Effect of Synbiotic Therapy on Renal Function Outcomes in Patients With Chronic Kidney Disease Stage III-IV: A Double-blind Randomized Placebo-controlled Trial.

THESIS PROTOCOL TITLE Effect of Synbiotic Therapy on Renal Function Outcomes in Patients with Chronic Kidney Disease Stage III-IV: A double-blind Randomized placebo-controlled Trial INVESTIGATOR: Dr. Md. Rezwanul Haque MD (Nephrology) Phase-B Resident Session: March, 2025 GUIDE: Prof. Dr. Md Nurul Huda MBBS, MCPS (Medicine), FCPS(Medicine), MD(Nephrology), FASN, FISN Professor and Head Department of Nephrology, Chittagong Medical College and Hospital CO-GUIDE: Dr. Rosanna Bintey Kamal MBBS, MD (Nephrology) Assistant professor Department of Nephrology Chittagong Medical College and Hospital To The Principal Chittagong Medical College Chattogram. Subject: Application for the approval of Thesis Protocol with the title, "Effect of Synbiotic Therapy on Renal Function Outcomes in Patients with Chronic Kidney Disease Stage III-IV: A Randomized Placebo-Controlled Trial" Sir, With due respect and humble submission, I would like to state that I am a student of MD (Nephrology) Phase B, Resident, at BMU, Dhaka. As per requirement of the course, I would like to perform my research work on the thesis with the above-mentioned title under the direct supervision of Prof. Dr. Md Nurul Huda, Professor and Head, Department of Nephrology, Chittagong Medical College and Hospital, Chattogram, Bangladesh. I therefore, like to request you to approve my protocol so that I can commence my work in your esteemed institute to complete my thesis in due time. Obediently Yours Dr. Md. Rezwanul Haque MD (Nephrology) Phase B, Resident Department of Nephrology Chittagong Medical College and Hospital Chattogram, Bangladesh CMC Ethical Review Committee Chittagong Medical College Chattogram-4000, Bangladesh Tel-031619400, Fax-630180 Application for Ethical Clearance of Studies for post-Graduate Thesis 1\. Name of the applicant : Dr. Md. Rezwanul Haque 2. Course : MD (Nephrology) Phase B, Resident 3. Category : Government 4. Title of the study : Effect of Synbiotic Therapy on Renal Function Outcomes in Patients with Chronic Kidney Disease Stage III-IV: A Randomized Placebo-Controlled Trial in Bangladesh 5. Type of the study : Double-blind, randomized, placebo-controlled trial 6. Duration of the study : One and half year from acceptance of protocol. 7. Any collaboration : No 8. Conflict of interest : None 9. Name of the Guide : Prof. Dr. Md Nurul Huda, Professor and Head, Department of Nephrology Chittagong Medical College and Hospital 10. Name of the Co-Guide : Dr. Rosanna Bintey Kamal MBBS, MD (Nephrology) Assistant professor Department of Nephrology Chittagong Medical College and Hospital. Check Documents being submitted herewith to committee: 1. Summary : Attached 2. Umbrella proposal initially : NA 3. Protocol and CRF : Attached 4. Informed consent form for subject : Attached 5. Verbal consent form for subjects : NA 6. Procedure for Maintaining Confidentiality : Attached 7. Schedule of the study : Attached Declaration I agree to obtain approval of the Ethical Review Committee for any changes involving the rights and welfare of subjects or any changes of the methodology before making any such changes. ………………………………… Principal investigator/Student Dr. Md. Rezwanul Haque MD (Nephrology) Phase B, Resident Department of Nephrology Chittagong Medical College and Hospital Chattogram, Bangladesh Forwarding from the Guide ……………………………… Guide Prof. Dr. Md Nurul Huda Professor and Head Department of Nephrology Chittagong Medical College and Hospital Chattogram, Bangladesh CHITTAGONG MEDICAL COLLEGE Application for the Ethical review of thesis protocol 1. Name of the applicant : Dr. Md. Rezwanul Haque 2. Course : MD (Nephrology) Phase B, Resident 3. Category : Government 4. Title of the study : Effect of Synbiotic Therapy on Renal Function Outcomes in Patients with Chronic Kidney Disease Stage III-IV: A Randomized Placebo-Controlled Trial. 5. Type of the study : Double-blind, randomized, placebo-controlled trial 6. Duration of the study : One and half year 7. Any collaboration : No 8. Conflict of interest : None 9. Name of the Guide : Prof. Dr. Md Nurul Huda, Professor and Head, Department of Nephrology Chittagong Medical College and Hospital 10. Name of the Co-Guide : Dr. Rosanna Bintey Kamal MBBS, MD (Nephrology) Assistant professor Department of Nephrology Chittagong Medical College and Hospital. 11. Signature of the Guide : 12. Signature of the Co-Guide : 13. Submission date : 14. Signature of the Student : For Official use: Serial No: Received on: Reviewed on: Comment: Member-Secretary ERC Chairperson ERC Circle the appropriate answer to each of the following (If not Applicable write NA) 1. Source Population: 4. Are subjects clearly informed about: 1. Ill Subjects √Yes No (a) Nature and purpose of the study √Yes No 2. Non\* ill subjects Yes √No (b) Procedures to be followed including alternatives used √Yes No 3. Minors or persons under guardianship Yes √No (c) Physical risks √Yes No 4. Private questions √Yes No 2. Does the study involve: (e) Invasion of the Body √Yes No (a) Physical risks to subjects Yes √No (f) Benefits to be Derived √Yes No (b) Social risks Yes √No (g) Right to refuse to participate or withdraw from the study √Yes No (c) Psychological risks to subjects Yes √No (h) Confidential handling of data √Yes No (d) Discomfort to Subjects Yes √No (i) Compensation where there are risks or loss of working time or privacy is involved in any particular procedure √Yes No (e) Invasion of the body √Yes No (f) Invasion of privacy Yes √No (g) Disclosure of information damaging to subject or others Yes √No Will informed consent be required (a) From subject √Yes No (b) From parent or Guardians Yes √No 3. Does the study involve: 1. Use of records (hospital, medical, death, birth or other) Yes √No 6. Will precautions will be taken to protect anonymity of subjects √Yes No 2. Use of fetal tissue or abortus Yes √No 3. Use of organs or body fluids Yes √No Chittagong Medical College Chattogram-4000, Bangladesh Tel-031619400, Fax-630180 Research Proposal For Post Graduate Thesis/Dissertation Part - A 1. Title of the study : Effect of Synbiotic Therapy on Renal Function Outcomes in Patients with Chronic Kidney Disease Stage III-IV: A Randomized Placebo-Controlled Trial. 2. Name of the applicant : Dr. Md. Rezwanul Haque 3. Course : MD (Nephrology) Phase B, Resident 4. Place of Study : Department of Nephrology, Chittagong Medical College Hospital, Chattogram. 5. Sponsoring : Not Applicable 6. Duration of the study : One and half year from acceptance of protocol 7. Date of Commencement : 8. Date of completion : 9. Total cost : 616000/= 10. Other support of proposed research i. In this research project being supported by any other source? No ii. Has an application for funding of this project has been submitted to any other organization (s)? No 11. Date of submission : 12. Signature of student : 13. Signature of Guide : 14. Endorsement of the course coordinator Name and Signature: Designation: Official Seal: Part - B Student's Information Sheet 1. Name : Dr. Md. Rezwanul Haque Designation : MD (Nephrology) Phase B, Resident Official address with telephone \& mail : Department of Nephrology, Chittagong Medical College Hospital, Chattogram Phone: 01710457014 Email:drrezwanulhaque@gmail.com Present residential address : 54B/2, Road#6, Nasirabad Housing Society 2. Academic Background : Degree Institute University/Board Field Year M.B.B.S Shaheed Ziaur Rahman Medical College Rajshahi Passed 2014 3\. Field of study : Nephrology 4. Research experience : None 5. Percentage of time to be devoted to this project : 50% 6. Number of Scientific Publication : None ………………………….. Signature of the Student PART-C Summary Background: Chronic kidney disease (CKD) represents a growing global public health challenge, with rising prevalence in low and middle-income countries, including Bangladesh. Progressive renal dysfunction is frequently accompanied by gut microbiota alterations, leading to increased intestinal permeability and systemic inflammation through the gut-kidney axis. Accumulation of uremic toxins derived from dysbiotic microbiota has been implicated in CKD progression. Synbiotic therapy, combining probiotics and prebiotics, has been proposed as a strategy to restore microbial balance and reduce inflammatory burden. Objective: To evaluate effect of Synbiotic Therapy on Renal Function Outcomes in Patients with Chronic Kidney Disease Stage III-IV. Materials and Methods: This Double-blind, randomized placebo-controlled trial will be conducted in the Department of Nephrology, Chittagong Medical College Hospital, Bangladesh. Approximately 96 adult non-dialysis CKD stage III-IV patients will be enrolled. Participants will be randomly allocated into two arms of treatment. The experimental arm and the control arm. Both arm with receive standard care according to KDIGO recommendations. The experimental arm will receive synbiotic therapy and the control arm with receive placebo in addition to standard therapy. Clinical and laboratory assessments will be performed at baseline, after 1.5 months and after 3 months. Outcome measures are change in S. Creatinine, e-GFR, Blood Urea Nitrogen (BUN), C-Reactive protein (CRP), and Gastrointestinal symptom dynamics using Gastrointestinal System Rating Scale (GSRS). Data Analysis Plan: An intention-to-treat or per protocol approach will be applied as applicable. Parametric or non-parametric tests will be applied as appropriate. Repeated-measures analysis will assess longitudinal changes. Conclusion: The expected findings may clarify the potential role of gut microbiota modulation as an adjunct in CKD management in Bangladesh and similar settings and may inform future multicenter trials. Keywords: Chronic Kidney Disease; Synbiotic; Gut-Kidney Axis PART-D 1. Introduction: Globally, chronic kidney disease (CKD) has emerged as a major non-communicable disease. Recent estimates suggest that approximately 9-13% of the world's population is affected, translating into hundreds of millions of individuals living with impaired renal function (Guo et al., 2025). CKD now ranks among the leading causes of years of life lost worldwide, with a disproportionate impact in low and middle-income countries (LMICs) (Ying et al., 2024). Stages III and IV CKD represent a critical window in the disease trajectory. During this period, progressive nephron loss, glomerulosclerosis, tubulointerstitial fibrosis, and microvascular rarefaction contribute to a steady decline in renal function (Reiss et al., 2024). Although renal replacement therapy remains the definitive treatment for ESRD, it is costly, resource-intensive, and associated with significant co-morbidities. Therefore, interventions aimed at slowing progression during earlier stages are central to nephrology practice. Current standard therapy for CKD focuses primarily on control of blood pressure, often with renin-angiotensin-aldosterone system (RAAS) blockade, glycaemic control in diabetic nephropathy, lipid management, dietary protein restriction as indicated, correction of anemia, and management of mineral and bone disorders (KDIGO, 2013; Navaneethan et al., 2023). While these strategies reduce cardiovascular risk and modestly slow renal function decline, many patients continue to experience progressive deterioration despite optimized therapy. This residual risk suggests the involvement of additional pathophysiological mechanisms not fully addressed by conventional approaches. Increasing attention has been directed towards systemic inflammation and the accumulation of gut-derived uremic toxins as contributory drivers of CKD progression. Elevated circulating levels of indoxyl sulfate, p-cresyl sulfate, and trimethylamine-N-oxide have been associated with oxidative stress, endothelial dysfunction, and further nephron injury (Tsuji et al., 2024; Vaziri et al., 2013). Chronic low-grade inflammation, reflected by elevated C-reactive protein (CRP) and pro-inflammatory cytokines, is consistently observed in moderate to advanced CKD and is independently associated with adverse renal and cardiovascular outcomes (Carrero et al., 2010). These findings indicate that CKD is not solely a hemodynamic or metabolic disorder, but also a systemic inflammatory condition with complex inter-organ interactions. Within this broader pathophysiological framework, disturbances in gut microbiota composition, often referred to as dysbiosis have been increasingly implicated. The recognition of a bidirectional "gut-kidney axis" has introduced new perspectives on CKD progression and potential therapeutic targets. Healthcare systems in Bangladesh operate under resource limitations, especially in the context of renal replacement therapy. Hemodialysis services are concentrated in urban tertiary centers, and out-of-pocket expenditure remains substantial (Mostafi et al., 2023). Consequently, many patients present at advanced stages, and long-term dialysis may not be financially sustainable for a significant proportion of the population. In such settings, strategies that may delay progression from stage III-IV CKD to ESRD are of considerable clinical and public health relevance. Nutritional patterns, recurrent infections, and environmental factors prevalent in South Asian contexts may further influence CKD progression and inflammatory burden (Vijayan et al., 2023). Diets relatively high in refined carbohydrates and low in dietary fiber may alter gut microbial diversity. Additionally, frequent exposure to antibiotics can disrupt microbial equilibrium, potentially exacerbating dysbiosis. These contextual elements intersect with metabolic comorbidities to shape disease trajectories. The concept of the gut-kidney axis posits that the gastrointestinal tract and kidneys engage in bidirectional communication through metabolic, immunologic, and endocrine pathways. Uremia has been shown to disrupt tight junction proteins in the intestinal epithelium, increasing permeability and facilitating translocation of endotoxins into systemic circulation (Vaziri et al., 2012). This process contributes to chronic inflammation, oxidative stress, and vascular dysfunction. Conversely, modulation of gut microbiota may influence the production of toxin precursors and inflammatory mediators. Emerging microbiome-directed therapies, including probiotics, prebiotics, and their combination as synbiotics have been proposed as potential strategies to restore microbial balance and reduce toxin generation. Accumulating evidence suggests that CKD is associated with significant alterations in gut microbial composition. Experimental and clinical studies have reported reduced populations of Lactobacillus and Bifidobacterium species and increased abundance of urease- and uricase-producing bacteria in CKD patients (Vaziri et al., 2013). These microbial shifts favor proteolytic fermentation, leading to increased production of uraemic toxins. Probiotics are defined as live microorganisms which, when administered in adequate amounts, confer a health benefit on the host (Gibson et al., 2017). Prebiotics are selectively fermented substrates that promote the growth or activity of beneficial microorganisms. Synbiotics combine both components, aiming to enhance microbial survival and colonization. Mechanistically, probiotics may compete with toxin-producing bacteria, enhance short-chain fatty acid production, strengthen epithelial barrier function, and modulate immune responses. Prebiotics such as inulin and oligosaccharides serve as substrates for beneficial bacteria, promoting saccharolytic fermentation and reducing proteolytic toxin generation. Through these mechanisms, synbiotics may reduce circulating concentrations of uremic toxins and inflammatory mediators. Several clinical investigations have evaluated microbiome-targeted interventions in CKD populations, though findings remain heterogeneous. Rossi et al. (2016) conducted a randomized controlled trial in non-dialysis CKD patients and observed reductions in serum p-cresyl sulfate following synbiotic supplementation, though changes in e-GFR were not statistically significant over short follow-up. Similarly, Guida et al. (2014) reported improvements in certain metabolic parameters and toxin levels in CKD patients receiving synbiotics. Recently, in another RCT Mitrović et al. (2023) confirmed that synbiotic treatment in CKD patients significantly modified gut microbiome, improved eGFR, and decreased level of high-sensitivity C-reactive protein. A recent meta-analysis of 21 randomized controlled trials reported that probiotic or synbiotic supplementation significantly reduced BUN and CRP levels in CKD patients, although consistent improvement in serum creatinine was not demonstrated (Liu et al., 2024). Similarly, another meta-analysis showed reductions in inflammatory and oxidative stress markers and modest improvements in lipid profiles following microbial therapy (Zheng et al., 2020). However, individual trials have yielded heterogeneous findings; for example, the SYNERGY II randomized trial confirmed microbiota modulation but observed no clear renal functional benefit and even a small decline in eGFR over time (McFarlane et al., 2021). Overall, current evidence suggests potential anti-inflammatory and metabolic benefits of synbiotic therapy in CKD, while its effect on renal function outcomes remains inconclusive and warrants further evaluation in well-designed trials involving non-dialysis stage III-IV populations. Thus, the aim of this study to evaluate effect of symbiotic therapy on renal function outcomes in CKD stage III-IV patients. 2. Rationale: The prevalence of CKD is increasing rapidly due to urbanization, lifestyle changes and delayed diagnosis. Conventional management strategies primarily aim to slow disease progression through blood pressure control, glycemic management, and renin-angiotensin system blockade; however, these approaches do not directly address the gut-kidney axis, which is now recognized as a significant contributor to CKD progression. Recent evidence suggests that gut dysbiosis in CKD leads to increased production of uraemic toxins, contributing to systemic inflammation, oxidative stress and further renal injury. In Bangladesh, where access to renal replacement therapy is limited and costly, identifying affordable adjunctive therapies is crucial. No adequately designed randomized, double-blind trial has evaluated synbiotic therapy in patients with CKD stages III-IV in Bangladesh. Population-specific factors such as dietary habits, environmental exposure and antibiotic use may influence gut microbiota and treatment response. Furthermore, there is a lack of locally relevant outcome data assessing renal function outcomes, uraemic toxin levels and inflammatory markers. 3.1 Research questions: Does adjunctive synbiotic therapy improve renal function outcomes in patients with chronic kidney disease stage III-IV compared with placebo? 3.2 Research Hypothesis: Adjunctive synbiotic therapy significantly improves renal function outcomes in patients with chronic kidney disease stage III-IV compared with placebo. 4\. Objectives General Objective To evaluate the effect of adjunctive synbiotic therapy on renal function outcomes in patients with chronic kidney disease stage III-IV compared with placebo. Specific Objectives i) To assess and compare progression of CKD with changes of S. Creatinine, eGFR and BUN between intervention and placebo group. ii) To compare the rate of e-GFR decline between intervention and placebo group. iii) To evaluate and compare the effect of synbiotic therapy on systemic inflammation by C-Reactive protein(CRP) between two groups. iv) To assess changes in Gastrointestinal symptoms using Gastrointestinal Symptom Rating Scale(GSRS) between two groups. v) To evaluate the safety and adverse effects of synbiotic therapy. 5\. Materials and method 5.1. Type of study: Double-blind, randomized, placebo-controlled trial. 5.2 Place of Study: Department of Nephrology, Chittagong Medical College Hospital, Chattogram, Bangladesh. 5.3 Study period: One and half year. 5.4 Study population: Chronic kidney disease stage III-IV patients. 5.5 Study groups: Eligible participants will be randomly assigned into two groups: Experimental Group ( Group-A): Synbiotic therapy (1 capsule per day) along with Standard therapy according to KDIGO guideline will be administered for 3 months. Control Group (Group-B): Placebo(1 capsule per day) along with standard therapy according to KDIGO guideline will be administered for 3 months. 5.6 Sampling technique: All patients attending the nephrology department during the study period will be screened for eligibility. Screening will be performed using clinical records, laboratory reports, and direct patient interviews. All eligible and consenting patients meeting the inclusion criteria during the recruitment period will be enrolled until the required sample size is achieved. Randomization will be performed using a computer-generated random allocation sequence. Allocation concealment will be maintained through the use of sealed, opaque envelopes prepared prior to enrollment. 5.7. Inclusion criteria: Age ≥18 years. Diagnosed chronic kidney disease stage III or IV as per KDIGO guidelines. No use of probiotics, prebiotics, or synbiotics within the previous two weeks. Willingness to provide written informed consent. 5.8 Exclusion criteria Current use of immunosuppressive therapy. Presence of chronic diarrhoeal disease, inflammatory bowel disease, or history of major bowel surgery. Fever or any acute illness within the study period. Pregnancy or lactation. Known hypersensitivity to probiotic or synbiotic formulations. Acute kidney injury or requirement for dialysis at the time of screening. 5.9. Sample size: The sample size will be calculated based on the primary outcome measure, namely change in eGFR between the intervention and control groups after three months of follow-up. The formula for comparison of two independent means will be used: n=(2(Z\_(α/2)+Z\_β )\^2 σ\^2)/d\^2 Where: n= required sample size per group Z\_(α/2)= standard normal deviate at 5% level of significance (1.96) Z\_β= standard normal deviate at 80% power (0.84) σ= pooled standard deviation of eGFR d= minimum clinically significant difference between groups Based on previous randomized studies evaluating synbiotic therapy in CKD patients, a standard deviation of approximately 8 mL/min/1.73 m² for eGFR change has been reported, and a difference of 5 mL/min/1.73 m² will be considered clinically meaningful (Mitrović et al., 2023). Substituting the values: n=(2(1.96+0.84)\^2 (8)\^2)/(5)\^2 ┤ n=(2(2.8)\^2 (64))/25 n=(2(7.84)(64))/25 n=1003.84/25 n≈40 Thus, approximately 40 participants will be required in each group. Considering a potential attrition rate of 20%, the final sample size will be adjusted to 48 participants per group. Therefore, a total of 96 participants will be recruited for the study. List of variables Sociodemographic Variables Age (years) Sex (male/female) Residence (urban/rural) 1. Independent Variable (Exposure Variable) Administration of synbiotic therapy (Yes/No) Group allocation: Intervention group (Standard therapy + synbiotic capsule): Group-A Control group (Standard therapy + placebo): Group-B 2. Dependent Variables (Outcome Variables) A. Primary Outcome Variable Changes in serum creatinine, estimated Glomerular Filtration Rate (eGFR) and Blood Urea Nitrogen(BUN) B. Scecondary Outcome Variables i. Changes in C-Reactive protein(CRP) ii. Gastrointestinal symptoms improvement * Measured using Gastrointestinal Symptom Rating Scale(GSRS)( Appendix A1 ) iii. Adverse effects(increased flatulence, abdominal discomfort/pain, diarrhoea) 5.11 Operational definitions: CKD: According to 2024 KDIGO guideline for CKD , CKD is defined as abnormalities of kidney structure or function, present for a minimum of 3 months, with implications for health . Criteria for chronic kidney disease (either of the following present for a minimum of 3 months) 1. Markers of kidney damage (1 or more): 1. Albuminuria (ACR ≥30 mg/g \[ ≥3 mg/mmol\]) 2. Urine sediment abnormalities 3. Persistent hematuria 4. Electrolyte and other abnormalities due to tubular disorders 5. Abnormalities detected by histology 6. Structural abnormalities detected by imaging 7. History of kidney transplantation CKD Stage III: -CKD stage III will be defined as eGFR between 30-59 mL/min/1.73 m², calculated using the CKD-EPI equation. CKD Stage IV: * CKD stage IV will be defined as eGFR between 15-29 mL/min/1.73 m², calculated using the CKD-EPI equation. Estimated Glomerular Filtration Rate (eGFR): Estimated glomerular filtration rate will be calculated using the CKD-EPI equation based on serum creatinine, age, and sex, and will be expressed in mL/min/1.73 m². It will be used as the primary indicator of renal function. The CKD-EPI equation, expressed as a single equation, is: GFR = 141 × min (Scr/κ,1)α × max(Scr/κ, 1)-1.209× 0.993Age × 1.018 \[if female\] × 1.159 \[if black\] Scr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1. 5\. Synbiotic Therapy Synbiotic therapy will be defined as the combined administration of probiotics and prebiotics in a single oral formulation. In this study, it will refer to a daily capsule containing Lactobacillus acidophilus (15 billion CFU), Bifidobacterium longum (15 billion CFU), Streptococcus thermophilus(15 billion CFU), along with xylo-oligosaccharide and inulin. 6\. Standard Therapy Standard therapy will be defined as guideline-directed medical management of CKD stage III-IV according to KDIGO recommendations, including blood pressure control , glycaemic control, dietary protein regulation, anemia management, and treatment of mineral and bone disorders. 15\. Adverse Event An AE is defined as any unwanted medical occurrence in a clinical trial patient during the study; the event does not necessarily have a causal relationship with that treatment. Therefore, an AE can be any unfavourable and unintended sign (including any clinically significant abnormal laboratory finding), symptoms, or disease, temporally associated with using a medicinal product. The common adverse events of symbiotic therapy is increased flatulence, abdominal discomfort/pain, diarrhoea. Major adverse events will be defined as any event leading to hospital admission, withdrawal, or death. Minor adverse events will be defined as minor if it does not require admission to the hospital or withdrawal of the drug. Drug intolerance refers to the inability to tolerate the adverse effects of medication at a therapeutic or substantial dose. Participants experiencing major adverse event or drug intolerance will be withdrawn from the study. 5.12 Data collection instrument: A structured pretested case record form. 5.13 Study procedure: Baseline Assessment After eligibility will have been confirmed and written informed consent will have been obtained, baseline assessment will be performed. Sociodemographic data including age, sex, residence, will be recorded using a structured data collection form. Detailed clinical history including duration of CKD, presence of diabetes mellitus, hypertension, and medication history will be documented. Physical examination will be conducted, and blood pressure, body weight, height, and body mass index (BMI) will be measured and recorded. Baseline laboratory investigations will be carried out, including serum creatinine, BUN, CRP. eGFR based on serum creatinine will be calculated using the CKD-EPI equation. Gastrointestinal symptoms assessment will be assessed by using Gastrointestinal Symptoms Rating Scale (GSRS), and scores will be calculated according to standardized scoring procedures. All baseline findings will be documented prior to allocation. Allocation with Randomization After completion of baseline assessment, participants will be randomly assigned to either experimental group or placebo group with a 1:1 allocation. Randomization will be carried out using online software (Research Randomizer Version 4.0 at https://www.randomizer.org). Allocation concealment will be maintained through the use of sequentially numbered, sealed, opaque envelopes. Participants will then be assigned to either: The intervention group (standard therapy plus synbiotic), or The control group (standard therapy plus placebo) Blinding: The study will be double blind, with both investigator and participants will be unaware of their treatment allocation. Intervention In the experimental group: Standard treatment + 1 synbiotic capsule daily(45 billion CFU) Duration: 3 months In the control group: Standard treatment + 1 Placebo capsule daily Duration: 3 months The synbiotic capsule will contain Lactobacillus acidophilus (15 billion CFU), Bifidobacterium longum (15 billion CFU), Streptococcus thermophilus (15 billion CFU), total 45 billion CFU along with xylo-oligosaccharide and inulin. Participants will be instructed regarding the timing and method of capsule intake (Per oral with meal during breakfast). Adherence will be monitored through patient self-report and capsule count during follow-up visits. Follow-Up Participants will be followed for a total duration of three months. After 1.5 months first follow up and after 3 months second follow up will be conducted. In each follow up, Clinical reassessment and laboratory investigations including serum creatinine, e-GFR, BUN, and CRP will be repeated. Gastrointestinal symptoms assessment will be assessed by using Gastrointestinal Symptoms Rating Scale (GSRS), Any adverse events occurring during the study period will be documented and managed according to standard clinical practice. All collected data will be recorded systematically in the study database for subsequent statistical analysis. 5.14. Data analysis: All collected data will be checked for completeness, consistency, and accuracy prior to analysis. Data will be entered into a secured database and subsequently analyzed using appropriate statistical software such as Statistical Package for the Social Sciences (SPSS) version 27.0 (IBM Corp., Armonk, NY, USA). Descriptive statistics will be used to summarize baseline characteristics of the study participants. Continuous variables will be presented as mean ± standard deviation (SD) for normally distributed data or median with interquartile range (IQR) for non-normally distributed data. Categorical variables will be expressed as frequencies and percentages. The normality of continuous variables will be assessed using statistical tests such as the Shapiro-Wilk test. Baseline comparability between the intervention and control groups will be evaluated using the independent samples Student's t-test for normally distributed continuous variables or the Mann-Whitney U test for skewed data.