Sudan Journal of Medical Sciences Volume 17, Issue no. 4, DOI 10.18502/sjms.v17i4.12547 Production and Hosting by Knowledge E Research Article Efficacy and Safety of Gum Arabic on Renal Failure Patients: Systematic Review and Meta-analysis Selma Abdelrahman Hussein1, Hammad Ali Fadlalmola2, Suzy Munir Salama3*, Eyas Gaffar Osman4, Abdalbasit Adam Mariod5 1Industrial and System Engineering, Engineering College, Princess Nourah Bint Abdulrahman 2Nursing College, Taibah University, Saudi Arabia 3Indigenous Knowledge and Heritage Center, Ghibaish College of Science and Technology, Ghibaish, Sudan 4College of Science and Humanities-Shaqra University, Saudi Arabia 5College of Sciences and Arts-Alkamil, University of Jeddah, Alkamil, Saudi Arabia ORCID: Suzy Munir Salama: https://orcid.org/0000-0003-0430-1436 Abstract Background: Chronic Renal Failure (CRF) is a long-term disease caused by progressive kidney dysfunction due to many reasons leading to a significant rise in serum levels of creatinine and urea reaching the advanced stage where the patient goes for frequent hemodialysis. This study aims to discuss the evaluation of the efficacy of gum Arabic (GA) supplementation on the serum level of creatinine, urea, sodium, and potassium in CRF patients. Methods: Four databases PubMed, Web of Science, Scopus, and the Cochrane Library were searched for clinical trials assessment of gum Arabic intervention in CRF patients. Animal trials and experimental protocols were excluded. Screening of data and data extraction were done by two reviewers independently of each other. Meta-analysis was conducted on the selected studies using RevMan and the resulting description was summarized through the Forest plot tool on the efficacy of GA on 4 variables, creatinine, urea, sodium, and potassium in CRF patients. Results: From 574 studies searched, only 4 studies were included in this systemic review and meta-analysis. Although one of the studies had proved the objectives of the review but it was removed from the meta-analysis due to the heterogeneity caused by its inclusion. Conclusion: The few studies included in the current review revealed significant efficacy of GA treatment on the serum level of creatinine, urea, and sodium, but not potassium. Keywords: Gum Arabic, Kidney, clinical How to cite this article: Selma Abdelrahman Hussein, Hammad Ali Fadlalmola, Suzy Munir Salama*, Eyas Gaffar Osman, Abdalbasit Adam Mariod (2022) “Efficacy and Safety of Gum Arabic on Renal Failure Patients: Systematic Review and Meta-analysis,” Sudan Journal of Medical Sciences, vol. 17, Issue no. 4, pages 459–475. DOI 10.18502/sjms.v17i4.12547 Page 459 Corresponding Author: Suzy Munir Salama; email: s.salama999@hotmail.com Received 5 June 2021 Accepted 9 September 2022 Published 31 December 2022 Production and Hosting by Knowledge E Selma Abdelrahman Hussein et al.. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Editor-in-Chief: Prof. Mohammad A. M. Ibnouf http://www.knowledgee.com http://crossmark.crossref.org/dialog/?doi=10.18502/sjms.v17i4.12547&domain=pdf&date_stamp=2022-12-12 https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/ Sudan Journal of Medical Sciences Selma Abdelrahman Hussein et al. 1. Introduction Gum Arabic (GA) is a natural dietary fiber; it is considered as the best of all soluble fibers and a direct additive to liquid foods [1]]. In addition to its high-soluble dietary fiber content (85-90%, w/w), GA is safe, odorless, tasteless, lowest in viscosity, and stable in acid solutions [2]]. GA has a high-molecular weight and is composed majorly of macromolecules (carbohydrates and protein), minerals, and amino acids; the major carbohydrates in GA are rhamnose, arabinose, galactose, and glucuronic acid [3]. It is rich in amino acids such as hydroxyproline, serine, threonine, proline, leucine, and histidine [4], GA is a valuable source of four antioxidant minerals like copper, iron, manganese, and zinc [5]. Studies demonstrated GA to be a successful prebiotic [6]. GA belongs to the class of nondigestible fibers, as it ferments with bacteria to convert into short-chain fatty acids in the digestive system [7]. The natural characteristics of GA associated with qualitative and quantitative indicators include moisture, ash content, volatile compounds, and inner energy, which exactly represents the world standards [8]. Recent studies have shown the therapeutic action of GA [9]. GA is used to treat many diseases as it improves the performance of the digestive system and improves the appetite [10]. As for patients with kidney failure, it helps them obtain sufficient energy from their food [11]. Chronic kidney failure is often associated with a lack of dietary fiber consumption, excessive utilization of antibiotics, edema of the intestinal wall, and iron intake [12]. Patients with renal disorders suffer from a state of inflammation originating from the gastrointestinal tract; and uremia is associated with a steady increase in the bacteria count in the large intestine and the jejunum, which results in the presence of bacteria in the stool [13]. Many studies have been conducted on the importance of GA for treating kidney diseases and kidney failure, adding GA to drinking water contributes significantly to alleviating kidney problems regardless of its effect on the metabolism of intestinal bac- terial ammonia [14-16]. The daily addition of 10-40 g of GA to the diet of ongoing kidney failure patients, substantially decreased the amount of C-reactive protein (CRP) level which could positively affect death of these patients [17]. In addition, 90 g GA/day was able to decrease the hyperglycemia in chronic renal disease [18]. Ali et al. hypothesized that addition of GA to patients with hemodialysis would decrease oxidative stress and thus decrease the state of hemodialysis-related chronic inflammatory activation [19]. Al- Mosawi announced that implementation with GA might be an option in contrast to renal substitution treatment to enhance the personal satisfaction and lessen the requirement DOI 10.18502/sjms.v17i4.12547 Page 460 Sudan Journal of Medical Sciences Selma Abdelrahman Hussein et al. for dialysis in kids in some countries [20]. The customary admission of GA notwith- standing a low-protein/high-calorie diet candelay the requirement for hemodialysis or peritoneal dialysis in kids’. Further, the impact of GA oral therapy on the metabolic profile of renal failure (RF) patients was evaluated, they found that oral intake of GA could possibly reduce antagonistic impacts of CRF [21]. RF which is the outcome of broadly contrasting illnesses of the kidney is an overwhelming clinical, social, and economic issue for patients and their families. Most patients with RF will in the long run arrive at the state of ESRD, become suggestive, and require replacement of their renal capacity [22]. The initial search for literature reviews on the effectiveness of GA on the metabolic profile of chronic kidney patients did not show any previous reviews. This systematic review was carried out to show the utilization of GA in healing and mitigating the side effects of chronic kidney disease and preserving the lives of kidney patients. 2. Materials and Methods 2.1. Study selection Based on the methodology of search and data extraction conducted previously [23], we searched PubMed, Web of Science, Scopus and the Cochrane Library for data from 1980 to 2020. All the studies before 1980 were omitted from the search, using the keywords ”Gum Arabic” or ”Sudani Gum” or ”Acacia Gum” or ”Gum Acacia” or ”Acacia” or ”Senegal Gum” or ”Indian gum” AND ”chronic kidney disease” or ”CKD” or ”chronic renal failure” or ”CRF” or ”renal insufficiency” or ”hemodialysis” or ”peritoneal dialysis” or ”dialysis”. We made some restrictions on RCTs, Human, and English language only studies. To ascertain the efficacy and safety of the GA for the treatment of patients with renal failure, we included controlled randomized trials examining the impact of GA on patients with renal failure. We excluded trials that used GA in the therapy of patients with renal failure for other purposes such as uric acid, fiber diet duration, controlled feeding, and non-English language publications. 2.2. Data extraction Each article was independently reviewed and had relevant data extracted by two independent reviewers (SS and EG). Extracted data included information on study DOI 10.18502/sjms.v17i4.12547 Page 461 Sudan Journal of Medical Sciences Selma Abdelrahman Hussein et al. setting, design, randomization, blinding, sample size, and participant characteristics; dose of the GA and comparator, follow-up, and funding. Mean and standard deviation data on serum urea and serum creatinine for end of treatment were extracted as priori end points. The preferred reporting items of systematic review and meta-analysis (PRISMA) flow diagram of the studies screened and selected for the present systematic review is mapped on Figure 1. 574 reports identified - PubMed 174 (1980 to Sept 1, 2020) - Scopus 105 (1980 to Sept 1, 2020) - Web of Science 277 (1980 to Sept 1, 2020) - Cochrane library 18 (1980 to Sept 1, 2020) S c r e e n in g In c lu d e d E li g ib il it y Id e n ti fi c a ti o n Additional records identified through other sources (n = 16) Records after duplicates removed (n = 476) Records screened (n = 476) Records excluded (n = 453) Full-text articles assessed for eligibility (n = 23) Full-text articles excluded, with reasons (n = 19) Studies included in qualitative synthesis (n = 4) Studies included in quantitative synthesis (meta-analysis) (n = 4) Figure 1: The PRISMA flow diagram of the studies’ screened and selected. DOI 10.18502/sjms.v17i4.12547 Page 462 Sudan Journal of Medical Sciences Selma Abdelrahman Hussein et al. 2.3. Statistical Analysis Data were analyzed using Review Manager (RevMan) version 5.4.1. Data were pooled using the generic inverse variance method with random-effects models and data were expressed as mean differences (MDs) with 95% confidence intervals (CIs). Inter-study heterogeneity was assessed by the Cochran Q statistic (χ2), with the significance at P value = 0.10 and quantified by the I2 statistic, where a value of ⩾ 50% indicates substan- tial heterogeneity. Potential sources of methodological heterogeneity were investigated by sensitivity analysis in which each individual trial was removed systematically and the pooled effect estimates were recalculated. We assessed and interpreted heterogeneity according to the recommendations in the Cochrane Handbook of Systematic Reviews and Meta-analysis [24]. 2.4. Creatinine For creatinine analysis, four studies were used in Figure 3-A, B, C, and D. The four studies showed high-heterogeneity test, as evidenced by the P value > 0.1 of I2 = 99%, and the total effect of the pooled effect estimated a probability value of 0.08. This effect was significant at a confidence interval of 90% but not effective at the level of 95%. To reduce the effect of the heterogeneity, we conducted a sensitivity analysis and used the leave-one-out method. The study of Farman et al., 2020, deviated the most from the rest of the studies based on the forest funnel plot, so it was removed and the pooled effect estimates were recalculated; the new results are shown in Figures 3-C and D. The decrease in the level of heterogeneity (I2) was recorded as 21% in the three studies, Ali et al., 2008, Bliss et al., 1996, and Elamin et al., 2017, and the hypothesis of homogeneity of the studies with a P value = 0.28 was accepted. The analysis of the pooled effect of GA on the decrease in creatinine despite the presence of the diamond shape left of the null line showed obvious, non-significant results (P value = 0.58). The funnel plot estimated that the three studies 1996, 2008, and 2017 were all within the confidence level, while the study of Elamin et al., 2017 recorded 41% higher weighted value compared to the other two studies. 2.5. Urea The Forest plot of the studies included in the analysis of the efficacy of GA intervention on the serum level of urea is displayed in Figures 4-E, F, G, H, I, and J. Because the P DOI 10.18502/sjms.v17i4.12547 Page 463 Sudan Journal of Medical Sciences Selma Abdelrahman Hussein et al. value was 0.05 and the level of heterogeneity was high (I2 = 97%), the four studies Ali et al., 2008; Bliss et al., 1996; Elamin et al., 2017; and Farman et al., 2020 revealed a significant effect on the decrease of urea by GA intervention. By using the leave-one-out method and omitting the study of Farman et al., 2020, the heterogeneity decreased to I2 = 72%, but the heterogeneity remained present (P value = 0.03). Results illustrated in Figure 4-G showed that the diamond shape is located on the left side of the null line, but without significant effect on the decrease of urea due to the doses of GA used during intervention periods. Additionally, when the study of Ali et al., 2008 was removed, the homogeneity occurred leading to the disappearance of variance, where the P value recorded was 0.14 and the overall effect of GA on the high level of urea was not significant (P value = 0.23). 2.6. Sodium Analysis of sodium was done based on three studies, Elkarib et al., 2016, Elamin et al., 2017, and Farman et al., 2020 using Forest Plot (Figures 5-K, L, M, and N). Analysis suggested that no overall significant decrease was recorded in serum level of sodium during GA intervention. Also, there was a high heterogeneity in the three studies analyzed. Therefore, the study of Farman et al., 2020 was removed resulting in reduction in the heterogeneity produced (P value = 0.16) despite the appearance of significant decrease in the blood sodium level during GA supplementation (P value = 0.001). The studies analyzed revealed clinically significant reduction rate of 2.21 m/mol in 95% confidence intervals of mean difference UCI = 3.54 and LCI = 0.87 m/mol as illustrated in Figure 5-M. 2.7. Potassium Analysis for potassium was based on three studies, as shown in Figures 6-O, P, Q, and R. All the studies included gave high heterogeneity and not significant increase in the serum level of potassium in the treated patients (Figure 5-Q), even after the removal of the study of Farman et al., 2020 that recorded decrease in potassium during intervention period. It is true that the studies of Elkarib et al., 2016 and Elamin et al., 2017 showed increase in the potassium level as the diamond shape moved to the right side of the null line, but this increase was still not significant (P value = 0.23). DOI 10.18502/sjms.v17i4.12547 Page 464 Sudan Journal of Medical Sciences Selma Abdelrahman Hussein et al. A Creatinine B Study or Subgroup Ali et al., 2008 Bliss et al., 1996 Elamin et al., 2017 Farman et al., 2020 Total (95% CI) Heterogeneity: Tau² = 13.55; Chi² = 423.32, df = 3 (P < 0.00001); I² = 99% Test for overall effect: Z = 1.75 (P = 0.08) Mean 4.44 4.5 2.57 0.93 SD 0.72 0.8 0.94 0.53 Total 12 16 30 50 108 Mean 4.93 4.4 2.54 13.7 SD 0.73 0.8 0.87 4.2 Total 12 16 30 50 108 Weight 25.1% 25.1% 25.2% 24.6% 100.0% IV, Random, 95% CI -0.49 [-1.07, 0.09] 0.10 [-0.45, 0.65] 0.03 [-0.43, 0.49] -12.77 [-13.94, -11.60] -3.23 [-6.86, 0.39] Intervention Group Control Group Mean Difference Mean Difference IV, Random, 95% CI -10 -5 0 5 10 Intervention Group Control Group -10 -5 0 5 10 0 0.2 0.4 0.6 0.8 1 MD SE(MD) Ali et al., 2008Bliss et al., 1996 Elamin et al., 2017 Farman et al., 2020 C D Study or Subgroup Ali et al., 2008 Bliss et al., 1996 Elamin et al., 2017 Farman et al., 2020 Total (95% CI) Heterogeneity: Tau² = 0.02; Chi² = 2.54, df = 2 (P = 0.28); I² = 21% Test for overall effect: Z = 0.55 (P = 0.58) Mean 4.44 4.5 2.57 0.93 SD 0.72 0.8 0.94 0.53 Total 12 16 30 50 58 Mean 4.93 4.4 2.54 13.7 SD 0.73 0.8 0.87 4.2 Total 12 16 30 50 58 Weight 28.4% 30.6% 41.0% 0.0% 100.0% IV, Random, 95% CI -0.49 [-1.07, 0.09] 0.10 [-0.45, 0.65] 0.03 [-0.43, 0.49] -12.77 [-13.94, -11.60] -0.10 [-0.44, 0.25] Intervention Group Control Group Mean Difference Mean Difference IV, Random, 95% CI -2 -1 0 1 2 Intervention Group Control Group -2 -1 0 1 2 0 0.1 0.2 0.3 0.4 0.5 MD SE(MD) Ali et al., 2008 Bliss et al., 1996 Elamin et al., 2017 Figure 2: Forest Plot in the meta-analysis of the studies included in the efficacy of GA intervention on serum level of creatinine. 3. Discussion Chronic renal disease (CRF) is a long-term disease that appears as gradual decrease in the renal function progressing to end-stage renal failure. The leading reasons of the disease can be referred to many factors including glomerular and tubular diseases, renal stones, and nephrotic disorders [4]. One of the important demands that has been DOI 10.18502/sjms.v17i4.12547 Page 465 Sudan Journal of Medical Sciences Selma Abdelrahman Hussein et al. E Urea F Study or Subgroup Ali et al., 2008 Bliss et al., 1996 Elamin et al., 2017 Farman et al., 2020 Total (95% CI) Heterogeneity: Tau² = 642.02; Chi² = 88.10, df = 3 (P < 0.00001); I² = 97% Test for overall effect: Z = 1.96 (P = 0.05) Mean 125.67 94.16 81.52 18.5 SD 62.12 10.7 31.77 2.7 Total 12 16 30 50 108 Mean 182.67 107 80.92 65.4 SD 36.03 12.84 29.97 10.4 Total 12 16 30 50 108 Weight 17.2% 28.0% 26.2% 28.6% 100.0% IV, Random, 95% CI -57.00 [-97.63, -16.37] -12.84 [-21.03, -4.65] 0.60 [-15.03, 16.23] -46.90 [-49.88, -43.92] -26.68 [-53.31, -0.06] Intervention group Control group Mean Difference Mean Difference IV, Random, 95% CI -50 -25 0 25 50 Intervention group control group -50 -25 0 25 50 0 10 20 30 40 50 MD SE(MD) Ali et al., 2008 Bliss et al., 1996 Elamin et al., 2017 Farman et al., 2020 G H I Study or Subgroup Ali et al., 2008 Bliss et al., 1996 Elamin et al., 2017 Farman et al., 2020 Total (95% CI) Heterogeneity: Tau² = 183.71; Chi² = 7.22, df = 2 (P = 0.03); I² = 72% Test for overall effect: Z = 1.50 (P = 0.13) Mean 125.67 94.16 81.52 18.5 SD 62.12 10.7 31.77 2.7 Total 12 16 30 50 58 Mean 182.67 107 80.92 65.4 SD 36.03 12.84 29.97 10.4 Total 12 16 30 50 58 Weight 15.3% 46.7% 38.0% 0.0% 100.0% IV, Random, 95% CI -57.00 [-97.63, -16.37] -12.84 [-21.03, -4.65] 0.60 [-15.03, 16.23] -46.90 [-49.88, -43.92] -14.50 [-33.49, 4.50] Intervention group Control group Mean Difference Mean Difference IV, Random, 95% CI -50 -25 0 25 50 Intervention group control group Study or Subgroup Ali et al., 2008 Bliss et al., 1996 Elamin et al., 2017 Farman et al., 2020 Total (95% CI) Heterogeneity: Tau² = 49.79; Chi² = 2.23, df = 1 (P = 0.14); I² = 55% Test for overall effect: Z = 1.21 (P = 0.23) Mean 125.67 94.16 81.52 18.5 SD 62.12 10.7 31.77 2.7 Total 12 16 30 50 46 Mean 182.67 107 80.92 65.4 SD 36.03 12.84 29.97 10.4 Total 12 16 30 50 46 Weight 0.0% 62.8% 37.2% 0.0% 100.0% IV, Random, 95% CI -57.00 [-97.63, -16.37] -12.84 [-21.03, -4.65] 0.60 [-15.03, 16.23] -46.90 [-49.88, -43.92] -7.84 [-20.57, 4.90] Intervention group Control group Mean Difference Mean Difference IV, Random, 95% CI -50 -25 0 25 50 Intervention group control group J -50 -25 0 25 50 0 2 4 6 8 10 MD SE(MD) Bliss et al., 1996 Elamin et al., 2017 Figure 3: Forest Plot in the meta-analysis of the studies included in the efficacy of GA intervention on serum level of urea in CRF disease. focused by healthcare organizations in both developed and developing countries is chronic renal failure (CRF) disease due to the high incidence of the disease, especially in DOI 10.18502/sjms.v17i4.12547 Page 466 Sudan Journal of Medical Sciences Selma Abdelrahman Hussein et al. K Sodium L M Study or Subgroup Alkarib et al., 2016 Elamin et al., 2017 Farman et al., 2020 Total (95% CI) Heterogeneity: Tau² = 56.85; Chi² = 286.12, df = 2 (P < 0.00001); I² = 99% Test for overall effect: Z = 0.42 (P = 0.67) Mean 135 136.3 142 SD 2.04 3.1 2.1 Total 24 30 50 104 Mean 137.86 137.8 132.1 SD 2.54 2.4 3.1 Total 24 30 50 104 Weight 33.3% 33.3% 33.4% 100.0% IV, Random, 95% CI -2.86 [-4.16, -1.56] -1.50 [-2.90, -0.10] 9.90 [8.86, 10.94] 1.86 [-6.71, 10.42] Intervention group Control group Mean Difference Mean Difference IV, Random, 95% CI -10 -5 0 5 10 Intervention group control group -10 -5 0 5 10 0 0.2 0.4 0.6 0.8 1 MD SE(MD) Alkarib et al., 2016 Elamin et al., 2017 Farman et al., 2020 Study or Subgroup Alkarib et al., 2016 Elamin et al., 2017 Farman et al., 2020 Total (95% CI) Heterogeneity: Tau² = 0.45; Chi² = 1.94, df = 1 (P = 0.16); I² = 48% Test for overall effect: Z = 3.25 (P = 0.001) Mean 135 136.3 142 SD 2.04 3.1 2.1 Total 24 30 50 54 Mean 137.86 137.8 132.1 SD 2.54 2.4 3.1 Total 24 30 50 54 Weight 51.9% 48.1% 0.0% 100.0% IV, Random, 95% CI -2.86 [-4.16, -1.56] -1.50 [-2.90, -0.10] 9.90 [8.86, 10.94] -2.21 [-3.54, -0.87] Intervention group Control group Mean Difference Mean Difference IV, Random, 95% CI -10 -5 0 5 10 Intervention group control group N -10 -5 0 5 10 0 0.2 0.4 0.6 0.8 1 MD SE(MD) Alkarib et al., 2016 Elamin et al., 2017 Figure 4: Forest Plot in the meta-analysis of the studies included in the efficacy of GA intervention on serum level of Sodium in CRF disease. some developing countries. Earlier studies on the incidence of CRF prevalence in Sudan had recorded a yearly average increase in CRF patients of about 100 cases per million population, most of them were below the age of 40 [25]. Studies attributed the reasons of incident CRF cases in Sudan to stone diseases, hypertension, and diabetes mellitus [26]. Lameire et al., 2005 reported that new patients treated with renal replacement therapy in 25 countries of the European Union due to end-stage renal failure was estimated to be 36,000 per year according to the report issued by the European Renal Association/European Dialysis and Transplant Association Registry 2001 [27]. 3.1. Effect of GA on serum creatinine and urea Recent studies exposed the positive effects of low-protein diet (LPD) and prebiotic activity of nutrients in managing the renal function of CRF patients [28]. In chronic renal DOI 10.18502/sjms.v17i4.12547 Page 467 Sudan Journal of Medical Sciences Selma Abdelrahman Hussein et al. O Potassium P Q Study or Subgroup Alkarib et al., 2016 Elamin et al., 2017 Farman et al., 2020 Total (95% CI) Heterogeneity: Tau² = 8.33; Chi² = 865.94, df = 2 (P < 0.00001); I² = 100% Test for overall effect: Z = 0.56 (P = 0.58) Mean 5.25 4.6 4.11 SD 0.4 0.6 0.32 Total 24 30 50 104 Mean 4.157 4.5 8.1 SD 0.74 0.5 0.7 Total 24 30 50 104 Weight 33.3% 33.3% 33.4% 100.0% IV, Random, 95% CI 1.09 [0.76, 1.43] 0.10 [-0.18, 0.38] -3.99 [-4.20, -3.78] -0.93 [-4.20, 2.34] Intervention group Control group Mean Difference Mean Difference IV, Random, 95% CI -4 -2 0 2 4 Control group Intervention group -4 -2 0 2 4 0 0.05 0.1 0.15 0.2 MD SE(MD) Alkarib et al., 2016 Elamin et al., 2017 Farman et al., 2020 Study or Subgroup Alkarib et al., 2016 Elamin et al., 2017 Farman et al., 2020 Total (95% CI) Heterogeneity: Tau² = 0.47; Chi² = 19.79, df = 1 (P < 0.00001); I² = 95% Test for overall effect: Z = 1.19 (P = 0.23) Mean 5.25 4.6 4.11 SD 0.4 0.6 0.32 Total 24 30 50 54 Mean 4.157 4.5 8.1 SD 0.74 0.5 0.7 Total 24 30 50 54 Weight 49.5% 50.5% 0.0% 100.0% IV, Random, 95% CI 1.09 [0.76, 1.43] 0.10 [-0.18, 0.38] -3.99 [-4.20, -3.78] 0.59 [-0.38, 1.56] Intervention group Control group Mean Difference Mean Difference IV, Random, 95% CI -4 -2 0 2 4 Control group Intervention group R -4 -2 0 2 4 0 0.05 0.1 0.15 0.2 MD SE(MD) Alkarib et al., 2016 Elamin et al., 2017 Figure 5: Forest Plot in the meta-analysis of the studies included in the efficacy of GA intervention on serum level of Potassium in CRF disease. disease patients, the advantageous intestinal bacteria, that produces the important short-chain fatty acids, are damaged leading to increase in the toxic bacteria that generate uremic toxic substances [29]. Additionally, studies showed that the prebi- otic ingredients in food supplements play crucial role in removing uremic toxins from blood via growth and stimulation of beneficial intestinal bacteria [30]. World Health Organization and Food and Drug Administration have approved the prebiotic activity of GA (Obaid, 2020). In the current systematic review and meta-analysis, the study of Bliss et al., 1996 suggested insignificant effect in the serum level of creatinine together with significant reduction in the serum level of urea in the CRF patients examined during the one-month intervention period of 50 g GA. The study attributed the decrease of blood urea in the intervention period to the low-protein diet and high-fiber content of GA that enhanced nitrogen excretion in the stool. Additionally, the fermentation of colon bacteria to the dietary fibers of GA and their increased utilization of the resulting nitrogen with growth had decreased urea during intervention compared to baseline. DOI 10.18502/sjms.v17i4.12547 Page 468 Sudan Journal of Medical Sciences Selma Abdelrahman Hussein et al. On the other hand, the non-significant effect of GA intervention to creatinine level was due to the short period of intervention [31]. Ali and his colleagues, 2008 reported that supplementation of CRF patients with 50 g GA for 3 months intervention had significantly decreased the serum levels of creatinine and urea. The study explained the decrease of intervention creatinine due to the high activity of colonic bacteria that utilized nitrogen from the nitrogenous human wastes. In addition, the decrease of blood urea was referred to the fiber content of GA that enhanced nitrogen excretion in the stool and decreased nitrogen content of blood urea [21]. Elamin et al., 2017 reported the non-significant effect of the dose tested (10 g) for GA on the serum creatinine and urea of all CRF patients in the trial study due to the short period of intervention (1 month), lack of low-protein diet (LPD) taken, and the advanced stage of renal insufficiency/dialysis dependency of patients subjected to the study [17]. The study of Farman et al., 2020 showed significant decline in the serum levels of creatinine and urea due to the long period of intervention dose (30 g of GA/6 months) as well as the prebiotic activity of GA [5]. Although the study of Farman et al., 2020 suggested clear evidence for the efficacy of long-term intervention (6 months) of GA on the high-blood level of creatinine and urea in CRF patients, but the study was removed from the meta-analysis of creatinine because of the heterogeneity caused with the inclusion of the study (I2 = 99%, P value = 0.08). Additionally, studies of Ali et al., 2008 and Farman et al., 2020 were removed to reverse the heterogeneity caused with their inclusion on the meta-analysis of urea (I2 = 97%, P value = 0.05) reaching homogeneity (I2 = 55%, P value = 0.14). The factors affecting the efficacy of GA supplementation on serum creatinine and urea in CRF patients are illustrated in Figure 6. Factors affecting the efficacy of decreasing serum creatinine and urea in CRF patients Period of treatment The stage of CRF patients The prebiotic activity of gum Arabic Longer period is more effective Efficacy in earlier stage of CRF than advanced stage Enhancing the bacteria with LPD Figure 6: Factors affecting the role of GA supplementation on patients with chronic renal failure (CRF). DOI 10.18502/sjms.v17i4.12547 Page 469 Sudan Journal of Medical Sciences Selma Abdelrahman Hussein et al. 3.2. Effect of GA on serum sodium and potassium Researches on the effect of GA supplementation has reported that the addition of GA to the diet decreased the serum level of sodium and potassium in experimentally-induced chronic renal failure [32]. Another study published that treatment experimental animals with GA did not show significant effect on the plasma level of sodium and potassium in Gentamycin-induced renal damage [33]. Alkarib et al., 2016 showed that gradual increase of intervention dose of GA (10 g – 25 g) for 4 months had significantly lowered the serum level of sodium and elevated the level of potassium in the CRF patients subjected to the trial study [34]. Elamin et al., 2017 reported that supplementation of CRF patients with 10 g of GA for one month showed a significant decrease in the blood level of sodium without affecting the blood level of potassium [17]. Farman et al., 2020 exposed that the intake of 30 g of GA on daily basis for 6 months caused significant increase in sodium and decrease in potassium level of blood in CRF patients. The study referred these reversed effects of GA on the blood level of sodium and potassium due to the high-calcium content of GA that stimulated the calcium receptor leading to inhibition of the sodium and potassium co-transport in the thick ascending limb [5, 35]. Accordingly, the meta-analysis study excluded the study of Farman et al., to reduce the heterogeneity caused from I2 = 99% to 48%, P value = 0.16. Regarding the high heterogeneity appeared (100%) in the meta-analysis of potassium with the inclusion of the three studies, the exclusion of the study of Farman et al., 2020, did not reduce the heterogeneity that remained very high (99%) indicating overall non-significant efficacy of gum Arabic intervention on the serum level of potassium in CRF patients. 4. Limitations The present systematic review and meta-analysis showed significant heterogeneity in the analysis performed due to the few clinical studies conducted on the efficacy of GA in chronic renal failure. More clinical case studies are required to be conducted on this topic to resolve the heterogeneity of the study and confirm the results analyzed. Also, complicated scientific terms were avoided in English language writing of the current study to be easy for all readers to understand the analysis performed. DOI 10.18502/sjms.v17i4.12547 Page 470 Sudan Journal of Medical Sciences Selma Abdelrahman Hussein et al. 5. Conclusion The efficacy of GA supplementation on the serum creatinine, urea, sodium, and potas- sium of chronic renal failure (CRF) patients depends on the period of treatment where a longer period of treatment is applied, the more significant reduction was obtained on serum urea and creatinine but not on sodium and potassium. In addition, the CRF stage of the patient plays a role in the efficacy of intervention where the efficacy of GA treatment in early stage is more significant than the advanced stage. Moreover, the intake of LPD shows obvious enhancement to the prebiotic activity of colon bacteria and subsequently significant reduction in the blood level of creatinine and urea. However, based on the studies collected and used in the present systematic review and meta- analysis, it can be confirmed that GA is effective in the early stages of renal failure more than late stages. More clinical trials are required to confirm the factors mentioned. Acknowledgements None. Ethical Considerations None. Competing Interests Authors declare no conflict of interest. Availability of Data and Material Data is available with corresponding author upon request. Funding None. DOI 10.18502/sjms.v17i4.12547 Page 471 Sudan Journal of Medical Sciences Selma Abdelrahman Hussein et al. References [1] Satti, N. M. 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