention group ... or control group ... by using computer‐generated 1:1 randomization sequences"
Allocation concealment (selection bias)	High risk	Quote: "Delivery of the intervention and assessment of outcomes were not blinded to the treatment assignment"
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: "Delivery of the intervention and assessment of outcomes were not blinded to the treatment assignment" Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	High risk	Quote: "Delivery of the intervention and assessment of outcomes were not blinded to the treatment assignment" Open‐label study
Incomplete outcome data (attrition bias) All outcomes	High risk	All participants were accounted for with reasons for withdrawals provided Attrition = 7% ITT analysis not undertaken
Selective reporting (reporting bias)	Unclear risk	Trial registration or a priori published protocol: not reported
Control for confounding factors	Unclear risk	Pre‐treatment period: not reported Study period: "During the 12‐week intervention, all patients with DN received low‐salt, low‐fat, and low‐protein dietary pattern and were given basic treatment such as glucose‐lowering, lipid‐lowering, and blood pressure–lowering treatment. But, patients were requested not to change their medicine and insulin treatment programs arbitrarily. All participants received dietary guidance from dietitians and completed 3‐day food records."
Other bias	Low risk	Conflicts declared: "The authors declare that they have no relevant financial interests" Funding declared: "This work was supported by the Medical Health and Science Development Project of Shandong Province (grant number: 2016ws0428)"

*Study characteristics*
Methods	Study design Cross‐over, 2‐arm, double‐blind, placebo‐controlled RCT Pilot study Time frame July 2007 to August 2008 Treatment: 12 weeks Follow‐up: none past 12 weeks treatment
Participants	Study characteristics Country: Canada Setting: single‐centre (Hospital) Inclusion criteria: 18 to 75 years; CKD stage 3 or 4; SCr > 2.5 mg/dL Exclusion criteria: pregnant; antibiotics; anticoagulants; active dependency on drugs or alcohol; HIV/AIDS/liver disease; any medical, psychiatric, debilitating disease/disorder or social condition Baseline characteristics Number (randomised/analysed): 16/13 Mean age ± SD (years): 54 ± 8.8 Sex (M/F): 9/4 CKD stage: 3 and 4 Kidney measurements: not reported Comorbidities: hypertension (11); hyperlipidaemia (1); type 2 DM (1); IgA nephritis (1); polycystic kidney disease (1) GI status: not reported
Interventions	Intervention group Probiotic: 1 oral capsule of Lactobacillusacidophilus KB31, Bifidobacteriumlongum KB35, and Streptococcusthermophilus KB27, total of 1.5 x 10¹⁰ CFU; 2 capsules 3 times/day Time: 12 weeks Washout None Control group Placebo: oral capsule placebo powder; 2 capsules 3 times/day Time: 12 weeks
Outcomes	Outcomes reported by this study at 12 weeks SCr Uric acid BUN CRP Faecal microbiological composition QoL
Notes	Baseline differences between groups None Publication type Full‐text article Pilot Available data No available data for meta‐analyses: first phase of cross‐over not reported as separate data
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization sequence was generated by alternative patient sequential methodology"
Allocation concealment (selection bias)	Unclear risk	Insufficient information provided to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The placebo was composed of wheat germ plus Psyllium husks. It was also matched in color, size and enteric coating identical to the interventional product"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information provided to permit judgement
Incomplete outcome data (attrition bias) All outcomes	High risk	All participants were accounted for with reasons for withdrawals provided Attrition = 19% ITT analysis not undertaken
Selective reporting (reporting bias)	Low risk	Trial registration or a priori published protocol NCT00760162
Control for confounding factors	Unclear risk	Pre‐treatment period Not reported Study period Dietary recall
Other bias	High risk	Conflicts declared "N.R. has disclosed that he is the Senior Vice‐President of research and development at Kibow Biotech, Inc. P.R. has disclosed that she is the Vice‐President for clinical and regulatory affairs, Kibow Biotech, Inc. N.R. and P.R. have both disclosed that they hold a substantial combined business interest in Kibow Biotech, Inc. R.D. has disclosed that he is an employee of Kibow Biotech, Inc. E.A.F. has disclosed that he serves, without compensation, as Chair of Kibow Biotech’s Scientific Advisory Board, and that his Renal Division currently receives research funding for a clinical trial of Kibow Probiotics. P.T. and V.R. have disclosed that they have not received any compensation from Kibow Biotech for conducting this pilot‐scale clinical study. All peer reviewers receive honoraria from CMRO for their review work. Peer Reviewer 1 has disclosed that he/she is a scientific consultant on clinical trials for Jamieson Laboratories Inc. Peer Reviewer 2 has disclosed that he/she has no relevant financial relationships. Funding declared "Funding for this Canadian study was provided by Gelda Scientific, Inc, Mississauga, Ontario, Canada (in exchange for rights to distribute the product in Canada). Kibow Biotech has funded the publication of this article."

Study	Reason for exclusion
Afaghi 2016	Wrong intervention: the intervention is multi‐vitamin and multi‐mineral powder that contains 2 probiotics and 1 prebiotic, but these are not the majority of the dose, and there are too many other ingredients to be able to ascertain any effect.  Group A: ISOWHEY oral nutritional supplement Whey protein concentrate (whey protein, soy lecithin), Litesse® (polydextrose), xylitol, maltodextrin, medium chain triglycerides, calcium carbonate (calcium), cream flavour, vanilla flavour, whey protein isolate, magnesium oxide heavy (magnesium), potassium citrate (potassium), glutamine, xanthan gum, seagreens (Ascophyllum nodosum seaweed), enzyme mix, ascorbic acid (vitamin C), ferrous fumarate (iron), Lactobacillus acidophilus, chromium picolinate (chromium), zinc oxide (zinc), d‐alpha tocopheryl succinate (vitamin E), nicotinamide (vitamin B3), potassium iodide (iodine), manganese sulfate monohydrate (manganese), vitamin A acetate (vitamin A), Bifidobacterium lactis, biotin, cupric sulfate pentahydrate (copper), folic acid (vitamin B9), selenomethionine (selenium), pyridoxine hydrochloride (vitamin B6), calcium d‐pantothenate (vitamin B5), riboflavin (vitamin B2), thiamine hydrochloride (vitamin B1), cholecalciferol (vitamin D3), cyanocobalamin (vitamin B12), sodium. Contains milk and soy.  Group B: BCAA (branded‐chain amino acid) oral nutritional supplement BCAA (L‐Leucine, L‐Isoleucine, L‐Valine), Citrulline Malate, L‐Glutamine, Minerals (Magnesium Phosphate, Calcium Phosphate, Sodium Chloride, Potassium Chloride), Flavour, Citric Acid, Sucralose, Vitamins (Calcium Ascorbate, Vitamin B6, Vitamin B12), Colour (Beta Carotene or Anthocyanins)  Group C: routine diet without any supplements
Cruz‐Mora 2014	Wrong intervention: blended with nutritional counselling, albeit in both groups; however, nutritional counselling directly related to diet and too similar to taking dietary supplement probiotics, so it wouldn't be possible to ascertain what has an effect
Eguchi 2011	Wrong population: liver transplantation
Ferrara 2009	Wrong population: girls with recurrent UTI, not CKD population
Firouzi 2015a	Wrong population: type 2 diabetes "Exclusion criteria include subjects who … have any acute or chronic disease other than diabetes, hyperlipidemia, and hypertension."
Fitschen 2015	Wrong intervention: not pre or probiotics
Fortes 2020	Wrong population: not CKD
Grat 2017	Wrong population: liver transplantation
Hassan 2017	Wrong intervention: not a prebiotic or probiotic treatment
Jiang 2021a	Wrong population: not entirely CKD study population
Lin 2021	Wrong intervention: Chinese Herbal Medicine
Orr 2016	Wrong population: liver transplantation
Pavan 2016	Wrong study design and intervention: quasi‐observational study with mixed controls
PrePro 2018	Wrong population: liver transplantation
ProLow CKD 2022	Wrong intervention: the primary intervention is a low‐protein diet compared to no‐protein control diet. Probiotics and prebiotics are mixed into these treatment arms, however there are too many variables and interventions to be able to ascertain a causal pathway for efficacy.
Rayes 2002	Wrong population: liver transplantation
Rayes 2002a	Wrong population: post‐op major abdominal surgery
Rayes 2005	Wrong population: liver transplantation
Saxena 2022	Wrong intervention: not including enzobiotics
Tayebi‐Khosroshahi 2016	Wrong intervention: not synbiotic, prebiotic or probiotic intervention treatment
Wang 2018e	Wrong intervention: not pre or probiotics

Methods	Study design Parallel, 2‐arm, single‐centre, placebo‐controlled trial Randomisation unclear from the abstract Blinding unclear from abstract Study duration Treatment period: not reported in the abstract Follow‐up: not reported in the abstract Study conducted on 92 kidney failure patients on regular HD from January 2017 to March 2017. Patients were divided into two groups: the intervention group (50 patients) received probiotics regimen containing 5 strains for 6 weeks, while the control group (42 patients) received placebo for the same period. Indoxyl sulphate using ELISA was measured before and after intervention
Participants	Study characteristics Country: Iran Setting: unclear from abstract Inclusion criteria: adults; regular HD Exclusion criteria: not reported in the abstract Baseline characteristics Number: 92
Interventions	Intervention group Probiotics (5 strains) Time: 6 weeks Control group Placebo Time: 6 weeks
Outcomes	Outcomes reported Indoxyl sulphate
Notes	Publication type Abstract only, not eligible according to inclusion criteria Unable to assess full methods and quality assessment Include in an update if full article and data are published Trial registration details None available

Methods	Study design Parallel, 2‐arm RCT Blinding unclear from abstract Time frame Treatment period: 4 months Follow‐up: 4 months, 5 months post‐transplant
Participants	Study characteristics Country: USA Setting: single‐centre (Hospital) Inclusion criteria: undergoing kidney transplantation Exclusion criteria: not reported in the abstract Baseline characteristics Number: intervention group (21); control group (22)
Interventions	Intervention group Probiotics: Bifidobacterium lactis, B. bifidum, B. longum, Lactobacillus acidophilus, L. rhamnosus, and L. paracasei, total of 50 billion CFU; 2 capsules/day Time: taken before transplant surgery, continued for 4 months Control group Placebo: 2 capsules/day Time: taken before transplant surgery, continued for 4 months
Outcomes	Outcomes reported Immunosuppression‐associated diarrhoea Adverse events
Notes	Publication type Abstract only, not eligible according to inclusion criteria Unable to assess full methods and quality assessment Include in an update if full article and data are published Trial registration details None available Attrition Notes Probiotic completers: 19/21 Placebo completers: 16/22 Baseline differences between groups None

Methods	Study design Parallel, double‐blind, placebo‐controlled RCT Time frame Treatment: 24 weeks Follow‐up: unclear from abstract
Participants	Study characteristics Country: Japan Setting: multi‐centre (dialysis centres) Inclusion criteria: patients receiving HD Exclusion criteria: not reported in the abstract Baseline characteristics Number: intervention group (37); control group (36)
Interventions	Intervention group Probiotic: combination of Streptococcus faecalis T‐110 2 mg, Clostridium butyricum TOA 10 mg, and Bacillusmesentericus TOA 10 mg; 6 tablets, 3 times/day Time: 24 weeks Control group Placebo: oral capsules matching Time: 24 weeks
Outcomes	Outcomes reported CRP to albumin ratio Gut microbiota composition (analysed by a 16s rRNA gene‐based sequencing)
Notes	Publication type Abstract only, not eligible according to inclusion criteria Unable to assess full methods and quality assessment Include in an update if full article and data are published Trial registration details None available