Gut microbiota in chronic kidney disease

La microflora intestinal mantiene una relación simbiótica con el huésped en condicionesnormales, sin embargo, su alteración se ha asociado recientemente con numerosas enfer-medades.En la enfermedad renal crónica (ERC) se ha descrito una disbiosis en la microflora intesti-nal con un aumento de la flora patógena sobre la simbionte. Además, la permeabilidad de labarrera intestinal está aumentada, lo que permite el paso de endotoxinas y otros productosbacterianos a la sangre. La microflora intestinal, mediante la fermentación de productosno digeridos que alcanzan el colon, produce indoles, fenoles, o aminas, entre otros, queson absorbidos por el huésped, se acumulan en la ERC y tienen efectos deletéreos sobre elorganismo. Estas toxinas urémicas generadas en el intestino y el aumento de la permeabi-lidad de la barrera intestinal en la ERC se han asociado a un aumento de la inflamación y elestrés oxidativo, y están implicados en diversas complicaciones asociadas a la ERC, como laenfermedad cardiovascular, la anemia, las alteraciones del metabolismo mineral o la progre-sión de la ERC. El uso de prebióticos, probióticos o simbióticos, entre otras aproximaciones,podrían mejorar la disbiosis o el aumento de la permeabilidad de la barrera intestinal en laERC.En este artículo se revisan la situación de la microflora intestinal en la ERC, la alteraciónde la barrera intestinal y sus consecuencias clínicas, los efectos deletéreos de las toxinasurémicas derivadas de la microflora intestinal, así como las posibles opciones terapéuticaspara mejorar esta disbiosis y reducir las complicaciones de la ERCThe intestinal microflora maintains a symbiotic relationship with the host under normal conditions, but its imbalance has recently been associated with several diseases. In chronic kidney disease (CKD), dysbiotic intestinal microflora has been reported with an increase in pathogenic flora compared to symbiotic flora. An enhanced permeability of the intestinal barrier, allowing the passage of endotoxins and other bacterial products to the blood, has also been shown in CKD. By fermenting undigested products that reach the colon, the intestinal microflora produce indoles, phenols and amines, among others, that are absorbed by the host, accumulate in CKD and have harmful effects on the body. These gut-derived uraemic toxins and the increased permeability of the intestinal barrier in CKD have been associated with increased inflammation and oxidative stress and have been involved in various CKD-related complications, including cardiovascular disease, anaemia, mineral metabolism disorders or the progression of CKD. The use of prebiotics, probiotics or synbiotics, among other approaches, could improve the dysbiosis and/or the increased permeability of the intestinal barrier in CKD. This article describes the situation of the intestinal microflora in CKD, the alteration of the intestinal barrier and its clinical consequences, the harmful effects of intestinal flora- derived uraemic toxins, and possible therapeutic options to improve this dysbiosis and reduce CKD-related complicationsEste trabajo ha sido financiado con becas del Fondo de Investigaciones Sanitarias (PI16/01298) y de la Sociedad Madrileña de Nefrología y REDinREN

Vegetable-Based Diets for Chronic Kidney Disease? It Is Time to Reconsider

Traditional dietary recommendations to renal patients limited the intake of fruits and vegetables because of their high potassium content. However, this paradigm is rapidly changing due to the multiple benefits derived from a fundamentally vegetarian diet such as, improvement in gut dysbiosis, reducing the number of pathobionts and protein-fermenting species leading to a decreased production of the most harmful uremic toxins, while the high fiber content of these diets enhances intestinal motility and short-chain fatty acid production. Metabolic acidosis in chronic kidney disease (CKD) is aggravated by the high consumption of meat and refined cereals, increasing the dietary acid load, while the intake of fruit and vegetables is able to neutralize the acidosis and its deleterious consequences. Phosphorus absorption and bioavailability is also lower in a vegetarian diet, reducing hyperphosphatemia, a known cause of cardiovascular mortality in CKD. The richness of multiple plants in magnesium and vitamin K avoids their deficiency, which is common in these patients. These beneficial effects, together with the reduction of inflammation and oxidative stress observed with these diets, may explain the reduction in renal patients' complications and mortality, and may slow CKD progression. Finally, although hyperkalemia is the main concern of these diets, the use of adequate cooking techniques can minimize the amount absorbed

Changes in clinical indicators related to the transition from dialysis to kidney transplantation-data from the ERA-EDTA Registry

Background. Kidney transplantation should improve abnormalities that are common during dialysis treatment, like anaemia and mineral and bone disorder. However, its impact is incompletely understood. We therefore aimed to assess changes in clinical indicators after the transition from chronic dialysis to kidney transplantation. Methods. We used European Renal Association-European Dialysis and Transplant Association Registry data and included adult dialysis patients for whom data on clinical indicators before and after transplantation (2005-15) were available. Linear mixed models were used to quantify the effect of transplantation and of time after transplantation for each indicator. Results. In total, 16 312 patients were included. The mean age at transplantation was 50.1 (standard deviation 14.2) years, 62.9% were male and 70.2% were on haemodialysis before transplantation. Total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol and triglycerides increased right after transplantation but decreased thereafter. All other indicators normalized or approached the target range soon after transplantation and these improvements were sustained for the first 4 years of follow-up. In patients with higher estimated glomerular filtration rate (eGFR) levels (30-60 and >60 mL/min/1.73 m(2)), the improvement of haemoglobin, ferritin, ionized calcium, phosphate, parathyroid hormone, HDL cholesterol, triglycerides, albumin and C-reactive protein levels was more pronounced than in patients with a lower eGFR ( Conclusions. Except for total cholesterol, LDL cholesterol and triglycerides, all clinical indicators improved after transplantation. These improvements were related to eGFR. Nevertheless, values remained out of range in a considerable proportion of patients and anaemia and hyperparathyroidism were still common problems. Further research is needed to understand the complex relationship between eGFR and the different clinical indicators.Peer reviewe

NFkB in the development of endothelial activation and damage in uremia: an in vitro approach

Impaired hemostasis coexists with accelerated atherosclerosis in patients with chronic kidney disease (CKD). The elevated frequency of atherothrombotic events has been associated with endothelial dysfunction. The relative contribution of the uremic state and the impact of the renal replacement therapies have been often disregarded. Plasma markers of endothelial activation and damage were evaluated in three groups of patients with CKD: under conservative treatment (predialysis), on hemodialysis, and on peritoneal dialysis. Activation of p38 MAPK and the transcription factor NFκB was assessed in endothelial cell (EC) cultures exposed to pooled sera from each group of patients. Most of the markers evaluated (VCAM-1, ICAM-1, VWF, circulating endothelial cells) were significantly higher in CDK patients than in controls, being significantly more increased in the group of peritoneal dialysis patients. These results correlated with the activation of both p38 MAPK and NFκB in EC cells exposed to the same sera samples, and also to the peritoneal dialysis fluids. Hemodialysis did not further contribute to the endothelial damage induced by the uremic state observed in predialysis patients, probably due to the improved biocompatibility of the hemodialysis technique in recent years, resulting in lower cellular activation. However, peritoneal dialysis seemed to exert a significant proinflammatory effect on the endothelium that could be related to the high glucose concentrations and glucose degradation products present in the dialysis fluid. Although peritoneal dialysis has been traditionally considered a more physiological technique, our results raise some doubts with respect to inflammation and EC damage

Non-valvular atrial fibrillation in CKD : role of vitamin K antagonists and direct oral anticoagulants. A narrative review

Atrial fibrillation (AF) is the most common arrhythmia in chronic kidney disease (CKD), with a close bidirectional relationship between the two entities. The presence of CKD in AF increases the risk of thromboembolic events, mortality and bleeding. Vitamin K antagonists (VKA) have been the mainstay of treatment for the prevention of thromboembolic events in AF until recently, with confirmed benefits in AF patients with stage 3 CKD. However, the risk-benefit profile of VKA in patients with AF and stages 4-5 CKD is controversial due to the lack of evidence from randomized controlled trials. Treatment with VKA in CKD patients has been associated with conditions such as poorer anticoagulation quality, increased risk of bleeding, faster progression of vascular/valvular calcification and higher risk of calciphylaxis. Direct oral anticoagulants (DOACs) have shown equal or greater efficacy in stroke/systemic embolism prevention, and a better safety profile than VKA in post-hoc analysis of the pivotal randomized controlled trials in patients with non-valvular AF and stage 3 CKD, yet evidence of its risk-benefit profile in more advanced stages of CKD is scarce. Observational studies associate DOACs with a good safety/effectiveness profile compared to VKA in non-dialysis CKD patients. Further, DOACs have been associated with a lower risk of acute kidney injury and CKD development/progression than VKA. This narrative review summarizes the evidence of the efficacy and safety of warfarin and DOACs in patients with AF at different CKD stages, as well as their effects on renal function, vascular/valvular calcification and bone health

Antioxidant and Anti-Inflammatory Strategies Based on the Potentiation of Glutathione Peroxidase Activity Prevent Endothelial Dysfunction in Chronic Kidney Disease

BACKGROUND/AIMS: Accelerated atherosclerosis in chronic kidney disease (CKD) is preceded by endothelial dysfunction (ED), which exhibits a proinflammatory and prothrombotic phenotype and enhanced oxidative stress. In this study, the effect of several compounds with anti-inflammatory and/or antioxidant properties on uremia-induced endothelial dysfunction has been evaluated in an in vitro model. METHODS: Endothelial cells (ECs) were exposed to sera from uremic patients in the absence and presence of the flavonoids apigenin, genistein and quercetin, the antioxidant enzyme mimetics (AEM) ebselen (glutathione peroxidase mimetic), EUK-134 and EUK-118 (both superoxide dismutase mimetics), and the pharmacological drug N-acetylcysteine (NAC). We explored changes in the expression of adhesion receptors on the cell surface, by immunofluorescence, the production of radical oxygen species (ROS), by fluorescence detection, and the activation of signaling proteins related to inflammation, by both a phosphospecific antibody cell-based ELISA and immunoblotting techniques. RESULTS: Uremic media induced a significantly increased expression of ICAM-1, overproduction of radical oxygen species (ROS) and activation of p38 mitogen activated protein kinase (p38MAPK) and Nuclear Factor kB (NFkB) in ECs. Quercetin, the AEM and NAC showed a significant inhibitory effect on both ICAM-1 expression and ROS generation (p<0.05). All the compounds reduced p38MAPK activation, but only the AEM, especially ebselen, and NAC, both potentiating the glutathione peroxidase pathway, also inhibited NFkB activation. These two compounds were capable of increasing endothelial glutathione levels, especially in response to uremia. CONCLUSION: Our results indicate that the potentiation of the antioxidant pathways can be an effective strategy to improve endothelial dysfunction in uremia and a potential target to reduce the cardiovascular risk in this population

Prevalence of anaemia and its clinical management in patients with stages 3-5 chronic kidney disease not on dialysis in Catalonia: MICENAS I study

Introducción: La anemia es una complicación frecuente de la enfermedad renal crónica (ERC). El objetivo de este estudio fue conocer la prevalencia de anemia en pacientes con ERC estadios 3-5 no en diálisis atendidos en consultas externas (CCEE) de Nefrología en Cataluña y su manejo clínico. Metodología: Estudio epidemiológico, de cohorte transversal, multicéntrico, en condiciones de práctica clínica habitual. Recogida de datos mediante un e-CRD que incluía datos de filiación y aquellos relacionados con la anemia (hemoglobina, estatus férrico, tratamiento con agentes estimuladores de la eritropoyesis [AEE] y con otros coadyuvantes). Se definió anemia como unos niveles de hemoglobina < 13,5 g/dl en varones o < 12 g/dl en mujeres o pacientes que recibieran tratamiento con AEE. Resultados: Se incluyeron 504 pacientes (56,4 % varones, edad media de 67,8 ± 15,5 años): 61,5 % presentaban ERC estadio 3, 30,2 % estadio 4 y 8,3 % estadio 5. Las principales causas de ERC fueron la vascular y la nefropatía diabética. La prevalencia de anemia fue del 58,5 % (n = 295); sin embargo, solo un 14,9 % de los pacientes tenían niveles de hemoglobina < 11 g/dl. Los niveles medios de hemoglobina disminuían y el tratamiento con AEE era más frecuente a medida que progresaba la ERC, pero no se observaron diferencias significativas respecto a la prescripción de hierro, según estadios. Los AEE e intervalos más frecuentemente prescritos fueron darbepoetina alfa con una dosis mediana de 40 μg/bisemanal, seguida por C.E.R.A., con una dosis mediana de 75 μg/mensual y epoetina beta con una dosis mediana de 5000 UI/semanal. De los pacientes con anemia (n = 295), un 36,3 % (n = 107) presentaban ferropenia y de ellos solo un 53,3 % recibía tratamiento con suplementos de hierro. Conclusiones: Este estudio demuestra la alta prevalencia de anemia, la cual aumenta a medida que progresa la enfermedad, así como el buen control de la misma en la población de pacientes con ERC atendidos en CCEE de Nefrología en Cataluña. Este control se consigue con dosis moderadas de AEE y prescripción de suplementos de hierro en más del 50 % de los pacientes anémicos

Endothelial damage, inflammation and immunity in chronic kidney disease

Chronic kidney disease (CKD) patients have an accelerated atherosclerosis, increased risk of thrombotic-ischemic complications, and excessive mortality rates when compared with the general population. There is also evidence of an endothelial damage in which the proinflammatory state, the enhanced oxidative stress, or the accumulation of toxins due to their reduced renal clearance in uremia play a role. Further, there is evidence that uremic endothelial cells are both involved in and victims of the activation of the innate immunity. Uremic endothelial cells produce danger associated molecular patterns (DAMPS), which by binding to specific pattern recognition receptors expressed in multiple cells, including endothelial cells, induce the expression of adhesion molecules, the production of proinflammatory cytokines and an enhanced production of reactive oxygen species in endothelial cells, which constitute a link between immunity and inflammation. The connection between endothelial damage, inflammation and defective immunity in uremia will be reviewed here

Carotid atherosclerotic disease predicts cardiovascular events in hemodialysis patients: A prospective study

Background To evaluate the predictive value of carotid atherosclerotic disease (CAD) and intima-media thickness (IMT) on incident cardiovascular disease and mortality in hemodialysis patients. Methods Multicenter, observational, prospective study including 110 patients, followed-up to 6 years. Carotid doppler ultrasonographic findings were classified in 4 degrees of severity: 1) IMT 0.9 mm, 3) carotid plaque with stenosis 50%. The associations between IMT and CAD and cardiovascular events, total and cardiovascular mortality were assessed. Results 83% of the patients had atherosclerotic plaques (CAD degrees 3-4). During follow-up, 29.1% of patients experienced cardiovascular events, and 28.2% died, 38.7% of cardiovascular origin. The presence of plaques was associated with cardiovascular events (p = 0.03) while calcified plaques were associated with both cardiovascular events (p = 0.01), cardiovascular mortality (p = 0.03) and non-significantly with overall mortality (p = 0.08) in the survival analysis. Carotid IMT was not associated with outcomes. Cardiovascular events correlated with CAD severity (HR 2.27, 95% CI 1.13-4.54), age (HR 1.04, 1.01-1.06), previous cardiovascular disease (HR 1.75, 1.05-4.42), dyslipidemia (HR 2.25, 1.11-4.53), lipoprotein (a) (HR 1.01, 1.00-1.02), troponin I (HR 3.89, 1.07-14.18), fibrinogen levels (HR 1.38, 0.98-1.94) and antiplatelet therapy (HR 2.14, 1.04-4.4). In an age-adjusted multivariate model, cardiovascular events were independently associated with previous coronary artery disease (HR 3.29, 1.52-7.15) and lipoprotein (a) (HR 1.01, 1.00-1.02). Conclusions The presence of carotid plaques and, especially, calcified plaques, are predictors of new cardiovascular events and cardiovascular mortality in hemodialysis patients, while IMT was not. The prognostic value of calcified plaques should be confirmed in future studies

Antioxidant and Anti-Inflammatory Strategies Based on the Potentiation of Glutathione Peroxidase Activity Prevent Endothelial Dysfunction in Chronic Kidney Disease

Background/Aims: Accelerated atherosclerosis in chronic kidney disease (CKD) is preceded by endothelial dysfunction (ED), which exhibits a proinflammatory and prothrombotic phenotype and enhanced oxidative stress. In this study, the effect of several compounds with anti-inflammatory and/or antioxidant properties on uremia-induced endothelial dysfunction has been evaluated in an in vitro model. Methods: Endothelial cells (ECs) were exposed to sera from uremic patients in the absence and presence of the flavonoids apigenin, genistein and quercetin, the antioxidant enzyme mimetics (AEM) ebselen (glutathione peroxidase mimetic), EUK-134 and EUK-118 (both superoxide dismutase mimetics), and the pharmacological drug N-acetylcysteine (NAC). We explored changes in the expression of adhesion receptors on the cell surface, by immunofluorescence, the production of radical oxygen species (ROS), by fluorescence detection, and the activation of signaling proteins related to inflammation, by both a phosphospecific antibody cell-based ELISA and immunoblotting techniques. Results: Uremic media induced a significantly increased expression of ICAM-1, overproduction of radical oxygen species (ROS) and activation of p38 mitogen activated protein kinase (p38MAPK) and Nuclear Factor kB (NFkB) in ECs. Quercetin, the AEM and NAC showed a significant inhibitory effect on both ICAM-1 expression and ROS generation (p&#x3c;0.05). All the compounds reduced p38MAPK activation, but only the AEM, especially ebselen, and NAC, both potentiating the glutathione peroxidase pathway, also inhibited NFkB activation. These two compounds were capable of increasing endothelial glutathione levels, especially in response to uremia. Conclusion: Our results indicate that the potentiation of the antioxidant pathways can be an effective strategy to improve endothelial dysfunction in uremia and a potential target to reduce the cardiovascular risk in this population