The efficacy of probiotic preparations on inflammatory cytokines in patients with chronic kidney disease: A protocol for systematic review and meta-analysis.

BACKGROUND: Probiotics supplementation has emerged as adjuvant therapy for chronic kidney disease (CKD) in recent years. However, the effects of probiotic preparations on serum inflammatory cytokine levels are still highly controversial and poorly documented. Therefore, we performed the protocol for systematic review and meta-analysis to further clarify the effects of probiotic preparations in CKD patients. METHODS: This review will develop following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines. We searched literature published until May, 2021 thoroughly in PUBMED, Scopus, EMBASE, Web of Science, and Cochrane Library databases on May, 2021. The risk of bias of included studies was estimated by taking into consideration the characteristics including random sequence generation, allocation concealment, blinding of patients, blinding of outcome assessment, completeness of outcome data, selective reporting, and other bias by Cochrane Collaboration's tool for assessing the risk of bias. Data synthesis and analyses were performed using Stata version 10.0 software. RESULTS: The results of this systematic review and meta-analysis will be published in a peer-reviewed journal. CONCLUSION: We hypothesized that probiotic preparations may decrease the serum levels of inflammatory cytokines and protect the intestinal epithelial barrier of patients with CKD.

Phosphate, Microbiota and CKD.

Phosphate is a key uremic toxin associated with adverse outcomes. As chronic kidney disease (CKD) progresses, the kidney capacity to excrete excess dietary phosphate decreases, triggering compensatory endocrine responses that drive CKD-mineral and bone disorder (CKD-MBD). Eventually, hyperphosphatemia develops, and low phosphate diet and phosphate binders are prescribed. Recent data have identified a potential role of the gut microbiota in mineral bone disorders. Thus, parathyroid hormone (PTH) only caused bone loss in mice whose microbiota was enriched in the Th17 cell-inducing taxa segmented filamentous bacteria. Furthermore, the microbiota was required for PTH to stimulate bone formation and increase bone mass, and this was dependent on bacterial production of the short-chain fatty acid butyrate. We review current knowledge on the relationship between phosphate, microbiota and CKD-MBD. Topics include microbial bioactive compounds of special interest in CKD, the impact of dietary phosphate and phosphate binders on the gut microbiota, the modulation of CKD-MBD by the microbiota and the potential therapeutic use of microbiota to treat CKD-MBD through the clinical translation of concepts from other fields of science such as the optimization of phosphorus utilization and the use of phosphate-accumulating organisms.

Role of Immune Dysregulation in Increased Mortality Among a Specific Subset of COVID-19 Patients and Immune-Enhancement Strategies for Combatting Through Nutritional Supplements.

Background: The COVID-19 pandemic has been causing varying severities of illness. Some are asymptomatic and some develop severe disease leading to mortality across ages. This contrast triggered us explore the causes, with the background that a vaccine for effective immunization or a drug to tackle COVID-19 is not too close to reality. We have discussed strategies to combat COVID-19 through immune enhancement, using simple measures including nutritional supplements. Discussion: A literature search on mortality-related comorbid conditions was performed. For those conditions, we analyzed the pro-inflammatory cytokines, which could cause the draining of the immune reservoir. We also analyzed the immune markers necessary for the defense mechanism/immune surveillance against COVID-19, especially through simple means including immune enhancing nutritional supplement consumption, and we suggest strategies to combat COVID-19. Major comorbid conditions associated with increased mortality include cardiovascular disease (CVD), diabetes, being immunocompromised by cancer, and severe kidney disease with a senile immune system. Consumption of Aureobasidium pullulans strain (AFO-202) beta 1,3-1,6 glucan supported enhanced IL-8, sFAS macrophage activity, and NK cells' cytotoxicity, which are major defense mechanisms against viral infection. Conclusion: People with co-morbid conditions who are more prone to COVID-19-related deaths due to immune dysregulation are likely to benefit from consuming nutritional supplements that enhance the immune system. We recommend clinical studies to validate AFO-202 beta glucan in COVID-19 patients to prove its efficacy in overcoming a hyper-inflammation status, thus reducing the mortality, until a definite vaccine is made available.

Effect of Vitamin D Supplementation on Vascular Function and Inflammation in Patients with Chronic Kidney Disease: A Controversial Issue.

Vitamin D deficiency is common in patients with CKD and is associated with vascular dysfunction and inflammation. In recent years, some randomized controlled trials have revealed the effect of vitamin D supplementation on vascular function and inflammation in CKD patients, but the results are inconsistent. Thus, in light of the controversy, we performed a systematic review and meta-analysis of the effect of vitamin D in patients with CKD. We searched the literature in multiple databases for clinical trials from the date of inception to December 2018. The standardized mean difference (SMD) effect size was pooled using fixed and random effects models. A total of 10 randomized controlled trials involving 579 patients were included in the meta-analysis; among these, 313 patients were treated with vitamin D, and the control group included 266 who received a placebo. This meta-analysis revealed no statistical significance in the levels of flow-mediated dilatation (SMD, 0.94; 95% CI, -0.33 to 2.21; P = 0.15); pulse wave velocity (SMD, -0.13; 95% CI, -0.38 to 0.13; P = 0.33); systolic BP (SMD, -0.04; 95% CI, -0.29 to 0.22; P = 0.77); diastolic BP (SMD, 0.01; 95% CI, -0.26 to 0.27; P = 0.97); and CRP (SMD, -0.09; 95% CI, -0.44 to 0.26; P = 0.61) between the vitamin D group and controls for patients with CKD. Short-term intervention with vitamin D was not associated with improvements in vascular function and inflammation, as measured by flow-mediated dilatation, pulse wave velocity, systolic BP, diastolic BP and CRP. This suggested that there is insufficient evidence to conclude the benefit of vitamin D supplementation on vascular function and inflammation in CKD patients.

Effect of L-carnitine and conjugated linoleic acid supplements on haemoglobin levels and haptoglobin genotype in chronic kidney disease.

OBJECTIVE: To investigate the efficacy of L-carnitine (LC) and conjugated linoleic acid (CLA) supplements on haemoglobin levels and inflammatory markers in chronic kidney disease (CKD) patients with different haptoglobin (HP) genotypes. METHODS: This clinical trial study was conducted at Imam Khomeini Hospital, Ardabil, and Labbafinejad Hospital, Tehran, Iran, from March 2014 to March 2015, and comprised male patients with CKD and anaemia. Anthropometric factors were recorded and demographic data was collected using general questionnaires. LC (1 g/day) and CLA (2.4 g/day) supplements were given to the patients for a month. Blood samples were taken to measure haematological and inflammatory markers at the beginning and end of the study. Haptoglobin genotypes were determined using polymerase chain reaction (PCR). SPSS 21 was used for data analysis. RESULTS: Among the 40 patients in the study, HP2-2 genotype was the most prevalent genotype (62.5%). The level of haemoglobin was significantly increased in the patients at the end of the study (p< 0.05). No significant changes were found in the weight, body mass index and serum levels of Interleukin-6, high-sensitivity C-reactive protein, ferritin, total iron-binding capacity and iron (p>0.05 each). CONCLUSIONS: Regular diet supplementation with LC plus CLA can improve haemoglobin levels in CKD patients with anaemia.

Effect of a low-protein diet supplemented with keto-acids on autophagy and inflammation in 5/6 nephrectomized rats.

Ketoacids (KA) are known to preserve muscle mass among patients with chronic kidney disease (CKD) on a low-protein diet (LPD). The present study was to compare the effects of KA supplemented diet therapy in autophagy and inflammation in CKD rats' skeletal muscle. Rats with 5/6 nephrectomy were randomly divided into three groups and fed with either 11 g/kg/day protein [normal-protein diet (NPD)], 3 g/kg/day protein (LPD) or 3 g/kg/day protein which including 5% protein plus 1% KA (LPD + KA) for 24 weeks. Sham-operated rats with NPD intake were used as control. LPD could improve body weight, gastrocnemius muscle mass, as well as gastrocnemius muscle cross-sectional area, with the effect being more obvious in the LPD + KA group. The autophagy marker LC3 (microtubule-associated protein 1 light chain 3), p62, Parkin and PTEN induced putative kinase 1 (PINK1) were significantly attenuate in LPD + KA group than LPD group. LPD + KA group had the lower total mtDNA (mitochondiral DNA) and cytosol mtDNA, NACHT-PYD-containing protein 3 (NALP3) inflammasome than LPD group, but its reactive oxygen species (ROS), caspase-1 and apoptosis-associated speck-like protein containing a CARD (ASC) level was higher. Immunoblotting showed IL-1ß (interleukin-1-beta) was lower in LPD and LPD + KA group than the NPD group, but IL-18 showed no significant difference among control and CKD group; toll-like receptor signalling-dependent IL-6 was higher in LPD + KA group than LPD group, but tumor necrosis factor-α (TNF-α) was not significantly changed between LPD + KA and LPD group. Systematic changes of the four cytokines were different from that of the tissue. Although LPD + KA could further ameliorate-activated autophagy than LPD, its effect on the activated inflammation state in CKD was not distinctly. Further study is still required to explore the method of ameliorating inflammation to provide new therapeutic approaches for CKD protein energy wasting (PEW).

Vitamin D and immune function in chronic kidney disease.

The common causes of death in chronic kidney disease (CKD) patients are cardiovascular events and infectious disease. These patients are also predisposed to the development of vitamin D deficiency, which leads to an increased risk of immune dysfunction. Many extra-renal cells possess the capability to produce local active 1,25(OH)2D in an intracrine or paracrine fashion, even without kidney function. Vitamin D affects both the innate and adaptive immune systems. In innate immunity, vitamin D promotes production of cathelicidin and ß-defensin 2 and enhances the capacity for autophagy via toll-like receptor activation as well as affects complement concentrations. In adaptive immunity, vitamin D suppresses the maturation of dendritic cells and weakens antigen presentation. Vitamin D also increases T helper (Th) 2 cytokine production and the efficiency of Treg lymphocytes but suppresses the secretion of Th1 and Th17 cytokines. In addition, vitamin D can decrease autoimmune disease activity. Vitamin D has been shown to play an important role in maintaining normal immune function and crosstalk between the innate and adaptive immune systems. Vitamin D deficiency may also contribute to deterioration of immune function and infectious disorders in CKD patients. However, it needs more evidence to support the requirements for vitamin D supplementation.

Tanshinone IIA attenuates renal fibrosis and inflammation via altering expression of TGF-ß/Smad and NF-κB signaling pathway in 5/6 nephrectomized rats.

PURPOSE: In traditional Chinese medicine, Tanshinone IIA is used to treat chronic kidney disease (CKD). However, its biological activity and mechanism of action in renal fibrosis and inflammation are not fully identified. The current study was conducted to determine the effects of Tanshinone IIA treatment on CKD by assessing potential modulation of the TGF-ß/Smad and NF-κB signaling pathway. METHODS: CKD was produced in rats by 5/6 nephrectomy. They were then divided into the following groups: control (sham operation); CKD (5/6 nephrectomy); 5/6 nephrectomy+Tanshinone IIA (10mg/kg in average, once a day for 16 weeks). Serum and urine samples were obtained from animals in each group, and serum creatinine (Scr), blood urea nitrogen (BUN) levels and 24h urinary protein excretion were measured. Tissue samples from the kidney were used for morphometric studies (Masson's trichrome). The expression of fibronectin protein and collagen types I, III, IV, and TGF-ß, TNF-α, CXCL-1, MCP-1, RANTES mRNA were evaluated using immunohistochemistry and RT-PCR analysis; the TGF-ß/Smad and NF-κB signaling pathway was detected by immunohistochemistry and Western blot analysis. RESULTS: The following effects were observed in CKD rats treated with Tanshinone IIA: (1) marked improvements in Scr, and 24h urine protein excretion; (2) significant reductions in protein and mRNA levels of fibronectin, collagen III, and collagen IV and TNF-α, MCP-1, and CXCL-1; (3) significantly inhibited the TGF-ß/Smad and NF-κB signaling activation. CONCLUSIONS: These results suggest that Tanshinone IIA suppresses renal fibrosis and inflammation via altering expression of TGF-ß/Smad and NF-κB pathway in the remnant kidney, thus supporting the potential of Tanshinone IIA as a new therapeutic agent for slowing the progression of CKD.

Clinical efficacy, safety and anti-inflammatory activity of two sevelamer tablet forms in patients on low-flux hemodialysis.

Sevelamer hydrochloride is an ionic exchange resin with high affinity for phosphate. This phosphate-binding agent has few serious adverse reactions with the advantage of reducing total and low density lipoprotein (LDL) cholesterol levels. However, it is controversial as to whether sevelamer hydrochloride can modulate the inflammatory response via endotoxin reduction. Therefore, a single-center, open-label, prospective and randomized study was performed to compare the clinical efficacy, safety and anti-inflammatory activity of two sevelamer hydrochloride tablet forms a branded tablet form, Renagel (Genzyme manufacturer) and its generic equivalent (EMS manufacturer). Twenty-eight chronic kidney disease volunteer patients at stage 5 (CDK 5D), on chronic low-flux hemodialysis carried out in 4-hour sessions, three times a week, were studied. The serum phosphorus, ionic calcium, total cholesterol and fractions, bicarbonate, blood pH, interleukin (IL)-6, IL-10, IL-1 beta and tumor necrosis factor-alpha (TNF-alpha) levels were collected prior to dialysis at mid-week. The incidence of gastrointestinal adverse effects were determined at the end of the phosphate-binder washout period as well as at the end of the fourth and eighth weeks of use of both tablet forms. The same magnitude of reduction in serum phosphorus was observed with both sevelamer tablet forms. Only the Renagel group showed lower total cholesterol and lower LDL cholesterol levels at the fourth and eighth week versus baseline. No significant differences in serum cytokine levels were identified in either drug group. However, the incidence of intestinal obstipation was higher among patients who used the generic equivalent form. In conclusion, Renagel and its EMS generic equivalent tablet forms have a similar clinical efficacy in reducing phosphorus in CKD 5D patients on low-flux hemodialysis and a similar safety profile.

Effects of Yishenjiangzhuo granules on immunity and bone metabolism in patients with stage 3-4 chronic kidney disease.

OBJECTIVE: To determine the effects of Yishenjiangzhuo granules (YJG) on bone metabolism and to explore the changes in levels of bone Gla protein (BGP), tartrate-resistant acid phosphatase (TRAP), as well as their relationships with levels of B cells, regulatory T cells (Treg) and interleukin (IL)-17 in patients with stage 3-4 chronic kidney disease (CKD) before and after treatment. METHODS: Fifty-three stage 3-4 CKD patients were divided randomly into two groups: YJG treatment and control. Peripheral blood was taken from two groups of CKD patients and 21 healthy subjects in the normal group. The parameters determined were the levels of CD4+, CD19+, CD19+ CD69+, CD19+ av, Treg (CD4 + CD25 + CD127lo), BGP, TRAP, IL-17, calcium, phosphate, blood urea nitrogen, serum creatinine (SCr), hemoglobin (Hb) in peripheral blood, and urinary creatinine. Calcium-phosphate products and endogenous creatinine clearance rate (CCr) were calculated according to standard protocols. RESULTS: In YJG and control groups, SCr levels were lowered (P < 0.01) after treatment, whereas CCr (P < 0.05) as well as Hb and albumin levels (P < 0.01) were increased. The changes in levels of CCr and SCr in the YJG group were more significant. After treatment, CD19+CD69+ and Treg levels in the two groups varied (P < 0.01) compared with those of the normal group; the level of CD19+ increased but the levels of CD4+ and CD19 + AV decreased (P < 0.01) in both groups. Compared with the control group, the changes of CD19+ and CD19 + AV in the YJG group were more apparent (P < 0.05). Compared with the normal group, levels of IL-17 in both groups increased significantly (P < 0.01), and the difference in the control group was more significant (P < 0.05). After treatment, the TRAP level increased (P < 0.05), but the difference in BGP level (P > 0.05) was not significant. CONCLUSION: In stage 3-4 CKD patients, B cells and IL-17 participated in the induction of osteoclast activation. YJG could also elevate the level of B cells and decrease their apoptosis, but showed no significant effects on active B cells, IL-17 or osteoclast activity.

Pirfenidone inhibits macrophage infiltration in 5/6 nephrectomized rats.

Tubulointerstitial macrophage infiltration is a hallmark of chronic kidney disease involved in the progression of renal fibrosis. Pirfenidone is a newly identified antifibrotic drug, the potential mechanism of which remains unclear. The aim of this study was to investigate the effects of pirfenidone on M1/M2 macrophage infiltration in nephrectomized rats. Nephrectomized rats were treated with pirfenidone by gavage for 12 wk. Twenty-four hour urinary protein, N-acetyl-ß-D-glycosaminidase (NAG) activity, systolic blood pressure, and C-reactive protein were determined. Paraffin-embedded sections were stained for CD68, CCR7, and CD163 macrophages. Monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α), as well as M1 and M2 macrophages secretory markers, were evaluated by real-time RT-PCR and Western blotting analysis. Pirfenidone significantly improved the elevated proteinuria and NAG activity from week 2 onward after surgery. Pirfenidone attenuated interstitial fibrosis and decreased expression of fibrotic markers including transforming growth factor-ß(1), connective tissue growth factor, α-smooth muscle actin, fibronectin, and fibroblast-specific protein-1. Pirfenidone significantly decreased the infiltrating macrophages. The number of M1 and M2 macrophages was significantly lower after pirfenidone treatment. MCP-1 and MIP-1α were increased in nephrectomized rats at mRNA and protein levels. Pirfenidone treatment significantly inhibited their expression. The TNF-α, IL-6, and nitric oxide synthases-2 expressed by M1 macrophages were increased in nephrectomized rats, and pirfenidone significantly attenuated their expression. Pirfenidone treatment also significantly decreased arginase-1, dectin-1, CD206, and CD86 expressed by M2 macrophages. Thus pirfenidone inhibits M1 and M2 macrophage infiltration in 5/6 nephrectomized rats, which suggests its efficacy in the early and late periods of renal fibrosis.

[Effects of Yishen Jiangzhuo Granule on the bone metabolism of patients with stage 3-4 chronic kidney disease and its correlation with the immune indices].

UNLABELLED: OBJECTIVE To explore the changes of bone gla protein (BGP) and tartrate resistant acid phosphatase (TRACP) in patients with stage 3 -4 chronic kidney disease (CKD) before and after treatment, to study their correlation with interleukin-17 (IL-17) and regulatory T cells (Treg), and the effects of Yishen Jiangzhuo Granule (YJG) on the bone metabolism. METHODS: Fifty-three patients with stage 3-4 CKD were randomly assigned to the treatment group and the control group using random digit table. The following parameters in blood were detected: Treg (CD4+ CD25+ CD127lo) using tri-chrism fluorescent labeling by flow cytometry; levels of TRACP, BGP, and IL-17 by double antibody sandwich ELISA. The hemoglobin (HGB) content was detected using Beckman-Coulter heme/analysis. The urinary contents of creatinine (UCr) were determined using reversed HPLC. The blood contents of calcium (Ca), phosphate (P), blood urea nitrogen (BUN), serum creatinine (SCr), and plasma albumin (ALB) were determined using automatic biochemical analyzer. Then the calcium-phosphate (Ca x P) product was calculated on the basis of blood contents of Ca and P. The clearance rate of endogenous creatinine (CCr) was calculated on the basis of blood BUN and SCr contents. RESULTS: (1) There was no obvious change in CD4+ CD25+ CD127lo in the two groups before and after treatment (P > 0.05). Compared with before treatment in the same group, there were statistical difference in the levels of CD4+ and TRACP in the two groups, as well as the IL-17 level in the control group (P < 0.01, P < 0.05). But compared with the healthy group, statistical difference was shown in each index (except CD4+) (P < 0.01). Compared with the control group after treatment, there was no statistical difference in each index of the treatment group after treatment (P > 0.05). Compared with before treatment in the same group, the levels of Hb, ALB, and CCr increased (P < 0.05, P < 0.01), and the SCr level decreased in the two groups after treatment (P < 0.05). Compared with the control group after treatment, the SCr level decreased and the CCr level increased more obviously in the treatment group (P < 0.05). There was no correlation among the levels of IL-17, TRACP, BGP, and Treg between before and after treatment in the two groups. CONCLUSIONS: YJG could improve the kidney function and delay the progression of micro-inflammation of stage 3 -4 CKD patients. It could not improve the level of CD4+ CD25+ CD127lo. It also showed no effects on bone metabolism. The CD4+ T cells were differentiated to Th17 cells in stage 3-4 CKD patients. Their immunity was in a state of anergy but continually activated. The inflammatory factors in patients with stage 3-4 CKD play important roles in inducing the activation of osteoclasts.

The effect of n-3 polyunsaturated fatty acids on leukotriene B4 and leukotriene B5 production from stimulated neutrophil granulocytes in patients with chronic kidney disease.

The proinflammatory leukotriene B4 (LTB4) may be of importance in the progression of chronic kidney disease (CKD). We investigated whether n-3 polyunsaturated fatty acids (PUFA) decrease LTB4 and increase the formation of the less inflammatory leukotriene B5 (LTB5) in patients with CKD. Fifty-six patients with CKD stage 2-5 were randomised to 2.4 g n-3 PUFA or olive oil for 8 weeks. Compared to controls, n-3 PUFA significantly decreased release of LTB4 (p<0.001) and 5-hydroxyeicosatetraenoic acid (5-HETE) (p<0.01) and significantly increased release of LTB5 (p<0.001) and 5-hydroxyeicosapentaenoic acid (5-HEPE) (p<0.001) from stimulated neutrophil granulocytes. Kidney function evaluated by creatinine clearance and proteinuria did not improve. In conclusion, n-3 PUFA supplementation for 8 weeks in patients with CKD stage 2-5 significantly decreased LTB4 and 5-HETE and significantly increased LTB5 and 5-HEPE. No effect was seen on kidney function.