Chronic kidney disease (CKD) is associated with a high prevalence of cardiovascular diseases. During CKD, the uremic toxin indoxyl sulfate (IS)-derived from tryptophan metabolism-accumulates. IS is ...involved in the pathophysiology of cardiovascular complications. IS can be described as an endotheliotoxin: IS induces endothelial dysfunction implicated in cardiovascular morbidity and mortality during CKD. In this review, we describe clinical and experimental evidence for IS endothelial toxicity and focus on the various molecular pathways implicated. In patients with CKD, plasma concentrations of IS correlate with cardiovascular events and mortality, with vascular calcification and atherosclerotic markers. Moreover, IS induces a prothrombotic state and impaired neovascularization. IS reduction by AST-120 reverse these abnormalities. In vitro, IS induces endothelial aryl hydrocarbon receptor (AhR) activation and proinflammatory transcription factors as NF-κB or AP-1. IS has a prooxidant effect with reduction of nitric oxide (NO) bioavailability. Finally, IS alters endothelial cell and endothelial progenitor cell migration, regeneration and control vascular smooth muscle cells proliferation. Reducing IS endothelial toxicity appears to be necessary to improve cardiovascular health in CKD patients.
Chronic kidney disease (CKD) is a major public health issue associated with increased cardiovascular, infectious and all-cause mortality. The neutrophil:lymphocyte ratio (NLR) is a predictive marker ...of the risk of death and cardiovascular events. Uremic toxins, notably indoxyl sulfate (IS), are involved in immune deficiency and cardiovascular complications associated with CKD. The aim of this study was to assess whether the NLR was related to uremic toxins and could predict clinical outcome in hemodialysis (HD) patients.
We conducted a prospective cohort study of 183 patients on chronic HD. The main objective was to study the correlation between the NLR and uremic toxin serum levels. The secondary objective was to test if the NLR can predict the incidence of mortality, cardiovascular events and infectious events.
Patients were separated into two groups according to the NLR median value (3.49). The NLR at inclusion was correlated with the NLR at the 6-month (r = 0.55, P < 0.0001) and 12-month (r = 0.62, P < 0.0001) follow-up. Among uremic toxins, IS levels were higher in the group with high NLR (104 µmol/L versus 81 µmol/L; P = 0.004). In multivariate analysis, the NLR remained correlated with IS (P = 0.03). The incidence of death, cardiovascular events and severe infectious events was higher in the group with high NLR respectively, 38% versus 18% (P = 0.004), 45% versus 26% (P = 0.01) and 33% versus 21% (P = 0.02) than in the low NLR group. Multivariate analysis showed an independent association of the NLR with mortality (P = 0.02) and cardiovascular events (P = 0.03) but not with severe infectious events.
In HD patients, the NLR predicted mortality and cardiovascular events but not severe infections and correlated positively with the level of the uremic toxin IS. The NLR could be an interesting marker for monitoring the risk of clinical events in CKD patients.
Kidney damage in COVID-19 Burtey, Stéphane; Sallée, Marion
Néphrologie & thérapeutique
17, Številka:
4
Journal Article
Recenzirano
Odprti dostop
COVID-19 is a disease caused by the RNA virus SARS-CoV-2. It is characterised by an attack mainly affecting the respiratory system. There is renal involvement which is characterised by three main ...types of damage, acute tubular necrosis occurring in the most severe cases, proximal tubulopathy which is a prognostic marker of the disease and segmental and focal hyalinosis occurring in a genetically predisposed terrain. The pathophysiology of SARS-CoV-2 renal involvement is not yet defined. The direct role of the virus is debated, whereas the cytokine storm and the hypoxic and thrombotic complications seem more important. The long-term outcome of the renal damage appears to be quite good. Long-term follow-up will allow us to say whether the renal damage is part of the long COVID.
Apheresis to treat systemic vasculitis Moussi-Frances, Julie; Sallée, Marion; Jourde-Chiche, Noémie
Joint, bone, spine : revue du rhumatisme,
March 2018, 2018-03-00, 20180301, Letnik:
85, Številka:
2
Journal Article
Recenzirano
Apheresis has been used in the treatment of severe systemic vasculitides, in conjunction with immunosuppressive therapies, for over 40 years. The aim is to rapidly remove autoantibodies or ...circulating immune complexes from the plasma. The two main indications at present are vasculitis associated with Antineutrophil Cytoplasmic Antibodies (ANCAs) manifesting as severe renal involvement and/or intraalveolar hemorrhage and antiglomerular basement membrane disease (Goodpasture syndrome). The ongoing PEXIVAS randomized controlled trial is assessing plasmapheresis to treat ANCA-associated vasculitis with or without severe renal involvement or intraalveolar hemorrhage. The two main apheresis techniques used to treat systemic vasculitis are plasmapheresis (by filtration, centrifugation, or double filtration) and immunoadsorption. The advantages and drawbacks of each technique are discussed here. Whether one technique is superior over the other in the current indications has not been proven.
Background
Familial steroid-sensitive nephrotic syndrome (SSNS) is a rare condition. The disease pathophysiology remains elusive. However, bi-allelic mutations in the
EMP2
gene were identified, and ...specific variations in
HLA-DQA1
were linked to a high risk of developing the disease.
Methods
Clinical data were analyzed in 59 SSNS families.
EMP2
gene was sequenced in families with a potential autosomal recessive (AR) inheritance. Exome sequencing was performed in a subset of 13 families with potential AR inheritance. Two variations in
HLA-DQA1
were genotyped in the whole cohort.
Results
Transmission was compatible with an AR (
n
= 33) or autosomal dominant (AD,
n
= 26) inheritance, assuming that familial SSNS is a monogenic trait. Clinical features did not differ between AR and AD groups. All patients, including primary (
n
= 7) and secondary steroid resistant nephrotic syndrone (SRNS), (
n
= 13) were sensitive to additional immunosuppressive therapy. Both
HLA-DQA1
variations were found to be highly linked to the disease (OR = 4.34 and OR = 4.89;
p
< 0.001). Exome sequencing did not reveal any pathogenic mutation, neither did
EMP2
sequencing.
Conclusions
Taken together, these results highlight the clinical and genetic heterogeneity in familial SSNS. Clinical findings sustain an immune origin in all patients, whatever the initial steroid-sensitivity. The absence of a variant shared by two families and the
HLA-DQA1
variation enrichments suggest a complex mode of inheritance.
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.
Background
We report the results of an observational study of arteriovenous fistula (AVF) cannulation and haemostasis practices in France.
Methods
The study (sponsored by Brothier Pharmaceutical ...Inc.) was conducted in 150 dialysis units. Data obtained from 150 supervisory nurses, 1538 nurses and 3588 patients with an AVF were analysed.
Results
The nurses reported using rope-ladder, area or buttonhole cannulation techniques in 68, 26 and 6% of cases, respectively. Metal needles were used most frequently (64%), with mainly a diameter of 15 G or 16 G. The needle was introduced with the bevel up in 56% of cases. Compression applied using dressings (in particular, pure calcium alginate dressings) was the method of choice for haemostasis of the puncture sites and was assessed as being strong by most of the nurses and very strong in cases of prolonged bleeding. Most (82%) of the patients reported the use of local anaesthetic before cannulation and 23% reported an allergic skin reaction to the anaesthetic. Bleeding of the puncture sites lasted for >10 min for 48% of the patients and it reappeared between two sessions for 29% of the patients. Whereas the nurses appeared to have a good understanding of AVF, more than half of the patients did not know how to care for it, with 55% requiring more information.
Conclusions
This study underlines the lack of national consensus concerning AVF cannulation practices. It suggests that haemostasis methods of the puncture sites can be improved and it highlights the need to improve patient knowledge.
Standard treatment for lupus nephritis, including corticosteroids and cyclophosphamide, is efficient but is still associated with refractory or relapsing disease, or severe deleterious effects. ...Rituximab, a monoclonal chimeric anti-B cell antibody, is increasingly used in patients with lupus nephritis, but reported series were small and had a short follow-up.
The authors analyzed clinical and histologic data of 20 patients who were treated with rituximab for lupus nephritis and followed up for at least 12 mo.
Nineteen women and one man received rituximab as induction treatment for an active class IV (15 cases) or class V (5 cases) lupus nephritis. Rituximab was given for lupus nephritis refractory to standard treatment (12 cases), for relapsing disease (6 cases), or as first-line treatment (2 cases). Three patients received cyclophosphamide concomitantly with rituximab. Ten received new injections of rituximab as maintenance therapy. Side effects included mainly five infections and four moderate neutropenias. After a median follow-up of 22 mo, complete or partial renal remission was obtained in 12 patients (60%). Lupus nephritis relapsed in one patient, who responded to a new course of rituximab. The achievement of B cell depletion 1 mo after rituximab, which negatively correlated with black ethnicity and hypoalbuminemia, was strongly associated with renal response. Rapidly progressive glomerulonephritis did not respond to rituximab.
Rituximab is an interesting therapeutic option in relapsing or refractory lupus nephritis when early B cell depletion is obtained.
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.
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