The Gut Microbiome,Kidney Disease,and Targeted Interventions

The human gut harbors >100 trillion microbial cells, which influence the nutrition, metabolism, physiology, and immune function of the host. Here, we review the quantitative and qualitative changes in gut microbiota of patients with CKD that lead to disturbance of this symbiotic relationship, how this may contribute to the progression of CKD, and targeted interventions to re-establish symbiosis. Endotoxin derived from gut bacteria incites a powerful inflammatory response in the host organism. Furthermore, protein fermentation by gut microbiota generates myriad toxic metabolites, including p-cresol and indoxyl sulfate. Disruption of gut barrier function in CKD allows translocation of endotoxin and bacterial metabolites to the systemic circulation, which contributes to uremic toxicity, inflammation, progression of CKD, and associated cardiovascular disease. Several targeted interventions that aim to re-establish intestinal symbiosis, neutralize bacterial endotoxins, or adsorb gut-derived uremic toxins have been developed. Indeed, animal and human studies suggest that prebiotics and probiotics may have therapeutic roles in maintaining a metabolically-balanced gut microbiota and reducing progression of CKD and uremia-associated complications. We propose that further research should focus on using this highly efficient metabolic machinery to alleviate uremic symptoms.The gut microbiota has coevolved with humans for a mutually beneficial coexistence and plays an important role in health and disease.¹ Normal gut microbiota influences the well-being of the host by contributing to its nutrition, metabolism, physiology, and immune function.^2,3 Disturbance of normal gut microbiota (dysbiosis) has been implicated in the pathogenesis of diverse illnesses, such as obesity,⁴ type 2 diabetes,⁵ inflammatory bowel disease,⁶ and cardiovascular disease.^7,8 Quantitative and qualitative alterations in gut microbiota are noted in patients with CKD and ESRD.^9–11 Preliminary evidence indicates that toxic products generated by a dysbiotic gut microbiome may contribute to progression to CKD and CKD-related complications (Figure 1).^12,13Open in a separate windowFigure 1.The human gut is host to >100 trillion bacteria with an enteric reservoir of >1 g of endotoxin. Alterations in gut microbiota and impaired intestinal barrier function in patients with CKD/ESRD have been linked to endotoxemia and accumulation of gut-derived uremic toxins leading to insulin resistance, protein energy wasting, immune dysregaulation, and atheroscleroisis. CVD, cardiovascular disease; IR, insulin resistance; PEW, protein energy wasting.     

The crosstalk of gut microbiota and chronic kidney disease: role of inflammation,proteinuria, hypertension,and diabetes mellitus

Chronic kidney disease (CKD) has been shown to result in profound changes in the composition and functions of the gut microbial flora which by disrupting intestinal epithelial barrier and generating toxic by-products contributes to systemic inflammation and the associated complications. On the other hand, emerging evidence points to the role of the gut microbiota in the development and progression of CKD by provoking inflammation, proteinuria, hypertension, and diabetes. These observations demonstrate the causal interconnection between the gut microbial dysbiosis and CKD. The gut microbiota closely interacts with the inflammatory, renal, cardiovascular, and endocrine systems via metabolic, humoral, and neural signaling pathways, events which can lead to chronic systemic inflammation, proteinuria, hypertension, diabetes, and kidney disease. Given the established role of the gut microbiota in the development and progression of CKD and its complications, favorable modification of the composition and function of the gut microbiome represents an appealing therapeutic target for prevention and treatment of CKD. This review provides an overview of the role of the gut microbial dysbiosis in the pathogenesis of the common causes of CKD including hypertension, diabetes, and proteinuria as well as progression of CKD.     

Indoxyl sulphate and kidney disease: Causes,consequences and interventions

In the last decade, chronic kidney disease (CKD), defined as reduced renal function (glomerular filtration rate (GFR) < 60 mL/min per 1.73 m²) and/or evidence of kidney damage (typically manifested as albuminuria) for at least 3 months, has become one of the fastest‐growing public health concerns worldwide. CKD is characterized by reduced clearance and increased serum accumulation of metabolic waste products (uremic retention solutes). At least 152 uremic retention solutes have been reported. This review focuses on indoxyl sulphate (IS), a protein‐bound, tryptophan‐derived metabolite that is generated by intestinal micro‐organisms (microbiota). Animal studies have demonstrated an association between IS accumulation and increased fibrosis, and oxidative stress. This has been mirrored by in vitro studies, many of which report cytotoxic effects in kidney proximal tubular cells following IS exposure. Clinical studies have associated IS accumulation with deleterious effects, such as kidney functional decline and adverse cardiovascular events, although causality has not been conclusively established. The aims of this review are to: (i) establish factors associated with increased serum accumulation of IS; (ii) report effects of IS accumulation in clinical studies; (iii) critique the reported effects of IS in the kidney, when administered both in vivo and in vitro; and (iv) summarize both established and hypothetical therapeutic options for reducing serum IS or antagonizing its reported downstream effects in the kidney.     

Uremic Toxins in Acute Kidney Injury

Acute kidney injury (AKI) is a serious and frequent condition which may fully resolve but is associated with markedly increased mortality. Mortality in AKI is caused by nonrenal, distant organ failure. Renal recovery from AKI is often not achieved on account of new injuries in the repair phase. Uremic toxins may be the missing link between AKI and nonrenal organ failure, tubular and endothelial injury. Compared with chronic kidney disease (CKD), research of uremic toxins in AKI is in its infancy. This review presents the current knowledge on uremic toxins in AKI which is predominately derived from experimental studies. Most uremic toxins investigated have previously been identified in CKD. The review focuses on those uremic toxins with biologic effect on the respective nonrenal organs failing in AKI and on the renal tubule and the endothelium. These uremic toxins may insofar be specific mediators of pathophysiological processes in AKI.     

Klotho Protects Against Indoxyl Sulphate-Induced Myocardial Hypertrophy

Left ventricular hypertrophy (LVH) is a common complication in patients with CKD and an independent risk factor for death. Changes in the levels of uremic solutes or Klotho have been reported to be related to CKD, whereas the relationships between these factors and CKD-associated LVH remain unclear. Here, we investigated the interaction between Klotho and indoxyl sulfate (IS), a typical uremic solute, in CKD-associated LVH. In a survey of 86 patients with CKD, a negative relationship was found between serum levels of IS and Klotho (r=−0.59, P<0.001). Furthermore, serum levels of IS and Klotho were independently associated with LVH (for IS: r=0.69, P<0.001; for Klotho: r=−0.49, P<0.001). In normal mice, intraperitoneal injection of IS for 8 weeks induced LVH accompanied by substantial downregulation of renal Klotho. Notably, IS-induced LVH was more severe in heterozygous Klotho-deficient (kl/+) mice. In vitro, treatment with Klotho strongly inhibited IS-induced cardiomyocyte hypertrophy by blocking oxidative stress and inhibiting p38 and extracellular signal–regulated protein kinase 1/2 signaling pathways. In a mouse model of CKD-associated LVH, the renal expression of Klotho was lower and the level of serum IS was higher than in healthy controls. Moreover, treatment of CKD mice with Klotho protein significantly restrained the development of LVH. Taken together, these results suggest that Klotho is an endogenous protector against IS-induced LVH, and the imbalance between Klotho and IS may contribute to the development of LVH in CKD.     

Curcumin modulates gut microbiota and improves renal function in rats with uric acid nephropathy

It is well known that the progression of hyperuricemia disease often contributes to renal dysfunction. However, there have been few studies on uric acid nephropathy (UAN), especially its relationship with gut microbiota. UAN is usually accompanied by disordered intestinal flora, and damaged gut barrier, which are closely related to tubulointerstitial fibrosis, and systemic inflammation. In previous studies, it has been confirmed that curcumin could alleviate tubulointerstitial fibrosis, and improve renal function through its antioxidant, anti-apoptotic, and anti-inflammatory efficacies. However, the effects curcumin exerts on intestinal flora in uric acid nephropathy are still unknown. Therefore, we used next-generation sequencing technology to investigate the effects of curcumin on gut microbiota in a rat model of UAN induced by adenine and potassium oxonate, and rats were randomly divided into control, model or curcumin treatment groups. The results demonstrated that, compared to the model group, the treatment group showed decreased serum uric acid (156.80 ± 11.90 μmol/L vs. 325.60 ± 18.65 μmol/L, p < 0.001), serum creatinine (66.20 ± 11.88 μmol/L vs. 182.20 ± 8.87 μmol/L, p < 0.001) and BUN level (13.33 ± 3.16 mmol/L vs. 36.04 ± 6.60 mmol/L, p < 0.001). The treatment group also displayed attenuated renal pathological lesions and metabolic endotoxemia (25.60 ± 5.90 ng/mL vs. 38.40 ± 4.98 ng/mL, p < 0.01), and improved tightly linked proteins expression. Besides, curcumin altered the gut microbiota structure in UAN rats. More specifically, curcumin treatment protected against the overgrowth of opportunistic pathogens in UAN, including Escherichia-Shigella and Bacteroides, and increased the relative abundance of bacteria producing short‐chain fatty acids (SCFAs), such as Lactobacillus and Ruminococcaceae. These results suggest that curcumin could modulate gut microbiota, fortify the intestinal barrier, attenuate metabolic endotoxemia, and consequently protect the renal function in UAN rats.     

Number and function impairment of resident C-Kit+ cardiac stem cells in mice with renal dysfunction caused by 5/6 nephrectomy

Abstract

Background: Cardiac stem cell (CSC) dysfunction exists in various kinds of cardiovascular diseases, and may be responsible for the insufficient regeneration of cardiac myocytes and coronary vessels. However, whether chronic renal failure (CRF) affected CSC is unknown. Method: CRF was induced in adult male mice by 5/6 nephrectomy. The mice were killed at 12 weeks after operation. C-kit+ CSC numbers was evaluated by flow cytometer. Apoptosis and DNA damage of C-kit+ CSC in the control and CRF mice was analyzed by immunohistochemistry. In the in vitro study, normal medium, and medium with uremic rat serum were used for the CSC culture. Results: CSC counts attenuated significantly in the chronic renal failure model, whereas apoptosis cells and 8-OHdG-positive cells significantly increased. CSC derived form 5/6 nephrectomy mice showed an impaired anti-oxidant potential. In the cultured cells, CSCs subjected to uremic rat serum showed a higher frequency of TUNEL stain-positive and 8-OHdG-positive cells. The uremia rat serum reduced the expression of hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) in CSC. Conclusions: The current study elucidated that CSC number and function disorders existed in mice with chronic renal insufficiency. Apoptosis, oxidative stress and reduced angiogenic factors secretion caused by uremic toxins in serum are contributors to CSC dysfunction.     

Effects of a high-phosphorus diet on the gut microbiota in CKD rats

ObjectiveTo investigate whether high-phosphorus diets alter gut microbiota in healthy rats and chronic kidney disease (CKD) rats.MethodsIn this 4-week randomized controlled trial, healthy rats and CKD rats were fed a regular-phosphorus (Pi: 0.8%) and high-phosphorus (Pi: 1.2%) diet. The subjects were divided into four groups: sham-group rats with regular-phosphorus diet intervention (CTL group), sham-group rats with high-phosphorus diet intervention (CTLP group), CKD model rats with regular-phosphorus diet intervention (CKD group), and CKD model rats with high-phosphorus diet intervention (CKDP group). The V3-V4 region of the 16S rRNA gene was sequenced to study the effect of a high-phosphorus diet on gut microbiota.ResultsA high-phosphorus intervention increased systolic blood pressure (SBP) and parathyroid hormone (PTH) in CTL and CKD rats but did not change serum creatinine and 25(OH)D levels. After the high-phosphorus diet, serum phosphate and fibroblast growth factor 23 (FGF23) increased in the CKDP group compared with the CKD group. The gut microbiota was significantly altered after intervention with a high-phosphorus diet in CTL and CKD group rats. A high-phosphorus diet reduced the Shannon index values of gut microbiota in all rats. The Chao1 and Ace indexes were decreased in the CTL group after high-phosphorus diet intervention. Some microbial genera were elevated significantly after high-phosphorus dietary intervention, such as Blautia and Allobaculum. The main bacteria linked to SBP and FGF23 also correlated directly with creatinine. After high-phosphorus diet intervention, the bacteria Prevotella were positively related to SBP in CTLP and CKDP groups.ConclusionsHigh-phosphorus diets were associated with adverse changes in gut microbiota and elevated SBP, which may have adverse consequences for long-term health outcomes.     

Randomized Placebo-Controlled EPPIC Trials of AST-120 in CKD

Reduced GFR in patients with CKD causes systemic accumulation of uremic toxins, which has been correlated with disease progression and increased morbidity. The orally administered spherical carbon adsorbent AST-120 reduces systemic toxin absorption through gastrointestinal sequestration, which may slow disease progression in these patients. The multinational, randomized, double-blind, placebo-controlled Evaluating Prevention of Progression in CKD (EPPIC)-1 and EPPIC-2 trials evaluated the effects of AST-120 on the progression of CKD when added to standard therapy. We randomly assigned 2035 adults with moderate to severe disease (serum creatinine at screening, 2.0–5.0 mg/dl for men and 1.5–5.0 mg/dl for women) to receive either placebo or AST-120 (9 g/d). The primary end point was a composite of dialysis initiation, kidney transplantation, and serum creatinine doubling. Each trial continued until accrual of 291 primary end points. The time to primary end point was similar between the AST-120 and the placebo groups in both trials (EPPIC-1: hazard ratio, 1.03; 95% confidence interval, 0.84 to 1.27; P=0.78) (EPPIC-2: hazard ratio, 0.91; 95% confidence interval, 0.74 to 1.12; P=0.37); a pooled analysis of both trials showed similar results. The estimated median time to primary end points for the placebo groups was 124 weeks for power calculations, but actual times were 189.0 and 170.3 weeks for EPPIC-1 and EPPIC-2, respectively. Thus, disease progression was more gradual than expected in the trial populations. In conclusion, the benefit of adding AST-120 to standard therapy in patients with moderate to severe CKD is not supported by these data.     

p-Cresyl Sulfate Promotes Insulin Resistance Associated with CKD

The mechanisms underlying the insulin resistance that frequently accompanies CKD are poorly understood, but the retention of renally excreted compounds may play a role. One such compound is p-cresyl sulfate (PCS), a protein-bound uremic toxin that originates from tyrosine metabolism by intestinal microbes. Here, we sought to determine whether PCS contributes to CKD-associated insulin resistance. Administering PCS to mice with normal kidney function for 4 weeks triggered insulin resistance, loss of fat mass, and ectopic redistribution of lipid in muscle and liver, mimicking features associated with CKD. Mice treated with PCS exhibited altered insulin signaling in skeletal muscle through ERK1/2 activation. In addition, exposing C2C12 myotubes to concentrations of PCS observed in CKD caused insulin resistance through direct activation of ERK1/2. Subtotal nephrectomy led to insulin resistance and dyslipidemia in mice, and treatment with the prebiotic arabino-xylo-oligosaccharide, which reduced serum PCS by decreasing intestinal production of p-cresol, prevented these metabolic derangements. Taken together, these data suggest that PCS contributes to insulin resistance and that targeting PCS may be a therapeutic strategy in CKD.The uremic syndrome is attributed to the progressive retention of numerous compounds, which in healthy individuals are normally excreted by the kidneys. At least 90 compounds, often referred to as uremic toxins, were described to accumulate in ESRD¹ and to be harmful for biologic systems. In recent years, the dialysis community has paid great attention to improve clearance of water-soluble molecules, such as urea. Unfortunately, several studies, including the HEMO study in hemodialysis,² and the ADEMEX study (Adequacy of Peritoneal Dialysis in Mexico),³ failed to significantly improve patient outcome. Protein-bound uremic toxins especially exert major toxic effects because of poor removal by the common dialysis techniques.^4,5 p-Cresol is the mother compound of an important group of protein-bound retention solutes.⁶ It is produced in the gut from the metabolism of aromatic amino acids by putrefactive bacteria of the gut microbiota.^7,8 As it crosses through the intestinal mucosa, p-cresol is then metabolized by a cytoplasmic sulfotransferase and therefore mainly circulates in blood as its sulfate conjugate, p-cresyl sulfate (PCS) (Supplemental Figure 1). PCS is excreted by the kidney mainly through proximal tubular secretion and therefore accumulates in serum of patients with renal dysfunction. Of note, p-cresol/PCS has been shown to be independently associated with mortality and cardiovascular disease in patients with CKD.^9–11 There are now accumulating in vitro data on the harmful effects of p-cresol/PCS and related protein-bound retention solutes.^7,9,12–15CKD is associated with a large range of metabolic alterations.¹⁶ As established by the pioneering work of DeFronzo et al., insulin resistance is a well documented feature of CKD.^17,18 Among patients with ESRD, insulin resistance is associated with higher prevalence of vascular diseases.¹⁹ Although the causes of CKD-associated insulin resistance remain poorly identified,²⁰ several abnormalities associated with renal dysfunction were reported to interfere with insulin signaling.^21,22 The exact mechanisms underlying insulin resistance in patients with CKD have not been clearly elucidated, but growing evidence suggests that the progressive retention of a large number of compounds, which under normal conditions are excreted by the healthy kidneys, could play a key role. In a recent study, D’Apolito et al.²³ demonstrated that increased urea levels in CKD could induce insulin resistance. However, to date no study has ruled out the role of protein-bound uremic toxins in the development of insulin resistance and metabolic disturbances in CKD. We hypothesized that increased concentrations of PCS associated with CKD might drive insulin resistance and metabolic disturbances associated with CKD. In this study, we demonstrate that PCS administrated to mice with normal renal function induces insulin resistance and metabolic disturbances mimicking those reported in CKD. We further show that the reduction of p-cresol intestinal production (and thus plasma PCS) by the use of a prebiotic (arabino-xylo-oligosaccharide [AXOS]) prevented insulin resistance and dyslipidemia in a mouse model of CKD.     

Specific alterations in gut microbiota in patients with chronic kidney disease: an updated systematic review

BackgroundEmerging evidence demonstrates that gut dysbiosis is implicated in the pathogenesis of chronic kidney disease (CKD) with underlying mechanisms involving mucosal and/or systematic immunity or metabolic disorders. However, the profile of gut microbiota in patients with CKD has not been completely explored.MethodsDatabases from their date of inception to 31 March 2020 were systematically searched for case-control or cross-sectional studies comparing the gut microbial profiles in adult patients with CKD or end-stage renal disease (ESRD) with those in healthy controls. Quantitative analysis of alterations in gut microbial profiles was conducted.ResultsTwenty-five studies with a total of 1436 CKD patients and 918 healthy controls were included. The present study supports the increased abundance of, phylum Proteobacteria and Fusobacteria, genus Escherichia_Shigella, Desulfovibrio, and Streptococcus, while lower abundance of genus Roseburia, Faecalibacterium, Pyramidobacter, Prevotellaceae_UCG-001, and Prevotella_9 in patients with CKD; and increased abundance of phylum Proteobacteria, and genus Streptococcus and Fusobacterium, while lower abundance of Prevotella, Coprococcus, Megamonas, and Faecalibacterium in patients with ESRD. Moreover, higher concentrations of trimethylamine-N-oxide and p-cresyl sulfate and lower concentrations of short-chain fatty acids were observed. Gut permeability in patients with CKD was not determined due to the heterogeneity of selected parameters.ConclusionsSpecific alterations of gut microbial parameters in patients with CKD were identified. However, a full picture of the gut microbiota could not be drawn from the data due to the differences in methodology, and qualitative and incomplete reporting of different studies.     

Removal of Protein‐Bound,Hydrophobic Uremic Toxins by a Combined Fractionated Plasma Separation and Adsorption Technique

Protein‐bound uremic toxins, such as phenylacetic acid, indoxyl sulfate, and p‐cresyl sulfate, contribute substantially to the progression of chronic kidney disease (CKD) and cardiovascular disease (CVD). However, based on their protein binding, these hydrophobic uremic toxins are poorly cleared during conventional dialysis and thus accumulate in CKD‐5D patients. Therefore, we investigated whether hydrophobic and cationic adsorbers are more effective for removal of protein‐bound, hydrophobic uremic toxins than conventional high‐flux hemodialyzer. Five CKD‐5D patients were treated using the fractionated plasma separation, adsorption, and dialysis (FPAD) system for 5 h. A control group of five CKD patients was treated with conventional high‐flux hemodialysis. Plasma concentrations of phenylacetic acid, indoxyl sulfate, and p‐cresyl sulfate were measured. Removal rates of FPAD treatment in comparison to conventional high‐flux hemodialysis were increased by 130% for phenylacetic acid, 187% for indoxyl sulfate, and 127% for p‐cresol. FPAD treatment was tolerated well in terms of clinically relevant biochemical parameters. However, patients suffered from mild nausea 2 h after the start of the treatment, which persisted until the end of treatment. Due to the high impact of protein‐bound, hydrophobic uremic toxins on progression of CKD and CVD in CKD‐5D patients, the use of an adsorber in combination with dialysis membranes may be a new therapeutic option to increase the removal rate of these uremic toxins. However, larger, long‐term prospective clinical trials are needed to demonstrate the impact on clinical outcome.     

The Cardiovascular Effect of the Uremic Solute Indole-3 Acetic Acid

In CKD, uremic solutes may induce endothelial dysfunction, inflammation, and oxidative stress, leading to increased cardiovascular risk. We investigated whether the uremic solute indole-3 acetic acid (IAA) predicts clinical outcomes in patients with CKD and has prooxidant and proinflammatory effects. We studied 120 patients with CKD. During the median study period of 966 days, 29 patients died and 35 experienced a major cardiovascular event. Kaplan–Meier analysis revealed that mortality and cardiovascular events were significantly higher in the higher IAA group (IAA>3.73 µM) than in the lower IAA group (IAA<3.73 µM). Multivariate Cox regression analysis demonstrated that serum IAA was a significant predictor of mortality and cardiovascular events after adjustments for age and sex; cholesterol, systolic BP, and smoking; C-reactive protein, phosphate, body mass index, and albumin; diastolic BP and history of cardiovascular disease; and uremic toxins p-cresyl sulfate and indoxyl sulfate. Notably, IAA level remained predictive of mortality when adjusted for CKD stage. IAA levels were positively correlated with markers of inflammation and oxidative stress: C-reactive protein and malondialdehyde, respectively. In cultured human endothelial cells, IAA activated an inflammatory nongenomic aryl hydrocarbon receptor (AhR)/p38MAPK/NF-κB pathway that induced the proinflammatory enzyme cyclooxygenase-2. Additionally, IAA increased production of endothelial reactive oxygen species. In conclusion, serum IAA may be an independent predictor of mortality and cardiovascular events in patients with CKD. In vitro, IAA induces endothelial inflammation and oxidative stress and activates an inflammatory AhR/p38MAPK/NF-κB pathway.     

Prognosis of severe drug-induced acute interstitial nephritis requiring renal replacement therapy

ObjectiveDrug-induced acute interstitial nephritis (DAIN) is often associated with improved outcomes, whereas some patients may still progress to chronic kidney disease (CKD). The aim of this study was to evaluate the prognosis of patients with severe DAIN requiring renal replacement therapy (RRT) at baseline, and to explore the risk factors of progression to CKD.MethodsWe performed a retrospective study of patients with severe DAIN confirmed by renal biopsies in our center over a 10 years period, all the patients received RRT at presentation. The clinical and pathological characteristics at baseline were recorded, and the outcomes (renal function recovered or progressed to CKD) during follow-ups were also evaluated. Univariate and multivariate logistic regression analysis were performed to identify the independent risk factors of progression to CKD.ResultsSeventy-two patients who met the inclusion criteria were enrolled, 13 patients (18.0%) progressed to CKD (GFR < 60 ml/min/1.73 m²) after at least 6 months of follow-up, the remaining 59 patients achieved a favorable renal function recovery. Compared with patients who achieved renal function recovery (recovery group), the patients progressed to CKD (progression group) were older and had longer interval from symptom onset to treatment with steroids. The peak serum cystatin C concentration was higher in progression group than recovery group. Higher score of interstitial fibrosis/tubular atrophy (IFTA) and more interstitial inflammatory cells infiltration were detected in renal tissue in progression group. According to multivariable analysis, higher peak cystatin C concentration (OR = 2.443, 95% CI 1.257, 4.746, p = 0.008), longer interval to treatment with corticosteroids (OR = 1.183, 95% CI 1.035, 1.352, p = 0.014) were independent risk factors of progression to CKD. The cutoff value of cystatin C concentration was 4.34 mg/L, at which the sensitivity and specificity were 76.9% and 89.3%, respectively; the cutoff value of interval to treatment with corticosteroids was 22.5 days, at which the sensitivity and specificity were 81.8% and 79.5%, respectively.ConclusionRenal function was reversible in majority of patients with severe DAIN requiring RRT when early identification and treatment. Higher peak cystatin C concentration and longer interval to treatment with corticosteroids associated with worse renal prognosis.     

An oral adsorbent, AST-120, suppresses oxidative stress in uremic rats

BACKGROUND: The production of reactive oxygen species (ROS) has been suggested to play an important role in the progression of chronic kidney disease (CKD). An oral adsorbent, AST-120, removes uremic toxins such as indoxyl sulfate (IS) and delays the progression of CKD, but the effect on ROS production is unknown. The present study aimed to determine whether AST-120 reduces oxidative stress in uremic rat kidneys using markers of ROS production such as acrolein and 8-hydroxy-2'-deoxyguanosine (8-OHdG). METHODS: Daily administration of AST-120 was started 6 weeks after 5/6 nephrectomy and continued for 18 weeks. The changes in metabolic data, serum and urine IS levels, urinary excretion of markers of oxidative stress, and renal histological findings were investigated in uremic rats with or without AST-120 treatment. RESULTS: In parallel with the increase in serum and urine IS, the serum creatinine, urinary protein and acrolein levels started to increase at 6 weeks, but urinary 8-OHdG remained unchanged and significantly increased at 18 weeks in uremic rats. AST-120 markedly and significantly attenuated increases in uremic toxins and oxidative stress levels as well as the histological changes in glomerular sclerosis, interstitial fibrosis, and the tubular staining of 8-OHdG. CONCLUSION: AST-120 suppressed the progression of CKD, at least in part, via attenuation of oxidative stress induced by uremic toxin.     

Thrombosis in the Uremic Milieu—Emerging Role of “Thrombolome”

Chronic kidney disease (CKD) is characterized by retention of a number of toxins, which unleash cellular damage. CKD environment with these toxins and a host of metabolic abnormalities (collectively termed as uremic milieu) is highly thrombogenic. CKD represents a strong and independent risk factor for both spontaneous venous and arterial (postvascular injury) thrombosis. Emerging evidence points to a previously unrecognized role of some of the prothrombotic uremic toxins. Here, we provide an overview of thrombosis in CKD and an update on indolic uremic toxins, which robustly increase tissue factor, a potent procoagulant, in several vascular cell types enhancing thrombosis. This panel of uremic toxins, which we term “thrombolome” (thrombosis and metabolome), represents a novel risk factor for thrombosis and can be further explored as biomarker for postvascular interventional thrombosis in patients with CKD.     

Molecular insights into preventive effects of AST-120 on the progression of renal failure

Circulating uremic toxins are considered to be involved in the progression of chronic renal failure (CRF). An oral adsorbent AST-120 (Kremezin) is effective in removing circulating uremic toxins from the digestive tract, and retards the progression of CRF. The administration of AST-120 combined with an angiotensin-converting enzyme inhibitor or a low-proein diet has an additive effect on the progression of CRF. In a variety of experimental models of CRF, AST-120 attenuates the progression of interstitial fibrosis and inflammation, as well as attenuating that of glomerular sclerosis. However, the precise mechanism by which AST-120 delays the progression of CRF had not been clear. Indoxyl sulfate, a dietary protein metabolite, is a circulating uremic toxin that stimulates the progression of CRF. AST-120 reduces the serum and urine levels of indoxyl sulfate and the accumulation of indoxyl sulfate in remnant tubular cells, by adsorbing its precursor, indole, in the intestine. The administration of indoxyl sulfate to uremic rats stimulated the expression of transforming growth factor (TGF)-β1, tissue inhibitor of metalloproteinase (TIMP)-1, and pro-α1(I)collagen in the kidneys. The administration of AST-120 to uremic rats reduced the extent of glomerular sclerosis and interstitial fibrosis, as well as reducing the renal expression of TGF-β1 and TIMP-1, by alleviating the overload of indoxyl sulfate in remnant tubular cells. We propose the protein metabolite theory, i.e., that endogenous protein metabolites such as indoxyl sulfate play an important role in the progression of CRF, and that AST-120 is effective in retarding the progression of CRF by adsorbing these protein metabolites in the intestine. Received: August 31, 2001 / Accepted: September 11, 2001     

Oral adsorbent AST-120 ameliorates gut environment and protects against the progression of renal impairment in CKD rats

Background

Oral charcoal adsorbent AST-120 (AST) is reported to ameliorate renal dysfunction by the absorption of toxic substance in the gut. Recent study revealed that, in CKD, gut environment is disturbed including the decrease in tight junctions and Lactobacillus (Lact). In this study, we examined whether AST improves the renal dysfunction through gut environment.

Method

Six-week-old spontaneously hypertensive rats (SHR) were rendered CKD by 5/6th nephrectomy (Nx). SHRs were divided into SHR (Sham), SHR with Nx (Nx), and Nx given AST (Nx?+?AST) (n?=?10, each). After 12 weeks, rats were killed and biochemical parameters were explored. The gut flora was analyzed. Furthermore, gut molecular changes in tight junctions and toll-like receptors were examined. We also investigated the effects of the combination therapy with AST and Lact.

Results

The increase in serum urea nitrogen and urinary protein excretion in Nx was restored in Nx?+?AST. The increased renal glomerulosclerosis in Nx was ameliorated in Nx?+?AST. Increases in serum uremic toxins and IL-6 in Nx were ameliorated in Nx?+?AST. The gut flora analysis revealed that the decrease in Lact in Nx was restored in Nx?+?AST. The downregulation in the tight junction and TLR2 in Nx was mitigated by AST. However, combination therapy failed to exhibit additional effects.

Conclusion

AST ameliorated renal function with the restoration of Lact and tight junction through TLR pathway, which would mitigate systemic inflammation and contributed to their renoprotective effects. Our study provides a novel mechanism of the renoprotective effects by AST.