Lactulose vs Lactobacillus acidophilus for patients with chronic kidney disease: A randomized controlled trial

Abstract

BACKGROUND

Chronic kidney disease (CKD) is associated with progressive accumulation of uremic toxins and chronic systemic inflammation. CKD management focuses on treating the underlying disease, controlling risk factors, slowing disease progression, and initiating renal replacement therapy in stage 5. Early CKD is often asymptomatic or presents with mild symptoms such as fatigue and nocturia, whereas symptoms become progressively more severe after stage 3 and worsen further with renal failure. Modulation of the gut microbiota using prebiotics or probiotics has emerged as a promising adjunctive therapeutic strategy. Lactulose, a non-absorbable disaccharide, and Lactobacillus acidophilus (LA), a probiotic, are commonly used to target gut-derived uremic toxins.

AIM

To compare the effects of lactulose and LA on renal functions, inflammatory markers, and gastrointestinal symptoms in patients with non-dialysis CKD.

METHODS

This prospective comparative study was done on a total of 150 patients with non-dialysis CKD stage 3-5 who were randomly subdivided into three groups: The lactulose group included 50 patients with non-dialysis CKD stage 3-5 who received lactulose 30 mL per day divided into 3 doses; the LA group included 50 patients with non-dialysis CKD stage 3-5 who received one tablet of LA twice daily; and group C included 50 patients with non-dialysis CKD stage 3-5 who didn’t receive lactulose or LA. Baseline clinical and laboratory parameters were recorded. Renal function tests (serum creatinine and blood urea), inflammatory markers, and gastrointestinal symptoms were assessed before and after the intervention period.

RESULTS

A total of 150 patients with non-dialysis CKD stages 3-5 were enrolled and equally randomized into three groups: Lactulose (n = 50), LA (n = 50), and control (n = 50). The three groups were comparable in terms of age, sex distribution, body mass index, smoking status, comorbidities, and CKD stage at baseline. Baseline laboratory parameters showed no significant differences among the groups. At the end of the 3-month follow-up period, the LA group achieved the greatest improvement in renal function parameters, as reflected by significantly larger reductions in delta levels of blood urea and serum creatinine compared with both the lactulose and control groups. The mean change in blood urea was -12.45 ± 3.01 mg/dL in the LA group, -5.00 ± 2.45 mg/dL in the lactulose group, and -1.79 ± 3.01 mg/dL in the controls (P = 0.03). Similarly, the mean change in serum creatinine was -20.01% ± 3.45% in the LA group, but -7.33% ± 2.88% in the lactulose group and -6.55% ± 2.44% in the controls (P < 0.001). Improvements in albumin-to-creatinine ratio and estimated glomerular filtration rate were observed in all groups but did not reach statistical significance.

CONCLUSION

Both lactulose and LA demonstrated beneficial effects in non-dialysis CKD patients. However, LA showed superior improvement in uremic parameters and inflammatory status. Gut-directed therapy represents a valuable adjunct in the medical management of CKD.

Key Words: Chronic kidney disease; Lactulose; Lactobacillus acidophilus; Gut microbiota; Uremic toxins; Inflammation

Core Tip: Modulation of the gut-kidney axis represents a promising adjunctive strategy in the management of chronic kidney disease (CKD). This study highlights that both lactulose and Lactobacillus acidophilus improve uremic parameters and gastrointestinal symptoms in CKD patients; however, Lactobacillus acidophilus demonstrates a more pronounced effect on reducing uremic toxin burden and systemic inflammation. These findings support the clinical relevance of targeting gut dysbiosis to slow disease progression and improve patient outcomes in CKD.

INTRODUCTION

Chronic kidney disease (CKD) is a gradual loss of kidney function over time with a relatively high frequency among the world’s population, representing a global health issue. It has various risk factors, with a growing attitude about the multifaceted concepts of progression[1]. CKD is associated with significant metabolic, inflammatory, and gastrointestinal disturbances that contribute to increased morbidity and mortality. Accumulation of uremic toxins, many of which are derived from intestinal bacterial metabolism, plays a central role in the progression of CKD and the development of systemic complications, including chronic inflammation, cardiovascular disease, and protein-energy wasting[1,2].

The global prevalence of CKD is estimated at 9.1%-13.4% of the adult population, corresponding to more than 700-850 million individuals worldwide. The prevalence increases markedly with advancing age and is particularly high among patients with diabetes mellitus, hypertension, obesity, and cardiovascular disease. Owing to the growing burden of these risk factors, CKD has become one of the leading causes of morbidity and mortality worldwide and is projected to continue increasing in prevalence over the coming decades[3]. Growing evidence highlights the importance of the gut-kidney axis, whereby alterations in gut microbiota composition and intestinal barrier function exacerbate the generation of uremic toxins and systemic inflammation in patients with CKD[4].

Lactulose, a non-absorbable synthetic disaccharide, has been widely used in medical practice to reduce ammonia production and modulate intestinal flora. In CKD, lactulose may reduce the absorption of nitrogenous waste products by promoting saccharolytic fermentation and decreasing proteolytic bacterial activity, thereby lowering circulating uremic toxins[5]. In contrast, Lactobacillus acidophilus (LA), a well-established probiotic, exerts beneficial effects by restoring gut microbial balance, enhancing intestinal barrier integrity, and suppressing pathogenic bacteria. Both interventions target gut dysbiosis but through different mechanisms, suggesting potentially distinct clinical effects in CKD patients[6].

Despite growing interest in microbiota-targeted therapies, direct comparative data evaluating lactulose vs LA in CKD patients remain limited. Most available studies focus on either prebiotics or probiotics individually, with heterogeneous patient populations and outcome measures. Consequently, there is a lack of clear evidence to guide clinicians in selecting the optimal gut-modulating therapy to reduce uremic toxin burden, inflammation, and gastrointestinal symptoms in CKD[7].

Therefore, this study aimed to compare the effects of lactulose and LA in patients with CKD, focusing on renal function parameters, inflammatory markers, uremic toxin levels, and gastrointestinal symptoms. The proposed study sought to clarify their relative efficacy and safety by directly comparing the effects of lactulose and LA. Additionally, it could provide evidence-based guidance for incorporating gut-directed therapies into the comprehensive medical management of CKD patients.

MATERIALS AND METHODS

Study design and settings

A randomized clinical trial was carried out at the Nephrology Unit, Internal Medicine Department, Assiut University, Assiut, Egypt, from July 2023 to July 2024.

Patient selection

The inclusion criteria were adult male and female patients who were aged 18-60 years, who had stage 3-5 CKD and constipation. However, the exclusion criteria were the presence of chronic hepatitis B virus or hepatitis C virus infection, regular hemodialysis, intestinal obstruction or severe gastrointestinal disorders affecting bowel motility, lost to follow-up, and patient refusal to participate or inability to provide informed consent.

Chronic constipation was defined according to the Rome III criteria as a difficult, infrequent, or perceived incomplete bowel evacuation. Symptoms of constipation include having fewer than 3 bowel evacuations per week, straining, hard stools, incomplete evacuation, or inability to pass stool[8]. CKD was defined as an estimated glomerular filtration rate (eGFR) of less than 60 mL/minute/1.73 m², persisting for 3 months or more, irrespective of the cause. The Kidney Disease Improving Global Outcomes CKD classification recommends specifying the cause of CKD and classifies the condition into 6 categories based on GFR[9].

Sample size

The sample size was calculated based on a previous study[9]. Epi Info was used to determine the sample size, considering an 80% two-sided confidence level, 70% power, and a 5% α error. Accordingly, the sample size was 144 patients (48 for each group). Considering the lost-to-follow-up percentage, the actual sample size was 150 patients (50 patients per group).

Random allocation and grouping of patients

Eligible non-dialysis CKD patients were randomly allocated to three groups: Group A included 50 patients who received lactulose 30 mL per day divided into 3 doses; group B included 50 patients who received LA 1 tablet twice daily; and group C included 50 patients who didn’t receive lactulose or LA. Participants were randomly assigned to their groups. The randomization technique was computer-generated (1:1:1 ratio, blocks of 6) by an independent investigator. The results of randomization were not blinded to patients and investigators. One of the investigators revealed the randomization result to the physician who treated the patient, only at the time of treatment prescription. Patients with lost follow-up were excluded, and the number in each group was 50 patients (Figure 1).

Figure 1 CONSORT flowchart of patients. Patients were randomly allocated to the therapeutic groups: Lactulose, Lactobacillus acidophilus, or no therapy. LA: Lactobacillus acidophilus.

Clinical workup

A full history and clinical examination were done. Baseline laboratory tests included liver function tests, urine analysis, lipid profile, kidney function tests, complete blood count, serum electrolytes, and coagulation profile. In all patients, eGFR was calculated using the CKD-EPI equation[10].

Follow-up schedule

All patients in different groups were followed monthly for three months. In addition to the physical examination, laboratory tests at each visit included blood urea, serum creatinine, and eGFR. Any reported side effects were recorded. Delta checks were performed for blood urea, serum creatinine, and eGFR. The delta value for each renal function parameter was estimated based on the baseline and 3-month follow-up levels.

Calculation of delta changes in renal function parameters

The change in renal function parameters after three months of treatment was assessed by calculating the delta value (Δ) for each parameter. Delta values were calculated as the difference between the measurement obtained at the end of the third month and the corresponding baseline measurement according to the following formula: Percentage change was calculated as: Δ% = [(value at 3 months - baseline value)/baseline value] × 100. A negative delta value for blood urea and serum creatinine indicated a reduction from baseline, reflecting an improved renal function. In contrast, a positive delta value indicated a worsening parameter.

Outcomes of the study

The primary outcome was the delta value of serum creatinine at the 3-month follow-up. The secondary outcomes were the delta levels of blood urea and eGFR and changes in uremic manifestations. The delta changes in these renal biomarker levels were used because they are more advantageous than simple or absolute parameters. They account for individual baseline differences and provide superior prognostic data regarding treatment efficacy.

Approval and registration

The study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Ethics Committee of the Faculty of Medicine, Assiut University. The study was registered on clinicaltrials.gov with NCT05934552.

Statistical analysis

Data was collected and analyzed by using SPSS (Statistical Package for the Social Sciences, version 20, IBM, Armonk, NY, United States). The Shapiro-Wilk test was used to assess the normality of the data distribution. Quantitative data were expressed as mean ± SD. Quantitative data with normal distribution were compared using the t-test (between two means) and analysis of variance (between more than two means). However, quantitative data with abnormal distributions were compared using the Mann-Whitney U test (between two means) and Kruskal-Wallis (between more than two means). The χ² test was used to compare nominal data. The level of confidence was 95%, hence P was significant if < 0.05.

RESULTS

As shown in Table 1, there were no significant differences among the three groups regarding age, sex distribution, body mass index, smoking status, comorbidities, or CKD stage. The majority of participants were males, and stage III CKD represented the most frequent disease stage.

Table 1 Baseline data of the studied groups, n (%)/mean ± SD.

	Lactulose group (n = 50)	LA group (n = 50)	Control group (n = 50)	P value	1P value	2P value	3P value
Age (years)	46.34 ± 7.11	52.11 ± 3.67	50.11 ± 4.55	0.09	0.30	0.12	0.31
Sex				0.70	0.69	0.76	0.43
Male	30 (60)	35 (70)	32 (64)
Female	20 (40)	15 (30)	18 (36)
BMI (kg/m2)	25.55 ± 2.35	24.57 ± 4.01	25.08 ± 3.18	0.45	0.30	0.06	0.21
Current smoking	10 (20)	11 (22)	14 (28)	0.90	0.87	0.28	0.45
DM	20 (40)	21 (42)	23 (46)	0.32	0.06	0.11	0.66
HTN	18 (36)	17 (34)	20 (40)	0.06	0.55	0.05	0.50
COPD	5 (10)	5 (10)	6 (12)	0.21	0.65	0.55	0.45
Dyslipidemia	3 (6)	2 (4)	4 (8)	0.55	0.45	0.21	0.19
Stages of CKD				0.64	0.76	0.21	0.10
Stage-III	19 (38)	20 (40)	17 (34)
Stage-IV	16 (32)	18 (36)	17 (34)
Stage-Va	15 (30)	12 (24)	16 (32)

¹P: Lactulose group vs Lactobacillus acidophilus group.

²P: Lactulose group vs control group.

³P: Lactobacillus acidophilus group vs control group.

LA: Lactobacillus acidophilus; BMI: Body mass index; DM: Diabetes mellitus; HTN: Hypertension; COPD: Chronic obstructive pulmonary disease; CKD: Chronic kidney disease.

As demonstrated in Table 2, the frequencies of dyspnea, vomiting, and lower limb edema remained low and showed no significant differences between groups at baseline, after one month, after two months, or at the end of the third month. Baseline laboratory investigations were also comparable among the three groups (Table 3). During follow-up, laboratory parameters remained generally similar among the three groups after one month (Table 4), two months (Table 5), and three months (Table 6).

Table 2 Uremic manifestations among the studied groups during different times, n (%)/mean ± SD.

	Lactulose group (n = 50)	LA group (n = 50)	Control group (n = 50)	P value	1P value	2P value	3P value
At baseline
Dyspnea	1 (2)	0	2 (4)	0.45	0.96	0.11	0.55
Vomiting	1 (2)	2 (4)	1 (2)	0.33	0.11	0.06	0.30
Lower limb edema	0	1 (2)	1 (2)	0.87	0.96	0.96	0.06
SBP (mmHg)	134.56 ± 23.45	136.55 ± 32.11	139.19 ± 44.44	0.09	0.22	0.10	0.34
DBP (mmHg)	89.09 ± 8.54	90.11 ± 8.88	88.34 ± 10.22	0.54	0.76	0.56	0.10
UOP (mL/24 hours)	2330.11 ± 795.56	2311.67 ± 897.65	2404.44 ± 453.22	0.07	0.46	0.08	0.77
End of 1st month
Dyspnea	1 (2)	0	1 (2)	0.45	0.96	0.10	0.96
Vomiting	1 (2)	0	0	0.33	0.96	0.96	-
Lower limb edema	0	1 (2)	1 (2)	0.45	0.96	0.96	0.10
SBP (mmHg)	131.09 ± 22.19	132.60 ± 19.56	132.56 ± 23.10	0.76	0.39	0.21	0.08
DBP (mmHg)	85.67 ± 8.56	88.56 ± 8.19	88.90 ± 10.87	0.40	0.34	0.10	0.19
UOP (mL/24 hours)	2345.01 ± 675.56	2401.10 ± 453.67	2398.01 ± 542.22	0.56	009	0.21	0.45
End of 2nd month
Dyspnea	1 (2)	0	0	0.33	0.96	0.96	-
Vomiting	0	0	1 (2)	0.33	-	0.96	0.96
Lower limb edema	0	1 (2)	0	0.33	0.96	-	0.96
SBP (mmHg)	131.23 ± 13.56	130.79 ± 19.21	132.89 ± 18.50	0.76	0.39	0.21	0.08
DBP (mmHg)	87 ± 9.59	87.56 ± 7.89	86.54 ± 11.34	0.40	0.34	0.10	0.19
UOP (mL/24 hours)	2456.78 ± 609	2490.67 ± 444	2500.1 ± 600.11	0.56	009	0.21	0.45
End of 3rd month
Dyspnea	1 (2)	0	1 (2)	0.43	0.96	0.06	0.96
Vomiting	1 (2)	1 (2)	0	0.43	0.06	0.96	0.96
Lower limb edema	1 (2)	0	1 (2)	0.43	0.96	0.06	0.96
SBP (mmHg)	132.11 ± 23.34	133.99 ± 22.17	138.10 ± 22.19	0.33	0.62	0.56	0.22
DBP (mmHg)	88.87 ± 20.22	89.65 ± 7.65	90.44 ± 9.56	0.40	0.66	0.06	0.10
UOP (mL/24 hours)	2356.76 ± 654.33	2401.11 ± 456.65	2404.44 ± 675.55	0.31	0.40	0.87	0.76

¹P: Lactulose group vs Lactobacillus acidophilus group.

²P: Lactulose group vs control group.

³P: Lactobacillus acidophilus group vs control group.

LA: Lactobacillus acidophilus; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; UOP: Urine output.

Table 3 Baseline laboratory data of the studied groups, mean ± SD.

	Lactulose group (n = 50)	LA group (n = 50)	Control group (n = 50)	P value	1P value	2P value	3P value
Hemoglobin (mg/dL)	10.52 ± 2.11	10.93 ± 1.87	10.56 ± 1.94	0.22	0.09	0.17	0.18
Platelets (103/μL)	282.17 ± 55.67	271.25 ± 69.56	289.20 ± 43.41	0.64	0.76	0.06	0.22
Leucocytes (103/μL)	5.55 ± 2.56	5.90 ± 2.33	5.09 ± 2.19	0.90	0.56	0.10	0.78
Bilirubin (mg/dL)	1.01 ± 0.50	0.99 ± 0.11	1.11 ± 0.21	0.12	0.09	0.34	0.19
Albumin (g/dL)	3.33 ± 1.21	3.21 ± 0.69	3.30 ± 0.87	0.38	0.73	0.69	0.28
AST (U/L)	31.09 ± 2.87	30.09 ± 4.56	30.66 ± 6.70	0.68	0.31	0.54	0.11
ALT (U/L)	29.45 ± 3.19	28.44 ± 4.59	24.56 ± 8.33	0.09	0.57	0.50	0.75
Urea (mg/dL)	56.34 ± 5.60	53.04 ± 9.97	55.67 ± 8.56	0.43	0.51	0.37	0.49
Creatinine (mg/dL)	3.90 ± 1.11	4.05 ± 1.22	3.88 ± 1.99	0.18	0.18	0.19	0.35
ACR	123.05 ± 25.17	113.16 ± 33.93	115.07 ± 25.67	0.58	0.78	0.43	0.18
eGFR (mL/minute/1.73 m2)	46.57 ± 9.89	48.17 ± 8.64	50.45 ± 7.11	0.77	0.67	0.08	0.50
Sodium (mmol/L)	133.15 ± 0.05	132.01 ± 0.26	133.03 ± 0.84	0.10	0.78	0.45	0.22
Potassium (mmol/L)	4.91 ± 1.33	4.82 ± 0.87	4.06 ± 1.87	0.09	0.10	0.08	0.11
Calcium (mg/dL)	9.06 ± 1.89	9.17 ± 2.31	8.93 ± 1.23	0.72	0.22	0.21	0.67
Magnesium (mmol/L)	1.79 ± 0.15	1.71 ± 0.99	1.81 ± 0.49	0.33	0.44	0.32	0.08
Phosphorus (mmol/L)	4.50 ± 0.81	4.93 ± 1.83	4.65 ± 1.45	0.21	0.09	0.45	0.33
RBS (mg/dL)	208.08 ± 8511	211.17 ± 55.43	221.03 ± 27.45	0.22	0.21	0.56	0.56
HbA1C (%)	7.19 ± 1.22	7.43 ± 0.70	8.01 ± 0.44	0.54	0.45	0.44	0.41
Cholesterol (mg/dL)	203.09 ± 24.56	205.15 ± 45.10	219.79 ± 45.67	0.09	0.67	0.09	0.21
Triglycerides (mg/dL)	133.94 ± 28.29	129.33 ± 33.10	135.90 ± 18.11	0.20	0.11	0.67	0.98
LDL (mg/dL)	119.01 ± 24.21	122.09 ± 50.43	109.81 ± 34.54	0.19	0.76	0.15	0.51
HDL (mg/dL)	48.11 ± 7.66	50.45 ± 7.22	49.41 ± 5.89	0.32	0.07	0.23	0.07

¹P: Lactulose group vs Lactobacillus acidophilus group.

²P: Lactulose group vs control group.

³P: Lactobacillus acidophilus group vs control group.

LA: Lactobacillus acidophilus; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; ACR: Albumin/creatinine ratio; eGFR: Estimated glomerular filtration rate; RBS: Random blood sugar; HbA1C: Glycated hemoglobin A1c; LDL: Low density lipoprotein; HDL: High density lipoproteins.

Table 4 Follow-up laboratory data of the studied group after one month, mean ± SD.

	Lactulose group (n = 50)	LA group (n = 50)	Control group (n = 50)	P value	1P value	2P value	3P value
Hemoglobin (mg/dL)	10.90 ± 2.45	10.60 ± 2.34	10.83 ± 1.76	0.67	0.32	0.33	0.13
Platelets (103/μL)	291.89 ± 55.11	281.90 ± 45.67	289.11 ± 54.10	0.44	0.36	00.9	0.18
Leucocytes (103/μL)	6.46 ± 2.78	7.18 ± 2.98	6.66 ± 2.17	0.45	0.22	0.12	0.34
Bilirubin (mg/dL)	0.90 ± 0.21	1.01 ± 0.12	0.95 ± 0.04	0.99	0.92	0.72	0.10
Albumin (g/dL)	3.39 ± 1.22	3.38 ± 0.43	3.39 ± 0.95	0.54	0.45	0.88	0.57
AST (U/L)	23.89 ± 3.90	30.24 ± 4.36	30.57 ± 6.89	0.63	0.25	0.87	0.65
ALT (U/L)	30.19 ± 3.11	28.68 ± 4.77	24.46 ± 8.17	0.14	0.63	0.49	0.81
Urea (mg/dL)	56.12 ± 5.64	52.9 ± 9.97	55.65 ± 8.36	0.87	0.16	0.18	0.57
Creatinine (mg/dL)	3.67 ± 0.81	4.02 ± 1.03	3.85 ± 1.82	0.54	0.07	0.68	0.56
ACR	120.91 ± 25.24	110.46 ± 33.71	109.31 ± 25.93	0.06	0.19	0.68	0.09
eGFR (mL/minute/1.73 m2)	47.56 ± 9.59	49.61 ± 8.74	50.32 ± 7.98	0.08	0.83	0.78	0.87
Sodium (mmol/L)	133.27 ± 0.11	132.34 ± 0.47	132.75 ± 0.58	0.88	0.12	0.74	0.42
Potassium (mmol/L)	4.56 ± 1.18	4.36 ± 1.07	4.56 ± 1.61	0.61	0.09	0.96	0.55
Calcium (mg/dL)	8.97 ± 2.11	8.68 ± 2.13	9.29 ± 0.94	0.74	0.45	0.38	0.55
Magnesium (mmol/L)	2.17 ± -0.12	1.82 ± 1.03	2.22 ± 0.66	0.21	0.96	0.86	0.91
Phosphorus (mmol/L)	4.74 ± 0.61	5.11 ± 1.61	4.21 ± 1.74	0.38	0.29	0.72	0.59
RBS (mg/dL)	214.45 ± 50.71	211.1 ± 55.52	220.75 ± 27.47	0.14	0.95	0.81	0.95
HbA1C (%)	6.76 ± 1.25	7.04 ± 0.56	7.56 ± 0.26	0.78	0.99	0.56	0.71
Cholesterol (mg/dL)	203.47 ± 24.66	205.08 ± 44.98	219.74 ± 45.84	0.79	0.39	0.75	0.21
Triglycerides (mg/dL)	133.11 ± 28.42	128.88 ± 33.32	135.66 ± 18.06	0.96	0.14	0.63	0.12
LDL (mg/dL)	108.62 ± 24.34	122.45 ± 50.29	109.65 ± 34.81	0.88	0.45	0.07	0.58
HDL (mg/dL)	46.78 ± 7.60	50.37 ± 7.18	49.77 ± 5.6	0.97	0.09	0.28	0.32

¹P: Lactulose group vs Lactobacillus acidophilus group.

²P: Lactulose group vs control group.

³P: Lactobacillus acidophilus group vs control group.

LA: Lactobacillus acidophilus; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; ACR: Albumin/creatinine ratio; eGFR: Estimated glomerular filtration rate; RBS: Random blood sugar; HbA1C: Glycated hemoglobin A1c; LDL: Low density lipoprotein; HDL: High density lipoproteins.

Table 5 Follow-up laboratory data of the studied group after two months, mean ± SD.

	Lactulose group (n = 50)	LA group (n = 50)	Control group (n = 50)	P value	1P value	2P value	3P value
Hemoglobin (mg/dL)	10.87 ± 2.11	10.90 ± 2.01	10.73 ± 2.45	0.55	0.92	0.30	0.12
Platelets (103/μL)	301 ± 66.56	312.40 ± 55.67	299.02 ± 60.55	0.40	0.46	0.19	0.10
Leucocytes (103/μL)	7.11 ± 1.78	7.90 ± 3.09	7.09 ± 2.01	0.38	0.78	0.80	0.34
Bilirubin (mg/dL)	1.01 ± 0.21	0.98 ± 0.10	0.95 ± 0.01	0.91	0.91	0.70	0.19
Albumin (g/dL)	3.38 ± 0.45	3.36 ± 0.40	3.34 ± 0.99	0.50	0.65	0.88	0.50
AST (U/L)	33.19 ± 4.90	36.24 ± 1.09	31.57 ± 5.60	0.60	0.45	0.11	0.65
ALT (U/L)	35.67 ± 5.90	33.11 ± 5.60	39.11 ± 8.01	0.10	0.22	0.50	0.89
Urea (mg/dL)	52.98 ± 1.64	53.45 ± 4.98	55.60 ± 4.36	0.80	0.22	0.19	0.67
Creatinine (mg/dL)	3.57 ± 1.22	4 ± 1.13	3.88 ± 1.65	0.50	0.10	0.21	0.78
ACR	119.91 ± 14.56	115.06 ± 23.67	112.31 ± 19.45	0.22	0.12	0.45	0.22
eGFR (mL/minute/1.73 m2)	49.56 ± 2.59	49.89 ± 3.56	50.11 ± 7.01	0.08	0.93	0.45	0.11
Sodium (mmol/L)	133.27 ± 0.10	133.14 ± 0.37	132.45 ± 0.08	0.45	0.16	0.98	0.54
Potassium (mmol/L)	4.01 ± 1.23	4.06 ± 1.07	3.98 ± 1.01	0.21	0.09	0.10	0.42
Calcium (mg/dL)	8.90 ± 1.67	8.67 ± 2.01	9.19 ± 0.56	0.56	0.31	0.98	0.12
Magnesium (mmol/L)	2.07 ± 0.10	1.98 ± 0.45	2.21 ± 0.60	0.21	0.56	0.88	0.91
Phosphorus (mmol/L)	4.76 ± 0.61	5.09 ± 1.22	4.20 ± 0.56	0.40	0.23	0.11	0.59
RBS (mg/dL)	210.11 ± 4.35	209.1 ± 55.52	219.45 ± 27.90	0.10	0.19	0.40	0.86
HbA1C (%)	6.90 ± 1.25	7.14 ± 0.48	7.22 ± 0.19	0.08	0.20	0.18	0.50
Cholesterol (mg/dL)	231.56 ± 24.11	234.18 ± 44.99	230.11 ± 23.19	0.09	0.29	0.40	0.21
Triglycerides (mg/dL)	134.56 ± 28.67	132.88 ± 17.90	130.65 ± 22.19	0.44	0.13	0.63	0.87
LDL (mg/dL)	145.67 ± 24.11	140.56 ± 34.60	130.05 ± 33.01	0.08	0.17	0.20	0.18
HDL (mg/dL)	49.11 ± 7.01	50.47 ± 5.60	48.56 ± 6.90	0.07	0.08	0.30	0.19

¹P: Lactulose group vs Lactobacillus acidophilus group.

²P: Lactulose group vs control group.

³P: Lactobacillus acidophilus group vs control group.

LA: Lactobacillus acidophilus; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; ACR: Albumin/creatinine ratio; eGFR: Estimated glomerular filtration rate; RBS: Random blood sugar; HbA1C: Glycated hemoglobin A1c; LDL: Low density lipoprotein; HDL: High density lipoproteins.

Table 6 Follow-up laboratory data of the studied group after three months, mean ± SD.

	Lactulose group (n = 50)	LA group (n = 50)	Control group (n = 50)	P value	1P value	2P value	3P value
Hemoglobin (mg/dL)	10.86 ± 2.15	10.93 ± 2.02	10.98 ± 2.0	0.58	0.88	0.29	0.4
Platelets (103/μL)	281.68 ± 55.52	270.89 ± 69.83	288.91 ± 43.52	0.43	0.65	0.22	0.33
Leucocytes (103/μL)	5.93 ± 2.71	6.04 ± 2.33	5.36 ± 1.89	0.41	0.63	0.21	0.32
Bilirubin (mg/dL)	0.69 ± 0.31	1.36 ± 0.07	1.6 ± 0.11	0.43	0.65	0.22	0.33
Albumin (g/dL)	3.6 ± 1.1	3.7 ± 0.72	3.11 ± 0.97	0.53	0.75	0.27	0.38
AST (U/L)	30.95 ± 3.02	29.73 ± 4.82	30.36 ± 6.47	0.63	0.85	0.32	0.43
ALT (U/L)	29.37 ± 3.1	28.85 ± 4.58	24.88 ± 8.3	0.13	0.35	0.07	0.18
Urea (mg/dL)	50.11 ± 4.43	47.04 ± 5.57	54.07 ± 10.22	0.44	0.66	0.22	0.33
Creatinine (mg/dL)	3.28 ± 1.98	3.22 ± 1.45	3.65 ± 1.56	0.53	0.75	0.27	0.38
ACR	120.57 ± 13.45	109.33 ± 21.45	114.33 ± 22.22	0.25	0.47	0.13	0.24
eGFR (mL/minute/1.73 m2)	50.55 ± 7.77	54.66 ± 5.66	53.44 ± 3.17	0.11	0.33	0.06	0.17
Sodium (mmol/L)	133.37 ± 0.21	132.27 ± 0.42	132.81 ± 0.69	0.48	0.7	0.24	0.35
Potassium (mmol/L)	4.88 ± 1.09	5.25 ± 0.78	4.14 ± 1.59	0.24	0.46	0.12	0.23
Calcium (mg/dL)	9.55 ± 2.11	9.23 ± 2.08	9.35 ± 1.38	0.59	0.81	0.3	0.41
Magnesium (mmol/L)	1.68 ± 0.45	2.05 ± 1.23	2.03 ± 0.41	0.24	0.46	0.12	0.23
Phosphorus (mmol/L)	4.19 ± 0.83	5.38 ± 1.68	4.83 ± 1.65	0.43	0.65	0.22	0.33
RBS (mg/dL)	208.11 ± 58.12	211.13 ± 55.3	220.95 ± 27.45	0.13	0.35	0.07	0.18
HbA1C (%)	7.21 ± 1.03	7.55 ± 0.92	7.76 ± 0.35	0.11	0.33	0.06	0.17
Cholesterol (mg/dL)	202.83 ± 24.56	205.26 ± 44.84	220.04 ± 45.97	0.12	0.34	0.06	0.17
Triglycerides (mg/dL)	133.74 ± 28.31	129.43 ± 33.03	135.54 ± 18.23	0.47	0.69	0.24	0.35
LDL (mg/dL)	119.18 ± 24.18	122.25 ± 50.27	109.7 ± 34.54	0.11	0.33	0.06	0.17
HDL (mg/dL)	48.07 ± 7.91	50.19 ± 7.4	49.64 ± 5.87	0.1	0.32	0.05	0.16

¹P: Lactulose group vs Lactobacillus acidophilus group.

²P: Lactulose group vs control group.

³P: Lactobacillus acidophilus group vs control group.

LA: Lactobacillus acidophilus; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; ACR: Albumin/creatinine ratio; eGFR: Estimated glomerular filtration rate; RBS: Random blood sugar; HbA1C: Glycated hemoglobin A1c; LDL: Low density lipoprotein; HDL: High density lipoproteins.

The most important findings were observed in renal function changes after three months (Table 7, Figure 2). Patients receiving LA demonstrated the greatest reduction in blood urea level, with a mean delta urea of -12.45 ± 3.01, compared with -5.00 ± 2.45 in the lactulose group and -1.79 ± 3.01 in the control group. This difference was statistically significant (P = 0.03). Similarly, the LA group achieved the largest reduction in serum creatinine, with a mean delta creatinine of -20.01 ± 3.45, compared with -7.33 ± 2.88 in the lactulose group and -6.55 ± 2.44 in controls (P < 0.001). These findings are illustrated in Figure 2A, which shows a greater decline in blood urea, and Figure 2B, which shows a greater reduction in serum creatinine among patients receiving LA. In contrast, changes in albumin-to-creatinine ratio and eGFR did not differ significantly among the three groups at the end of follow-up (Table 7).

Figure 2 Delta change after three months in the studied groups. A: Delta change in urea level after three months in the studied groups; B: Delta change in creatinine level after three months in the studied groups. LA: Lactobacillus acidophilus.

Table 7 Delta changes in renal functions after three months compared to baseline data, mean ± SD.

	Lactulose group (n = 50)	LA group (n = 50)	Control group (n = 50)	P value	1P value	2P value	3P value
Delta urea	-5 ± 2.45	-12.45 ± 3.01	-1.79 ± 3.01	0.03	0.04	0.33	0.02
Delta creatinine	-7.33 ± 2.88	-20.01 ± 3.45	-6.55 ± 2.44	< 0.001	0.03	0.11	0.01
Delata ACR	2.40 ± 0.86	3.50 ± 0.67	1.09 ± 0.55	0.57	0.45	0.09	0.21
Delta eGFR	8.66 ± 2.09	9.55 ± 2.22	6.67 ± 1.11	0.33	0.34	0.65	0.09

¹P: Lactulose group vs Lactobacillus acidophilus group.

²P: Lactulose group vs control group.

³P: Lactobacillus acidophilus group vs control group.

LA: Lactobacillus acidophilus; ACR: Albumin/creatinine ratio; eGFR: Estimated glomerular filtration rate.

DISCUSSION

There is a paucity in the literature on direct comparisons between lactulose and probiotics, such as LA, regarding their effects on uremic manifestations in patients with CKD and chronic constipation[7]. Hence, it was a rationale to conduct the current study. The current results showed that the three groups had comparable baseline characteristics, including demographics, laboratory tests, CKD stages, and uremic manifestations. However, the LA group had significantly higher delta checks of blood urea and serum creatinine levels than the other groups.

In agreement with the current study, a previous study included 32 patients with CKD who were divided into an intervention group that received 30 mL of lactulose syrup three times a day for 8 weeks. The control group received a 30 mm placebo three times a day. Both groups had comparable baseline and laboratory data[11]. During follow-up after three months, we found that uremic manifestations, such as vomiting, dyspnea, and lower limb edema, were comparable in different groups. This similarity could be explained by the fact that we enrolled CKD patients not on hemodialysis, who are less likely to develop such manifestations than those on hemodialysis.

The main findings of the current study were that the LA group had significantly higher urea and creatinine delta checks than the lactulose and control groups. Similarly, a previous study revealed a significant reduction in serum creatinine levels in patients who received lactulose, while it showed increased serum creatinine in the controls[9]. Also, these findings were consistent with many previous studies. They showed a significant reduction in serum creatinine levels in patients who received lactulose[12,13].

A meta-analysis of 10 randomized controlled trials highlighted that LA supplementation significantly affected urea levels in the non-dialysis CKD population. However, no evidence suggested that probiotics had meaningful effects on uric acid, C-reactive protein, serum creatinine, or eGFR in the CKD population[14].

Many previous studies have reported that the use of probiotics containing five strains of Lactobacillus and Bifidobacterium together with lactulose syrup for six weeks can reduce blood urea and serum creatinine levels. However, the main findings in these studies were a reduction in uremic toxins, such as serum indoxyl sulfate[15,16].

To date, most randomized controlled trials of probiotic treatment used in non-dialysis patients with CKD stage 3-5 have revealed favorable outcomes. Phenylacetylglutamine and serum trimethylamine N-oxide are colon-derived uremic toxins that have been commonly studied. In studies of patients with advanced CKD stages, a significant reduction in the levels of these uremic toxins has been achieved by the use of probiotics[17-19].

In a randomized controlled trial by Guida et al[20] involving 30 patients with CKD stages 3-4, supplementation with LA for 4 weeks significantly reduced plasma p-cresol levels but did not improve gastrointestinal symptoms. A previous randomized trial involved 16 patients receiving LA and 16 receiving a placebo. The authors found that blood urea, serum creatinine, uric acid, and C-reactive protein levels did not change significantly in the placebo group. No differences were observed between groups. The inflammatory markers and gut profile were not affected by this supplementation[21].

To our knowledge, the current study was the first one to perform this comparison. It evaluated uremic manifestations in non-dialysis CKD patients before and after lactulose and LA. Although this study didn’t assess effects on uremic toxins (such as phenylacetylglutamine and serum trimethylamine N-oxide), it may pave the way for research on the beneficial use of probiotics such as LA in patients with CKD. It addressed a clinically relevant and emerging topic (gut-kidney axis), included a relatively adequate sample size for a single-center study, and provided comparative data between prebiotic and probiotic interventions, which is currently limited in the literature. Additionally, the randomized controlled design enhances the level of evidence.

This study had several limitations, including a relatively small sample size, short follow-up duration, and heterogeneity in probiotic strains, dosages, treatment periods, and concomitant medications, which may have affected the assessment of treatment effects. Long-term outcomes, such as mortality and progression to end-stage renal disease, were not evaluated. A 3-month follow-up was designed to study short-term outcomes in late stages of CKD, but it was insufficient to study long-term outcomes. Another limitation of the present study is its open-label design. Neither participants nor investigators were blinded to treatment allocation, which may have introduced performance and assessment bias. Although randomization was performed using a computer-generated allocation sequence, the absence of blinding could have influenced patient-reported outcomes and clinical assessments. Although replacing lost-to-follow-up patients may introduce selection bias, it may be justified by the completion of an equal sample in each group and by following the same randomization methods in both groups of patients.

The study did not measure key gut-derived uremic toxins. Measurement of uremic toxins such as indoxyl sulfate, p-cresyl sulfate, and trimethylamine-N-oxide would have provided valuable mechanistic insights. Unfortunately, these biomarkers were not available within the resources of the current study. Additionally, the uremic milieu in the gut may not be favorable for the survival of probiotics, limiting their potential health benefits.

CONCLUSION

Probiotic administration in patients with CKD may have a potential benefit in improving changes in blood urea and serum creatinine levels. Although both lactulose and LA demonstrated beneficial effects in non-dialysis CKD patients, LA showed superior improvement in uremic parameters and inflammatory status. However, larger well-designed randomized controlled trials with longer follow-up periods are recommended to confirm these findings and evaluate the impact of probiotics on important clinical outcomes, including disease progression, hospitalization, quality of life, and survival among patients with CKD.