Huang Gan Formula Alleviates Systemic Inflammation and Uremia in Adenine-Induced Chronic Kidney Disease Rats May Associate with Modification of Gut Microbiota and Colonic Microenvironment.

Purpose: This study aims to investigate the effects of Huang Gan formula (HGF), a Chinese herbal prescription used for chronic kidney disease (CKD), on the regulation of the gut microbiota and colonic microenvironment of CKD. Methods: CKD rats were induced by 150 mg/kg adenine gavage for 4 weeks, then orally treated with or without 3.6 g/kg or 7.2 g/kg of HGF for 8 weeks. The renal function and structure were analyzed by biochemical detection, hematoxylin and eosin, Masson's trichrome, Sirius red and immunochemical staining. Average fecal weight and number in the colon were recorded to assess colonic motility. Further, the changes in the gut microbiota and colonic microenvironment were evaluated by 16S rRNA sequencing, RT-PCR or immunofluorescence. The levels of inflammatory cytokines, uremic toxins, and NF-κB signaling pathway were detected by RT-PCR, ELISA, chloramine-T method or Western blotting. Redundancy analysis biplot and Spearman's rank correlation coefficient were used for correlation analysis. Results: HGF significantly improved renal function and pathological injuries of CKD. HGF could improve gut microbial dysbiosis, protect colonic barrier and promote motility of colonic lumens. Further, HGF inhibited systemic inflammation through a reduction of TNF-α, IL-6, IL-1ß, TGF-ß1, and a suppression of NF-κB signaling pathway. The serum levels of the selected uremic toxins were also reduced by HGF treatment. Spearman correlation analysis suggested that high-dose HGF inhibited the overgrowth of bacteria that were positively correlated with inflammatory factors (eg, TNF-α) and uremic toxins (eg, indoxyl sulfate), whereas it promoted the proliferation of bacteria belonging to beneficial microbial groups and was positively correlated with the level of IL-10. Conclusion: Our results suggest that HGF can improve adenine-induced CKD via suppressing systemic inflammation and uremia, which may associate with the regulations of the gut microbiota and colonic microenvironment.

Can curcumin supplementation break the vicious cycle of inflammation, oxidative stress, and uremia in patients undergoing peritoneal dialysis?

BACKGROUND & AIMS: Turmeric (a source of curcumin) is an excellent food to modulate oxidative stress, inflammation, and gut dysbiosis in patients with chronic kidney disease (CKD). However, no studies report the benefits of curcumin in patients undergoing peritoneal dialysis (PD). This study aims to evaluate the effects of curcuminoid supplementation on oxidative stress, inflammatory markers, and uremic toxins originating from gut microbiota in patients with CKD undergoing PD. METHODS: This longitudinal, randomized, single-blind, placebo-controlled trial evaluated 48 patients who were randomized into two groups: Curcumin (three capsules of 500 mg of Curcuma longa extract, with 98.42 % total curcuminoids) or placebo (three capsules of 500 mg of starch) for twelve weeks. In the peripheral blood mononuclear cells (PBMCs), the transcriptional expression levels of Nrf2, HOX-1 and NF-κB were evaluated by quantitative real-time PCR. Oxidative stress was evaluated by malondialdehyde (MDA) and total Thiol (T-SH). TNF-α and IL-6 plasma levels were measured by ELISA. P-cresyl sulphate plasma level, a uremic toxin, was evaluated by high-performance liquid chromatography (HPLC) with fluorescent detection. RESULTS: Twenty-four patients finished the study: 10 in the curcumin group (57.5 ± 11.6 years) and 14 in the placebo group (56.5 ± 10.0 years). The plasma levels of MDA were reduced after 12 weeks in the curcumin group (p = 0.01), while the placebo group remained unchanged. However, regarding the difference between the groups at the endpoint, no change was observed in MDA. Still, there was a trend to reduce the p-CS plasma levels in the curcumin group compared to the placebo group (p = 0.07). Likewise, the concentrations of protein thiols, mRNA expression of Nrf2, HOX-1, NF-κB, and cytokines plasma levels did not show significant changes. CONCLUSION: Curcuminoid supplementation for twelve weeks attenuates lipid peroxidation and might reduce uremic toxin in patients with CKD undergoing PD. This study was registered on Clinicaltrials.gov as NCT04413266.

Protective effect of activated charcoal against progression of chronic kidney disease: A randomized clinical study.

Chronic kidney disease (CKD) is a non-reversible and progressive disease affecting the kidneys, significantly impacting global public health. One of the complications of chronic kidney disease is impaired intestinal barrier function, which may allow harmful products such as urea to enter the bloodstream and cause systemic inflammation. This study aimed to investigate whether supplementation with activated charcoal could reduce uremic toxins in patients with end-stage renal disease (ESRD). The study was a randomized clinical trial conducted at the Dialysis Center of al Diwaniyah Medical Hospital in the Diwaniyah Governorate. Eighty-two patients with ESRD on regular hemodialysis were enrolled, with 15 patients receiving oral supplementation with activated charcoal in addition to standard care and 13 patients receiving only standard care. Blood samples were collected at baseline and after eight weeks, and several biomarkers were measured, including estimated glomerular filtration rate (eGFR), creatinine, urea, phosphorus, albumin, and indoxyl sulfate. The results showed a significant reduction in both serum urea and serum phosphorus levels after eight weeks of oral-activated charcoal treatment. However, the other biomarkers were not affected by the treatment. In conclusion, the use of oral-activated charcoal for eight weeks in Iraqi patients undergoing maintenance hemodialysis improved urea and phosphorus levels.

ω-3 Polyunsaturated Fatty Acids Improve the Blood-Brain-Barrier Integrity in Contrast-Induced Blood-Brain-Barrier Injury in Uremic Mice.

In patients with chronic kidney disease, the need for examinations using contrast media (CM) increases because of underlying diseases. Although contrast agents can affect brain cells, the blood-brain barrier (BBB) protects against brain-cell damage in vivo. However, uremia can disrupt the BBB, increasing the possibility of contrast-agent-induced brain-cell damage in patients with chronic kidney disease (CKD). ω-3 polyunsaturated fatty acids (PUFAs) have shown protective effects on various neurological disorders, including uremic brain injury. This study examined whether ω-3 PUFAs attenuate damage to the BBB caused by uremia and contrast agents in a uremic mouse model and evaluated its associated mechanisms. C57BL/6 mice (eight weeks old, male) and fat-1 mice (b6 background/eight weeks old, male) were divided into groups according to uremic induction, CM, and ω-3 PUFA administration. Uremia was induced via 24 h ischemia-reperfusion (IR) renal injury. One day after CM treatment, the brain tissue, kidney tissue, and blood were collected. The expression levels of glial fibrillary acidic protein (GFAP), claudin 5, CD31, laminin α4, and laminin α5 increased in ω-3 PUFA + CM-treated uremic mice and the brain of fat-1 + CM-treated uremic mice compared with those in the brains of CM-treated uremic mice. The pro-apoptotic protein expression decreased, whereas the anti-apoptotic proteins increased in ω-3 PUFA + CM-treated uremic mice and fat-1 + CM-treated uremic mice compared with CM-treated uremic mice. In addition, the brain-expression levels of p-JNK, p-P53, and p-P38 decreased in the ω-3 PUFA + CM-treated uremic mice and fat-1 + CM-treated uremic mice compared with those in wild-type uremic mice. Our results confirm that uremic toxin and CM damage the BBB and cause brain-cell death. ω-3 PUFAs play a role in BBB protection caused by CM in uremic mice.

Role of nutritional vitamin D in chronic kidney disease-mineral and bone disorder: A narrative review.

Chronic kidney disease-mineral and bone disorder has complex and diverse clinical manifestations, including the simplest abnormalities of calcium, phosphorus and parathyroid hormone detected in blood, abnormalities of bone transformation and mineralization in bone, and calcification of blood vessels or other soft tissues detected on imaging. Patients with CKD-MBD combined low bone mineral density and fragility fractures are referred to as CKD-MBD with low bone mineral density. Vascular calcification refers to ectopic deposition of calcium phosphate in the blood vessel walls and heart valves. The degree of vascular calcification was inversely proportional to bone mineral density. The more severe the degree of vascular calcification, the lower the bone mineral density, and the higher the risk of death, indicating that the bone-vascular axis exists. Activation and alteration of the Wnt signaling pathway are central to the treatment of vascular diseases in uremia. Vitamin D supplementation can prevent secondary hyperparathyroidism, activate osteoblasts, relieve muscle weakness and myalgia, and reduce vascular calcification. Nutritional vitamin D may improve vascular calcification in uremia patients by regulating Wnt signaling pathway.

Magnesium Improves Cardiac Function in Experimental Uremia by Altering Cardiac Elastin Protein Content.

Cardiovascular complications are accompanied by life-threatening complications and represent the major cause of death in patients with chronic kidney disease (CKD). Magnesium is important for the physiology of cardiac function, and its deficiency is common in CKD. In the present study, we investigated the impact of oral magnesium carbonate supplementation on cardiac function in an experimental model of CKD induced in Wistar rats by an adenine diet. Echocardiographic analyses revealed restoration of impaired left ventricular cardiac function in animals with CKD. Cardiac histology and real-time PCR confirmed a high amount of elastin protein and increased collagen III expression in CKD rats supplemented with dietary magnesium as compared with CKD controls. Both structural proteins are crucial in maintaining cardiac health and physiology. Aortic calcium content increased in CKD as compared with tissue from control animals. Magnesium supplementation numerically lowered the increases in aortic calcium content as it remained statistically unchanged, compared with controls. In summary, the present study provides evidence for an improvement in cardiovascular function and aortic wall integrity in a rat model of CKD by magnesium, as evidenced by echocardiography and histology.

Prevalence and determinants of severity of uremic pruritus in hemodialysis patients: a multicentric study.

Uremic pruritus (UP) is a common and distressing symptom in patients with advanced or end-stage renal disease under hemodialysis (HD). The present multicentric study aimed to identify prevalence and determinants of severity of UP among Egyptian patients. Performed investigations included serum urea, creatinine, calcium, phosphorus, parathormone, ferritin and liver enzymes. Pruritus was evaluated using the visual analog scale. The study included 295 patients on maintenance HD. They comprised 151 patients (51.2%) with UP. Independent predictors of UP included associated hypertension (OR: 0.48, 95% CI 0.28 to 0.83, p=0.008), higher calcium levels (OR: 1.29, 95% CI 1.02 to 1.62, p=0.032), higher phosphorus levels (OR: 1.18, 95% CI 1.02 to 1.37, p=0.03) and higher high-sensitivity C-reactive protein (hsCRP) levels (OR: 1.0, 95% CI 1.0 to 1.01, p=0.049). Independent predictors of significant UP included longer HD duration (OR: 1.23, 95% CI 1.1 to 1.38, p<0.001), lack of vitamin D supplementation (OR: 3.71, 95% CI 1.03 to 13.4, p=0.045), lower albumin levels (OR: 0.32, 95% CI 0.14 to 0.74, p=0.008) and higher hsCRP levels (OR (CRP): 1.02 (1.0-1.03), p=0.011). In conclusion, UP is fairly common among Egyptian HD patients. Independent predictors of UP severity include longer HD duration, lack of vitamin D supplementation, lower albumin levels and higher hsCRP levels.

Uremic toxins in chronic kidney disease highlight a fundamental gap in understanding their detrimental effects on cardiac electrophysiology and arrhythmogenesis.

Chronic kidney disease (CKD) and cardiovascular disease (CVD) have an estimated 700-800 and 523 million cases worldwide, respectively, with CVD being the leading cause of death in CKD patients. The pathophysiological interplay between the heart and kidneys is defined as the cardiorenal syndrome (CRS), in which worsening of kidney function is represented by increased plasma concentrations of uremic toxins (UTs), culminating in dialysis patients. As there is a high incidence of CVD in CKD patients, accompanied by arrhythmias and sudden cardiac death, knowledge on electrophysiological remodeling would be instrumental for understanding the CRS. While the interplay between both organs is clearly of importance in CRS, the involvement of UTs in pro-arrhythmic remodeling is only poorly investigated, especially regarding the mechanistic background. Currently, the clinical approach against potential arrhythmic events is mainly restricted to symptom treatment, stressing the need for fundamental research on UT in relation to electrophysiology. This review addresses the existing knowledge of UTs and cardiac electrophysiology, and the experimental research gap between fundamental research and clinical research of the CRS. Clinically, mainly absorbents like ibuprofen and AST-120 are studied, which show limited safe and efficient usability. Experimental research shows disturbances in cardiac electrical activation and conduction after inducing CKD or exposure to UTs, but are scarcely present or focus solely on already well-investigated UTs. Based on UTs data derived from CKD patient cohort studies, a clinically relevant overview of physiological and pathological UTs concentrations is created. Using this, future experimental research is stimulated to involve electrophysiologically translatable animals, such as rabbits, or in vitro engineered heart tissues.

Zhen-Wu decoction and lactiflorin, an ingredient predicted by in silico modelling, alleviate uremia induced cardiac endothelial injury via Nrf2 activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Cardiorenal syndrome type 4 (CRS type 4), with high rates of morbidity and mortality, has become a social and economic problem worldwide over the last few decades. Zhen-Wu decoction, a traditional medicine used in East Asia, has been widely used in the treatment of cardiovascular disease and kidney disease, and has shown potential therapeutic effects for the clinical treatment of CRS type 4. However, the underlying mechanism has not been extensively explored. AIM OF THE STUDY: The purpose of this study was to investigate the effect and underlying mechanism of Zhen-Wu decoction on uremic cardiomyopathy, offering a potential target for clinical treatment of CRS type 4. MATERIALS AND METHODS: Five/six nephrectomized mice were utilized for experiments in vivo. The cardioprotective effects of Zhen-Wu decoction were evaluated by echocardiography and tissue staining. RNA-Seq data were used to investigate the potential pharmacological mechanism. The prediction of targets and active components was based on our previous strategy. Subsequently, the protective effect of the selected compound was verified in experiments in vitro. RESULTS: Zhen-Wu decoction alleviated cardiac dysfunction and endothelial injury in 5/6 nephrectomized mice, and the mechanism may involve the inflammatory process and oxidative stress. The activation of the Nrf2 signaling pathway was predicted to be a potential target of Zhen-Wu decoction in protecting endothelial cells. Through our machine learning strategy, we found that lactiflorin as an ingredient in Zhen-Wu decoction, alleviates IS-induced endothelial cell injury by blocking Keap1 and activating Nrf2. CONCLUSIONS: The present study demonstrated that Zhen-Wu decoction and lactiflorin could protect endothelial cells against oxidative stress in mice after nephrectomy by activating the Nrf2 signaling pathway.

Carbamylation of Integrin α IIb ß 3: The Mechanistic Link to Platelet Dysfunction in ESKD.

BACKGROUND: Bleeding diatheses, common among patients with ESKD, can lead to serious complications, particularly during invasive procedures. Chronic urea overload significantly increases cyanate concentrations in patients with ESKD, leading to carbamylation, an irreversible modification of proteins and peptides. METHODS: To investigate carbamylation as a potential mechanistic link between uremia and platelet dysfunction in ESKD, we used liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to quantify total homocitrulline, and biotin-conjugated phenylglyoxal labeling and Western blot to detect carbamylated integrin α IIb ß 3 (a receptor required for platelet aggregation). Flow cytometry was used to study activation of isolated platelets and platelet-rich plasma. In a transient transfection system, we tested activity and fibrinogen binding of different mutated forms of the receptor. We assessed platelet adhesion and aggregation in microplate assays. RESULTS: Carbamylation inhibited platelet activation, adhesion, and aggregation. Patients on hemodialysis exhibited significantly reduced activation of α IIb ß 3 compared with healthy controls. We found significant carbamylation of both subunits of α IIb ß 3 on platelets from patients receiving hemodialysis versus only minor modification in controls. In the transient transfection system, modification of lysine 185 in the ß 3 subunit was associated with loss of receptor activity and fibrinogen binding. Supplementation of free amino acids, which was shown to protect plasma proteins from carbamylation-induced damage in patients on hemodialysis, prevented loss of α IIb ß 3 activity in vitro. CONCLUSIONS: Carbamylation of α IIb ß 3-specifically modification of the K185 residue-might represent a mechanistic link between uremia and dysfunctional primary hemostasis in patients on hemodialysis. The observation that free amino acids prevented the carbamylation-induced loss of α IIb ß 3 activity suggests amino acid administration during dialysis may help to normalize platelet function.

The Dual Roles of Protein-Bound Solutes as Toxins and Signaling Molecules in Uremia.

In patients with severe kidney disease, renal clearance is compromised, resulting in the accumulation of a plethora of endogenous waste molecules that cannot be removed by current dialysis techniques, the most often applied treatment. These uremic retention solutes, also named uremic toxins, are a heterogeneous group of organic compounds of which many are too large to be filtered and/or are protein-bound. Their renal excretion depends largely on renal tubular secretion, by which the binding is shifted towards the free fraction that can be eliminated. To facilitate this process, kidney proximal tubule cells are equipped with a range of transport proteins that cooperate in cellular uptake and urinary excretion. In recent years, innovations in dialysis techniques to advance uremic toxin removal, as well as treatments with drugs and/or dietary supplements that limit uremic toxin production, have provided some clinical improvements or are still in progress. This review gives an overview of these developments. Furthermore, the role protein-bound uremic toxins play in inter-organ communication, in particular between the gut (the side where toxins are produced) and the kidney (the side of their removal), is discussed.

Omega-3 fatty acid and menaquinone-7 combination are helpful for aortic calcification prevention, reducing osteoclast area of bone and Fox0 expression of muscle in uremic rats.

BACKGROUND: Osteopenia, sarcopenia, and vascular calcification (VC) are prevalent in patients with chronic kidney disease and often coexist. In the absence of proven therapies, it is necessary to develop therapeutic or preventive nutrients supplementation for osteopenia, sarcopenia, and VC. The present study investigated the effect of omega-3 fatty acid (FA) and menaquinone-7 (MK-7) on osteopenia, sarcopenia, and VC in adenine and low-protein diet-induced uremic rats. METHODS: Thirty-two male Sprague-Dawley rats were fed diets containing 0.75% adenine and 2.5% protein for three weeks. Rats were randomly divided into four groups that were fed diets containing 2.5% protein for four weeks: adenine control (0.9% saline), omega-3 FA (300 mg/kg/day), MK-7 (50 µg/kg/day), and omega-3 FA/MK-7. Von Kossa staining for aortic calcification assessment was performed. Osteoclast surface/bone surface ratio (OcS/BS) of bone and muscle fiber were analyzed using hematoxylin and eosin staining. Osteoprotegerin (OPG) immunohistochemical staining was done in the aorta and bone. Molecules related with sarcopenia were analyzed using western blotting. RESULTS: Compared to the normal control, OcS/BS and aortic calcification, and OPG staining in the aorta and bone were significantly increased in the adenine controls. OPG staining and aortic calcification progressed the least in the group supplemented with both omega-3 FA/MK-7. In the adenine controls, the regular arrangement of muscle fiber was severely disrupted, and inflammatory cell infiltration was more prominent. These findings were reduced after combined supplementation with omega-3 FA/MK-7. Furthermore, decreased mammalian target of rapamycin and increased Forkhead box protein 1 expression was significantly restored by combined supplementation. CONCLUSIONS: Combined nutrients supplementation with omega-3 FA and MK-7 may be helpful for aortic VC prevention, reducing osteoclast activation and improving sarcopenia-related molecules in adenine and low-protein diet induced uremic rats.

Novel intestinal dialysis interventions and microbiome modulation to control uremia.

PURPOSE OF REVIEW: In patients with chronic kidney disease (CKD), the gut plays a key role in the homeostasis of fluid and electrolyte balance and the production and disposal of uremic toxins. This review summarizes the current evidence on the gut-targeted interventions to control uremia, fluid overload, hyperkalemia and hyperphosphatemia in CKD. RECENT FINDINGS: Studies have emerged that support the concept of intestinal dialysis, such as colonic perfusion with a Malone antegrade continence enema stoma or colonic irrigation with a rectal catheter, as a promising adjuvant approach to control uremia in CKD, although most findings are preliminary. The use of AST-120, an oral adsorbent, has been shown to reduce circulating levels of indoxyl sulfate and p-cresol sulfate and have potential renoprotective benefits in patients with advanced CKD. Diarrhea or inducing watery stools may modulate fluid retention and potassium and phosphorus load. Accumulating evidence indicates that plant-based diets, low-protein diets, and pre-, pro-, and synbiotic supplementation may lead to favorable alterations of the gut microbiota, contributing to reduce uremic toxin generation. The effects of these gut-targeted interventions on kidney and cardiovascular outcomes are still limited and need to be tested in future studies including clinical trials. SUMMARY: Interventions aimed at enhancing bowel elimination of uremic toxins, fluid and electrolytes and at modulating gut microbiota may represent novel therapeutic strategies for the management of uremia in patients with CKD.

Protection of Intestinal Barrier in Uremic Mice by Electroacupuncture via Regulating the Cannabinoid 1 Receptor of the Intestinal Glial Cells.

Intestinal barrier injuries are common in uremia, which aggravates uremia. The goal of this study is to learn moreabout how electroacupuncture regulates gastrointestinal function, as well as to identify the importance of microglia in electroacupuncture regulation and the cannabinoid receptor signaling pathway in controlling the activity of intestinal glial cells. The mice were arbitrarily assigned to four groups: control, CKD, electroacupuncture stimulation, or AM251 (CB1 receptor antagonist). The mice model of uremia was established by adenine gavage. Western blotting revealed the development of tight junction proteins ZO-1, cannabinoid 1 receptor, glial specific GFAP, occludin, S100 ß, claudin-1, and JNK. GFAP and CB1R protein expression and co-localization of the intestinal glial cells were observed by double-labeled fluorescence. The expression of cannabinoid 1 receptor CB1R in the intestinal glial cells was increased after electroacupuncture. The expression of tight junction protein, GFAP, S100 ß, and CB1R protein was up-regulated after electroacupuncture, and the dysfunction of the intestinal barrier in uremia was corrected. Nevertheless, AM251, a CB1R antagonist, reversed the effect of electroacupuncture. Electroacupuncture can protect the intestinal barrier through the intestinal glial cell CB1R, and the effect is achieved by inhibiting the JNK pathway.

Clinical Efficacy and Safety of Sodium Thiosulfate in the Treatment of Uremic Pruritus: A Meta-Analysis of Randomized Controlled Trials.

Uremic pruritus is a distressful complication of chronic kidney disease and results in impaired quality of life and higher mortality rates. Intravenous sodium thiosulfate has been reported to alleviate pruritus in hemodialysis patients. We performed a systematic review and meta-analysis to estimate the efficacy of intravenous sodium thiosulfate in patients with uremic pruritus. A systematic search of electronic databases up to June 2021 was conducted for randomized controlled trials that evaluated the clinical effects of sodium thiosulfate in the management of patients with uremic pruritus. Two reviewers selected eligible articles and evaluated the risk of bias; the results of pruritus assessment and uremic pruritus-related laboratory parameters in selected studies were analyzed. There are four trials published between 2018 and 2021, which include 222 participants. The sodium thiosulfate group displayed significant decrease in the pruritus score (standardized mean difference = -3.52, 95% confidence interval = -5.63 to -1.41, p = 0.001), without a significant increase in the adverse effects (risk ratio = 2.44, 95% confidence interval = 0.37 to 15.99, p = 0.35) compared to the control group. Administration of sodium thiosulfate is found to be a safe and efficacious complementary therapy in improving uremic pruritus in patients with chronic kidney disease.

Omega-3 Polyunsaturated Fatty Acid Attenuates Uremia-Induced Brain Damage in Mice.

Although the cause of neurological disease in patients with chronic kidney disease (CKD) has not been completely identified yet, recent papers have identified accumulated uremic toxin as its main cause. Additionally, omega-3 polyunsaturated fatty acid (ω-3 PUFA) plays an important role in maintaining normal nerve function, but its protective effects against uremic toxin is unclear. The objective of this study was to identify brain damage caused by uremic toxicity and determine the protective effects of ω-3 PUFA against uremic toxin. We divided mice into the following groups: wild-type (wt) sham (n = 8), ω-3 PUFA sham (n = 8), Fat-1 sham (n = 8), ischemia-reperfusion (IR) (n = 20), and ω-3 PUFA+IR (n = 20) Fat-1+IR (n = 20). Brain tissue, kidney tissue, and blood were collected three days after the operation of mice (sham and IR operation). This study showed that Ki67 and neuronal nuclei (NeuN) decreased in the brain of uremic mice as compared to wt mice brain, but increased in the ω-3 PUFA-treated uremic mice and the brain of uremic Fat-1 mice as compared to the brain of uremic mice. The pro-apoptotic protein expressions were increased, whereas anti-apoptotic protein expression decreased in the brain of uremic mice as compared to wt mice brain. However, apoptotic protein expression decreased in the ω-3 PUFA-treated uremic mice and the brain of uremic Fat-1 mice as compared to the brain of uremic mice. Furthermore, the brain of ω-3 PUFA-treated uremic mice and uremic Fat-1 mice showed increased expression of p-PI3K, p-PDK1, and p-Akt as compared to the brain of uremic mice. We confirm that uremic toxin damages the brain and causes cell death. In these injuries, ω-3 PUFA plays an important role in neuroprotection through PI(3)K-Akt signaling.

Effects of Uremic Clearance Granules in Uremic Pruritus: A Meta-Analysis.

Uremic pruritus is common among patients with advanced or end-stage renal disease, with an incidence of >40% among patients on dialysis. Uremic clearance granules (UCGs) are effective in managing uremic pruritus and delay the progression of chronic kidney disease. We conducted a systematic review and a meta-analysis to evaluate the efficacy of UCG in patients with uremic pruritus. Several electronic databases were searched systematically from their inceptions until 19 July 2021. Randomized control trials evaluating the efficacy of UCG in patients with uremic pruritus were selected. Eleven trials including 894 participants were published between 2011 and 2021. Patients administered UCGs had a significantly decreased visual analog scale score (mean difference [MD], -2.02; 95% confidence interval [CI], -2.17 to -1.88), serum levels of hsCRP (MD, -2.07 mg/dL; 95% CI, -2.89 to -1.25; p < 0.00001), TNF-α (MD, -15.23 mg/L; 95% CI, -20.00 to -10.47; p < 0.00001]), ß2-MG (MD, -10.18 mg/L; 95% CI, -15.43 to -4.93; p < 0.00001), and IL-6 (MD, -6.13 mg/L; 95% CI, -7.42 to -4.84; p < 0.00001). In addition, UCGs significantly reduced serum levels of creatinine, BUN, PTH, iPTH, phosphorus, and the overall effectiveness rate. UCGs could be an attractive complementary therapy for patients with uremic pruritus.

Hepatic and Vascular Vitamin K Status in Patients with High Cardiovascular Risk.

Vitamin K dependent proteins (VKDP), such as hepatic coagulation factors and vascular matrix Gla protein (MGP), play key roles in maintaining physiological functions. Vitamin K deficiency results in inactive VKDP and is strongly linked to vascular calcification (VC), one of the major risk factors for cardiovascular morbidity and mortality. In this study we investigated how two vitamin K surrogate markers, dephosphorylated-undercarboxylated MGP (dp-ucMGP) and protein induced by vitamin K absence II (PIVKA-II), reflect vitamin K status in patients on hemodialysis or with calcific uremic arteriolopathy (CUA) and patients with atrial fibrillation or aortic valve stenosis. Through inter- and intra-cohort comparisons, we assessed the influence of vitamin K antagonist (VKA) use, vitamin K supplementation and disease etiology on vitamin K status, as well as the correlation between both markers. Overall, VKA therapy was associated with 8.5-fold higher PIVKA-II (0.25 to 2.03 AU/mL) and 3-fold higher dp-ucMGP (843 to 2642 pM) levels. In the absence of VKA use, non-renal patients with established VC have dp-ucMGP levels similar to controls (460 vs. 380 pM), while in HD and CUA patients, levels were strongly elevated (977 pM). Vitamin K supplementation significantly reduced dp-ucMGP levels within 12 months (440 to 221 pM). Overall, PIVKA-II and dp-ucMGP showed only weak correlation (r2 ≤ 0.26) and distinct distribution pattern in renal and non-renal patients. In conclusion, VKA use exacerbated vitamin K deficiency across all etiologies, while vitamin K supplementation resulted in a vascular VKDP status better than that of the general population. Weak correlation of vitamin K biomarkers calls for thoughtful selection lead by the research question. Vitamin K status in non-renal deficient patients was not anomalous and may question the role of vitamin K deficiency in the pathogenesis of VC in these patients.

Impact of intravenous iron on cardiac and skeletal oxidative stress and cardiac mitochondrial function in experimental uraemia chronic kidney disease.

Introuction: Uraemia leads to changes in cardiac structure, metabolic remodeling and anaemia, key factors in the development of heart failure in patients with chronic kidney disease. Previous studies have identified abnormalities in mitochondrial function, potentially impairing energy provision and enhancing oxidative stress. This study characterised oxidant status and changes in mitochondrial function in uraemia and the impact of correcting anaemia via intravenous iron therapy. Methods: Experimental uraemia was induced in male Sprague-Dawley rats via a subtotal nephrectomy and parenteral iron administration given 6 weeks post-surgery. Oxidative stress from tissue samples was evaluated by measuring pro-oxidant activities and anti-oxidant capacities in both sham and uraemic animals with and without iron supplementation. Thiobarbituric acid-reactive substances (TBARS), aconitase activity and cardiolipin were measured. Mitochondrial function was assessed using the Seahorse XFp analyser on isolated mitochondria excised from cardiac tissue. Results: Oxidative stress in this uraemic model was increased in cardiac tissue (increased GSSG/GSH ratio, TBARS and increased activities of pro-oxidant enzymes). There was no impact on skeletal tissue. Parenteral iron ameliorated oxidative stress by enhancing the anti-oxidant defense system in cardiac tissue and skeletal tissue. Examination of respiratory reserve in cardiac mitochondria demonstrated that parenteral iron restored mitochondrial function. This experimental model of uraemia demonstrated a specific oxidative stress on the heart muscle without significant changes in skeletal oxidant status. Iron therapy improved anti-oxidant defence system, consequently reducing oxidative stress in the heart and skeletal tissue. There was an improvement in cardiac mitochondrial function. Conclusions: This experimental evidence indicates that iron therapy could reduce vulnerability to oxidative stress and potentially improve both cardiac and skeletal functional capacity from improvements in mitochondrial function.

The Therapeutic Strategies for Uremic Toxins Control in Chronic Kidney Disease.

Uremic toxins (UTs) are mainly produced by protein metabolized by the intestinal microbiota and converted in the liver or by mitochondria or other enzymes. The accumulation of UTs can damage the intestinal barrier integrity and cause vascular damage and progressive kidney damage. Together, these factors lead to metabolic imbalances, which in turn increase oxidative stress and inflammation and then produce uremia that affects many organs and causes diseases including renal fibrosis, vascular disease, and renal osteodystrophy. This article is based on the theory of the intestinal-renal axis, from bench to bedside, and it discusses nonextracorporeal therapies for UTs, which are classified into three categories: medication, diet and supplement therapy, and complementary and alternative medicine (CAM) and other therapies. The effects of medications such as AST-120 and meclofenamate are described. Diet and supplement therapies include plant-based diet, very low-protein diet, probiotics, prebiotics, synbiotics, and nutraceuticals. The research status of Chinese herbal medicine is discussed for CAM and other therapies. This review can provide some treatment recommendations for the reduction of UTs in patients with chronic kidney disease.