In chronic kidney disease (CKD), uremic solutes accumulate in blood and tissues. These compounds probably contribute to the marked increase in cardiovascular risk during the progression of CKD. The ...uremic solutes indoxyl sulfate and indole-3-acetic acid (IAA) are particularly deleterious for endothelial cells. Here we performed microarray and comparative PCR analyses to identify genes in endothelial cells targeted by these two uremic solutes. We found an increase in endothelial expression of tissue factor in response to indoxyl sulfate and IAA and upregulation of eight genes regulated by the transcription factor aryl hydrocarbon receptor (AHR). The suggestion by microarray analysis of an involvement of AHR in tissue factor production was confirmed by siRNA inhibition and the indirect AHR inhibitor geldanamycin. These observations were extended to peripheral blood mononuclear cells. Tissue factor expression and activity were also increased by AHR agonist dioxin. Finally, we measured circulating tissue factor concentration and activity in healthy control subjects and in patients with CKD (stages 3–5d), and found that each was elevated in patients with CKD. Circulating tissue factor levels were positively correlated with plasma indoxyl sulfate and IAA. Thus, indolic uremic solutes increase tissue factor production in endothelial and peripheral blood mononuclear cells by AHR activation, evoking a ‘dioxin-like’ effect. This newly described mechanism of uremic solute toxicity may help understand the high cardiovascular risk of CKD patients.
Vascular dysfunction induced by uremia has 4 main aspects. (1) Atherosclerosis is increased. Intima-media thickness is increased, and animal studies have established that uremia accelerates ...atherosclerosis. Uremic toxins are involved in several steps of atherosclerosis. Leukocyte activation is stimulated by guanidines, advanced glycation end products (AGE), p-cresyl sulfate, platelet diadenosine polyphosphates, and indoxyl sulfate. Endothelial adhesion molecules are stimulated by indoxyl sulfate. Migration and proliferation of vascular smooth muscle cells (VSMC) are stimulated by local inflammation which could be triggered by indoxyl sulfate and AGE. Uremia is associated with an increase in von Willebrand factor, thrombomodulin, plasminogen activator inhibitor 1, and matrix metalloproteinases. These factors contribute to thrombosis and plaque destabilization. There is also a decrease in nitric oxide (NO) availability, due to asymmetric dimethylarginine (ADMA), AGE, and oxidative stress. Moreover, circulating endothelial microparticles (EMP) are increased in uremia, and inhibit the NO pathway. EMP are induced in vitro by indoxyl sulfate and p-cresyl sulfate. (2) Arterial stiffness occurs due to the loss of compliance of the vascular wall which induces an increase in pulse pressure leading to left ventricular hypertrophy and a decrease in coronary perfusion. Implicated uremic toxins are ADMA, AGE, and oxidative stress. (3) Vascular calcifications are increased in uremia. Their formation involves a transdifferentiation process of VSMC into osteoblast-like cells. Implicated uremic toxins are mainly inorganic phosphate, as well as reactive oxygen species, tumor necrosis factor and leptin. (4) Abnormalities of vascular repair and neointimal hyperplasia are due to VSMC proliferation and lead to severe reduction of vascular lumen. Restenosis after coronary angioplasty is higher in dialysis than in nondialysis patients. Arteriovenous fistula stenosis is the most common cause of thrombosis. Uremic toxins such as indoxyl sulfate and some guanidine compounds inhibit endothelial proliferation and wound repair. Endothelial progenitor cells which contribute to vessel repair are decreased and impaired in uremia, related to high serum levels of β(2)-microglobulin and indole-3 acetic acid. Overall, there is a link between kidney function and cardiovascular risk, as emphasized by recent meta-analyses. Moreover, an association has been reported between cardiovascular mortality and uremic toxins such as indoxyl sulfate, p-cresol and p-cresyl sulfate.
Many hypotheses could explain the mortality decrease observed using hemodiafiltration, such as reduction of intradialytic hypotension and more efficient toxin removal. We led a systematic analysis of ...representative uremic toxin removal with hemodialysis (HD), online postdilution hemodiafiltration (postHDF) and online predilution hemodiafiltration (preHDF), in a single-center crossover and prospective observational study. The primary outcome was the reduction ratio of uremic toxins of the three categories defined by the Eutox group. Twenty-six patients were treated by those three techniques of extra renal epuration. Mean Kt/Vurea was not different between the treatment methods. Mean reduction ratio of beta2microglobulin was significantly higher for both HDF treatments than for HD (
< 0.001). Myoglobin, kappa, and lambda free light chain reduction ratio was significantly different between the modes: 37.75 ± 11.95%, 45.31 ± 11% and 61.22 ± 10.56%/57.21 ± 12.5%, 63.53 ± 7.93%, and 68.40 ± 11.79%/29.12 ± 8.44%, 34.73 ± 9.01%, and 45.55 ± 12.31% HD, preHDF, and postHDF, respectively (
< 0.001). Mean protein-bound solutes reduction ratio was not different between the different treatments except for PCS with a higher reduction ratio during HDF treatments. Mean albumin loss was always less than 2 g. HDF improved removal of middle molecules but had no effect on indoles concentration without any difference between synthetic dialysis membranes.
Patients with chronic kidney disease (CKD) are exposed to uremic toxins and have an increased risk of cardiovascular disease. Some uremic toxins, like indoxyl sulfate, are agonists of the ...transcription factor aryl hydrocarbon receptor (AHR). These toxins induce a vascular procoagulant phenotype. Here we investigated AHR activation in patients with CKD and in a murine model of CKD. We performed a prospective study in 116 patients with CKD stage 3 to 5D and measured the AHR-Activating Potential of serum by bioassay. Compared to sera from healthy controls, sera from CKD patients displayed a strong AHR-Activating Potential; strongly correlated with eGFR and with the indoxyl sulfate concentration. The expression of the AHR target genes Cyp1A1 and AHRR was up-regulated in whole blood from patients with CKD. Survival analyses revealed that cardiovascular events were more frequent in CKD patients with an AHR-Activating Potential above the median. In mice with 5/6 nephrectomy, there was an increased serum AHR-Activating Potential, and an induction of Cyp1a1 mRNA in the aorta and heart, absent in AhR–/– CKD mice. After serial indoxyl sulfate injections, we observed an increase in serum AHR-AP and in expression of Cyp1a1 mRNA in aorta and heart in WT mice, but not in AhR–/– mice. Thus, the AHR pathway is activated both in patients and mice with CKD. Hence, AHR activation could be a key mechanism involved in the deleterious cardiovascular effects observed in CKD.
Abstract
Background
Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder associated with progressive enlargement of the kidneys and liver. ADPKD patients may require ...renal volume reduction, especially before renal transplantation. The standard treatment is unilateral nephrectomy. However, surgery incurs a risk of blood transfusion and alloimmunization. Furthermore, when patients are treated with peritoneal dialysis (PD), surgery is associated with an increased risk of temporary or definitive switch to haemodialysis (HD). Unilateral renal arterial embolization can be used as an alternative approach to nephrectomy.
Methods
We performed a multicentre retrospective study to compare the technique of survival of PD after transcatheter renal artery embolization with that of nephrectomy in an ADPKD population. We included ADPKD patients treated with PD submitted to renal volume reduction by either surgery or arterial embolization. Secondary objectives were to compare the frequency and duration of a temporary switch to HD in both groups and the impact of the procedure on PD adequacy parameters.
Results
More than 700 patient files from 12 centres were screened. Only 37 patients met the inclusion criteria (i.e. treated with PD at the time of renal volume reduction) and were included in the study (21 embolized and 16 nephrectomized). Permanent switch to HD was observed in 6 embolized patients (28.6%) versus 11 nephrectomized patients (68.8%) (P = 0.0001). Renal artery embolization was associated with better technique survival: subdistribution hazard ratio (SHR) 0.29 95% confidence interval (CI) 0.12–0.75; P = 0.01. By multivariate analysis, renal volume reduction by embolization and male gender were associated with a decreased risk of switching to HD. After embolization, a decrease in PD adequacy parameters was observed but no embolized patients required temporary HD; the duration of hospitalization was significantly lower 5 days interquartile range (IQR) 4.0–6.0 in the embolization group versus 8.5 days (IQR 6.0–11.0) in the surgery group.
Conclusions
Transcatheter renal artery embolization yields better technique survival of PD in ADPKD patients requiring renal volume reduction.
Chronic kidney disease (CKD) is associated with an increased risk of cognitive impairment. This cognitive impairment is associated with an increased permeability of blood-brain barrier (BBB) in ...rodents with CKD, linked to activation of aryl hydrocarbon receptor (AhR) by indoxyl sulphate (IS). The objective of the BREIN study was to confirm the increased BBB permeability in humans with CKD.
The BREIN comparative study (NCT04328415) prospectively included patients with end-stage kidney disease (ESKD) and controls healthy volunteers matched in age, sex, and level of education to a patient. In all participants, BBB permeability was quantified by brain 99mTc-DTPA SPECT/CT as a percentage of injected activity (% IA). A battery of neurocognitive tests was performed, and serum uremic toxins accumulation and AhR activation were assessed.
Fifteen patients with ESKD and 14 healthy volunteers were analyzed. Patients with ESKD had higher BBB permeability compared to controls: 0.29 ± 0.07 versus 0.14 ± 0.06 %IA, P = 0.002. Patients with ESKD displayed lower Montreal Cognitive Assessment test (MoCA) score: 22.0 ± 5.0 versus 27.3 ± 2.8, P = 0.008; impaired short-term memory (doors test): 12.5 ± 3.4 versus 16.5 ± 3.4, P = 0.005; higher Beck depression score 8.1 ± 9.1 versus 2.7 ± 3.4, P = 0.046; and slightly more daily cognitive complaints: 42.5 ± 29.3 versus 29.8 ± 14.0 P = 0.060. Patients with ESKD displayed higher IS levels (86.1 ± 48.4 vs. 3.2 ± 1.7 μmol/l, P = 0.001) and AhR activating potential (37.7 ± 17.8% vs. 24.7 ± 10.4%, P = 0.027). BBB permeability was inversely correlated with MoCA score (r = −0.60, 95% confidence interval −0.772 to −0.339, P = 0.001) in the overall population.
Patients with ESKD display an increased BBB permeability compared to matched healthy volunteers. Association with uremic toxins and cognitive impairment needs to be assessed in larger cohorts of patients.
To identify factors related to the choice of peritoneal dialysis as a first dialysis technique: the viewpoint of patients and viewpoint of nephrologists.
A retrospective multicenter study, type ...case-control was conducted in patients starting dialysis between 2010 and 2014 in 4 dialysis facilities in the PACA region. Nephrologists take care of patients included in the study were also interviewed. Data were collected using two standardized questionnaires: One for the patient and one for the nephrologists and using the French REIN registry.
One hundred and fifty patients were interviewed, the average age was 63.7 years. The medical contraindication for PD was present in 26.7%. Among patients eligible for both dialysis techniques, 46.7% had a preference for DP, 31.8% for HD and 21.5% did not have any preference. Patient preference is strongly influenced by information and the duration of predialysis nephrologist care (referral of nephrologist). The main factors related to personal choice of peritoneal dialysis are autonomy and desire for autonomy. Emergency dialysis influences negatively the choice of the PD.
A third of eligible patients for the 2 techniques could and wanted to be on PD. The limitations for PD are mainly related to professional practices. Better information could increase the utilization of PD to 32%.
Identifier les facteurs liés au choix de la dialyse péritonéale (DP) comme première technique de dialyse selon le point de vue des patients et celui des néphrologues.
Il s’agit d’une étude ...multicentrique rétrospective, de type cas-témoins, qui a été réalisée auprès de patients ayant démarré la dialyse entre 2010 et 2014 dans quatre établissements de la région Provence-Alpes-Côte d’Azur. Les néphrologues prenant en charge les patients inclus et acceptant de participer ont également été interrogés. Les données ont été recueillies à l’aide de deux questionnaires standardisés : un destiné aux patients et un destiné aux néphrologues. Les données démographiques et cliniques à l’initiation de la dialyse sont issues du registre Rein.
Au total, 150 patients ont été interrogés, ils avaient en moyenne 63,7 ans. La DP était contre-indiquée pour 26,7 % d’entre eux. Pour les patients éligibles aux deux techniques de dialyse, 46,7 % avaient exprimé une préférence pour la DP, 31,8 % pour l’HD et 21,5 % n’avaient exprimé aucune préférence. La préférence était influencée fortement par l’information et l’ancienneté du suivi néphrologique. Les principaux facteurs liés au choix personnel de la DP étaient l’autonomie et le désir d’autonomie. La mise en dialyse en urgence influençait négativement le choix de la DP.
Un tiers des patients éligibles aux deux techniques pouvaient et voulaient être sous DP. Les freins étaient essentiellement liés aux pratiques professionnelles. Une meilleure information pourrait augmenter ce potentiel de patients.
To identify factors related to the choice of peritoneal dialysis as a first dialysis technique: the viewpoint of patients and viewpoint of nephrologists.
A retrospective multicenter study, type case-control was conducted in patients starting dialysis between 2010 and 2014 in 4 dialysis facilities in the PACA region. Nephrologists take care of patients included in the study were also interviewed. Data were collected using two standardized questionnaires: One for the patient and one for the nephrologists and using the French REIN registry.
One hundred and fifty patients were interviewed, the average age was 63.7 years. The medical contraindication for PD was present in 26.7%. Among patients eligible for both dialysis techniques, 46.7% had a preference for DP, 31.8% for HD and 21.5% did not have any preference. Patient preference is strongly influenced by information and the duration of predialysis nephrologist care (referral of nephrologist). The main factors related to personal choice of peritoneal dialysis are autonomy and desire for autonomy. Emergency dialysis influences negatively the choice of the PD.
A third of eligible patients for the 2 techniques could and wanted to be on PD. The limitations for PD are mainly related to professional practices. Better information could increase the utilization of PD to 32%.
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