-
[show abstract]
[hide abstract]
ABSTRACT: Evidence has accumulated that oxidative stress resulting from the increased generation of oxidants (reactive oxygen species and chlorinated oxidants) by activated phagocytes at the contact of dialysis membranes and dialysate endotoxins and from the uremia-related profound deficiency in antioxidants (glutathion system mainly) plays a prominent role in the pathogenesis of the accelerated atherosclerosis process which accounts for almost one half of deaths in dialysis patients. However more recent studies of large cohorts of uremic patients have shown that oxidative stress is already present at an early stage of chronic renal failure, increases with the progression of uremia and that phagocytic cells are elective targets of uremic toxins. Our recent studies aimed at better characterizing oxidative stress in dialysis patients have led to describe the presence in the plasma of uremic patients of AOPP (Advanced Oxidation Protein Products) which proved to be potential uremic toxins and mediators of inflammation. A better knowledge of the respective contribution of bioincompatibility and uremic toxins at the origin of phagocyte activation will allow to develop therapeutic strategies aimed at reducing the incidence of oxidative stress related complications and with AOPP as a gauge of their efficacy.
Néphrologie 02/2003; 24(7):377-9.
-
R Vanholder,
A Argilés,
U Baurmeister,
P Brunet,
W Clark,
G Cohen,
P P De Deyn,
R Deppisch, B Descamps-Latscha,
T Henle,
A Jorres,
Z A Massy,
M Rodriguez,
B Stegmayr,
P Stenvinkel,
M L Wratten
[show abstract]
[hide abstract]
ABSTRACT: The uremic syndrome is a complex mixture of organ dysfunctions, which is attributed to the retention of a myriad of compounds that under normal condition are excreted by the healthy kidneys (uremic toxins). In the area of identification and characterization of uremic toxins and in the knowledge of their pathophysiologic importance, major steps forward have been made during recent years. The present article is a review of several of these steps, especially in the area of information about the compounds that could play a role in the development of cardiovascular complications. It is written by those members of the Uremic Toxins Group, which has been created by the European Society for Artificial Organs (ESAO). Each of the 16 authors has written a state of the art in his/her major area of interest.
The International journal of artificial organs 11/2001; 24(10):695-725. · 1.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Uraemic bone disease is the result of a number of factors modulating bone formation and resorption in a complex manner. In the present study, the hypothesis tested was that the type of haemodialysis membrane used for renal replacement therapy might also play a role.
We conducted a prospective, open study in 24 chronic haemodialysis patients who were randomized to dialysis treatment with either cellulosic (CELL group, n=11) or polyacrylonitrile (AN-69 group, n=13) membrane for 9 months. Repeated determinations of plasma parameters reflecting bone turnover were done in all patients, and a bone biopsy in a subgroup at the start and end of study.
At the start, mean plasma intact parathyroid hormone levels were comparable between the two groups and they did not vary significantly at 9 months of treatment. Similarly, plasma bone-specific alkaline phosphatase and osteocalcin (markers of bone formation), and cross-laps (marker of bone resorption) remained unchanged. However, plasma insulin-like growth factor-I (IGF-I) progressively decreased from 169 to 119 ng/ml in AN-69 group (P<0.01), whereas it remained unchanged in CELL group. In addition, the levels of IGF binding protein (IGFBP)-1 and IGFBP-2 were increased while the levels of IGFBP-5 were decreased in AN-69 group. In the five patients of each group who had repeat bone biopsies, histomorphometric analysis showed a decrease in osteoblast surface, osteoclast surface and osteoclast number in AN-69 group at 9 months, compared with baseline values measured at the start of the study. In contrast, all three parameters significantly increased in the CELL group at 9 months (P<0.001 for the difference between each of the three parameters). Bone formation rate decreased by 31% in the AN-69 group, but increased by 50% in CELL group. However, this latter difference was not statistically significant. Plasma interleukin (IL)-6 and soluble IL-6 receptor levels did not change in the two groups of patients who had undergone bone biopsy.
Dialysis with CELL membrane was associated with increased bone turnover whereas the use of AN-69 membrane was associated with decreased bone turnover, suggesting a beneficial effect of the latter on high-turnover uraemic bone disease. However, as the number of patients with repeat bone biopsies was small, these findings need to be confirmed in a larger study. Further studies are also needed to evaluate whether or not the changes in IGF system components play a role in decreased bone cell activity in patients on dialysis using the AN-69 polyacrylonitrile membrane.
Nephrology Dialysis Transplantation 06/2001; 16(6):1230-8. · 3.40 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Moderate hyperhomocyst(e)inemia and impaired endothelium-dependent vasodilatation are present in uremic patients. However, the precise mechanism(s) underlying the link between moderate hyperhomocyst(e)inemia and endothelium dysfunction in uremic patients remains to be determined. Experimental and clinical evidence have led to the suggestion that moderate hyperhomocyst(e)inemia may predispose to endothelium dysfunction through a mechanism that involves generation of reactive oxygen species and a decrease in nitric oxide bioavailability. Recent preliminary findings in uremic patients provide support for some aspects of this suggestion. These data must be confirmed in additional studies. Moreover, the relative importance of homocysteine-induced oxidant stress versus other potential mechanisms of endothelium dysfunction in these patients remains to be determined.
Kidney international. Supplement 03/2001; 78:S243-5.
-
[show abstract]
[hide abstract]
ABSTRACT: Considerable evidence has accumulated that chronic uremia is associated with a multifactorial immunoinflammatory syndrome, which occurs early in the course of renal failure, is accentuated with the progression of uremia, and culminates in maintenance dialysis therapy. We previously described the presence of a circulating oxidized plasma protein named advanced oxidation protein products (AOPPs). Beyond evidence that AOPPs represent an exquisite marker of oxidative stress, their role(s) in the pathophysiology of chronic renal failure and dialysis-related complications might be of great importance. Regarding the mechanisms of generation of AOPP, we underscore the importance of the chlorinated oxidants, previously solely considered as microbicidal agents, in the generation of AOPP. Indeed, AOPPs appear to act as true inflammatory mediators since they are able to trigger the oxidative burst in neutrophils as well as in monocytes. Thus, it is hypothesized that the AOPPs, which arise from the reaction between chlorinated oxidants and plasma proteins, constitute a new molecular basis for the deleterious activity of oxidants, and they could be considered to be true mediators of the proinflammatory effect of oxidative stress in uremia.
Kidney international. Supplement 03/2001; 78:S108-13.
-
[show abstract]
[hide abstract]
ABSTRACT: Lipoprotein oxidation is involved in the genesis of atherosclerosis. In chronic renal failure (CRF), oxidative stress is enhanced because of an imbalance between pro-oxidant and antioxidant systems. Oxidative modifications of low-density lipoproteins (LDLs) occur not only at the level of lipid moiety, but also of protein moiety. We have shown that oxidation of LDL by hypochlorous acid (HOCl) in vitro, reflecting increased myeloperoxidase activity in vivo, leads to modifications of apoliproteins such that the latter in turn are capable of triggering macrophage nicotinamide adenine dinucleotide phosphate-oxidase activation. These oxidative changes of LDL protein moiety, if shown to occur to a significant extent in uremic patients in vivo, may represent an important alternative pathway in the pathogenesis of atheromatous lesions.
Kidney international. Supplement 03/2001; 78:S114-9.
-
Advances in nephrology from the Necker Hospital 02/2001; 31:153-71.
-
[show abstract]
[hide abstract]
ABSTRACT: Oxidized low-density lipoproteins (oxLDL) play a critical role in atherogenesis. We investigated the apoptotic process in human monocytic THP-1 cell line, exposed to oxLDL generated by treatment of native LDL either with hypochlorous acid (HOCl), mainly affecting the protein moiety, or with copper sulfate (CuSO(4)), mainly affecting the lipid moiety. After incubation with both types of oxLDL, we observed: (i) microscopy signs of apoptosis in THP-1 cells, (ii) a significant increase of apoptotic cells proportional to LDL protein concentration, either by annexin V or by cell cycle phase analysis with propodium iodide flow cytometry, (iii) a reduction of THP-1 cell apoptosis in presence of the caspase inhibitor Z-VAD.fmk, (iv) the resistance of THP-1 cells apoptosis after PMA-elicited differentiation. In conclusion, HOCl-oxLDL are as potent as Cu-oxLDL to induce high rates of apoptosis in monocytes through a caspase-dependent pathway. Moreover, the resistance of differentiated THP-1 cells to oxLDL-induced apoptosis is compatible with the hypothesis that mature macrophages have prolonged survival and thereby enhance the atherogenic process.
Biochemical and Biophysical Research Communications 08/2000; 273(3):948-54. · 2.48 Impact Factor
-
Laboratory Investigation 06/2000; 80(5):617-53. · 3.64 Impact Factor
-
Néphrologie 02/2000; 21(7):337-8.
-
[show abstract]
[hide abstract]
ABSTRACT: Dyslipidaemia is common in patients with chronic renal failure (CRF), and there is increasing evidence to support the role of dyslipidaemia as a contributing factor in the progression of chronic renal disease. However, few prospective studies have been carried out which address the possible relationship between dyslipidaemia and the rate of progression of renal disease in patients with renal failure.
Between January 1985 and December 1997, we prospectively assessed the risk of CRF progression to dialysis in a cohort of 138 patients. Forty CRF patients reached end-stage renal disease (ESRD) and had to start supportive therapy during the follow-up period [group ESRD(+)]. The remaining 98 CRF patients served as controls [group ESRD(-)]. Potential clinical and laboratory risk factors for more rapid CRF decline to dialysis, including lipid abnormalities and baseline creatinine clearance were determined at the start of the follow-up period.
Several significant differences were found in univariate analysis between the two groups of CRF, ESRD(+) and ESRD(-), namely a shorter follow-up period, a lower level of baseline creatinine clearance, a faster rate of creatinine clearance decline, a higher level of serum triglycerides, fibrinogen, total homocyst(e)ine and proteinuria, and a lower level of serum high-density lipoprotein in the ESRD(+) group than in the ESRD(-) group. However, by multivariate Cox analysis proteinuria [relative risk (95% confidence interval) 1.32 (1.16-1.50) for each g/day P = 0.001], baseline creatinine clearance [0.53 (0.40-0.70) for each 10 ml/min, P = 0.001] and chronic interstitial nephritis and hypertensive nephrosclerosis [0.38 (0.17-0.84) for presence, P = 0.005] were the only significant risk factors for CRF progression to dialysis. Hypertriglyceridaemia and male gender were selected in the final model, but were of borderline significance.
These results suggest a limited role for dyslipidaemia in the progression of chronic renal disease to dialysis in CRF patients, in contrast with the powerful influence of proteinuria, baseline creatinine clearance and nephropathy type in predicting this progression.
Nephrology Dialysis Transplantation 11/1999; 14(10):2392-7. · 3.40 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Oxidized low-density lipoproteins (oxLDL) play a crucial role in atherogenesis mainly via their capacity to bind and to activate macrophages. However, the role of the protein LDL moiety in this process is not yet established. In this study, human LDL were exposed to hypochlorous acid (HOCl), a selective protein oxidant, or copper sulfate (CuSO(4)), a major lipid oxidant, and tested for their capacity to activate the NADPH-oxidase of human THP-1- and U937-derived macrophages as measured by lucigenin chemiluminescence (CL). Compared to native LDL which had no effect, HOCl-oxLDL triggered potent CL responses in both U937 and THP-1 cells but only when these were fully differentiated into macrophages by phorbol myristate acetate. In contrast, Cu-oxLDL only triggered a moderate CL response of U937 cells and had little effect on THP-1 cells. While delipidation did not affect HOCl-oxLDL-induced CL response it abolished that induced by Cu-oxLDL. Interestingly, U937 cells showed higher CL responses to both types of oxLDL than THP-1 cells, a finding which could be related to their higher expression of the scavenger receptor CD36. Taken together these results strongly support the role of the protein moiety in oxLDL-induced macrophage activation.
Biochemical and Biophysical Research Communications 11/1999; 263(3):804-9. · 2.48 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We investigated whether the total peroxyl radical-trapping antioxidant potential (TRAP) assay, which has recently been proposed as a gauge of oxidative stress, could serve to evaluate plasma and low density lipoprotein (LDL) antioxidant state in hemodialysis (HD) patients.
TRAP was determined by the lag time of the chemiluminescence reaction induced by azo-initiator-catalyzed linoleic acid peroxidation in the plasma and corresponding LDL preparations of 23 HD patients and 22 healthy subjects. Antioxidant systems, including glutathione peroxidase (GSH-Px), ascorbate, vitamin E, and uric acid, oxidative stress markers including malondialdehyde (MDA), carbonyls, and advanced oxidation protein products (AOPP), and lipids, including cholesterol and triglycerides, were also determined in the plasma.
Both plasma and LDL-TRAP were significantly increased in HD patients despite decreased GSH-Px and ascorbate and increased MDA, carbonyl, and AOPP plasma levels. Plasma TRAP values were closely related to both uric acid and AOPP levels, and LDL-TRAP values were related to triglycerides and AOPP levels. In vitro studies showed that: (a) plasma TRAP of control plasma increased regularly with supplementation of uric acid, although not reaching that of HD plasma with similar uric acid levels; (b) the addition of human serum albumin-AOPP also regularly increased control plasma TRAP, but was close to that of HD plasma with similar AOPP levels; and (c) LDL-TRAP was increased following LDL enrichment with triglycerides.
Our study demonstrates that TRAP is not a relevant parameter for evaluating plasma or LDL antioxidant capacity in HD patients, due to the high plasma levels of uric acid, triglycerides and AOPP, which by themselves do not exert efficient antioxidant activity in vivo, but in vitro are able to scavenge the peroxyl radicals involved in the TRAP assay.
Kidney International 09/1999; 56(2):747-53. · 6.61 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We evaluated the roles of proteinase 3 (PR3) and human neutrophil elastase (HNE), two neutrophil serine proteinases in the mechanisms leading to airway inflammation and hypersecretion in cystic fibrosis (CF). Using specific enzyme-linked immunosorbent assay (ELISA), we found higher levels of PR3 than HNE in sputum from CF patients. Using two inhibitors, ICI (Imperial Chemical Industries) 200,355 (which inhibits both HNE and PR3) and secretory leukoproteinase inhibitor (SLPI) (which inhibits only HNE), we showed that PR3 was enzymatically active in sputum, and its activity, as assessed by SLPI-resistant serine proteinase activity, correlated highly with its antigenic concentration measured by ELISA. Interestingly, sputum pellet-associated serine proteinase activity was mostly due to HNE. PR3 purified from neutrophil azurophil granules triggered airway gland secretion, as measured by the release of radiolabeled molecules from cultured bovine tracheal serous cells pulse-labeled with Na235SO4. This secretory activity was inhibited by ICI 200,355. PR3 concentration in CF sputum was highly correlated with taurine concentration, a reliable marker of airway inflammation and respiratory scores (e.g., FEV1%), whereas no significant correlation was observed with HNE. We verified that Pseudomonas aeruginosa proteinases did not interfere with the assessment of PR3 and HNE. Indeed, the PR3/HNE ratio was greatest in patients chronically infected by P. aeruginosa. We suggest that PR3 may play a role in the hypersecretory process that is characteristic of CF.
American Journal of Respiratory Cell and Molecular Biology 05/1999; 20(4):729-36. · 5.13 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: An abnormally high mortality from atherosclerotic cardiovascular (CV) accidents has long been reported in patients on maintenance haemodialysis (HD). However, incidence of atherosclerotic CV accidents had not been so far assessed in predialysis patients. In order to evaluate the respective influence of uraemia and the dialysis procedure, we compared incidence of atherosclerotic accidents before and after initiation of HD in a large population of patients.
A total of 748 patients (411 male) were included in a retrospective study based on anamnestic data of patients living on maintenance haemodialysis in March 1993 in nine dialysis units of the Paris area. Incidence of first myocardial infarction (MI) or cerebral infarction (CI) was calculated by reference to the number of years of exposure to the risk both before and after initiation of HD in the various age groups.
Overall, 103 first atherosclerotic accidents were recorded, including 10 CI (7 in males) and 93 MI (68 in males). Of the latter, 39 occurred before and 54 after start of HD, at a mean (+/-SD) age of 62.4+/-9.9 and 63.7+/-11.1 years respectively. The annual incidence of MI in males was 8.0, 19.5 and 28.3/1000 patient-years, before and 18.8, 21.6 and 29.9 patient-years after start of HD in the age groups 45-54.9, 55-64.9 and > or = 65 years respectively, compared to figures of 3.4, 7.5 and 10.4/1000 subject-years in the corresponding age groups in the general French population.
Incidence of atherosclerotic CV accidents is nearly three times higher in uraemic patients than in the general population in the same age range in both genders. The fact that incidence and age at onset of first MI was similar in predialysis and in dialysed patients suggests that the uraemic state per se is a main determinant of such accelerated atherosclerosis.
Nephrology Dialysis Transplantation 04/1999; 14(4):898-902. · 3.40 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The aim of this hypothesis is to provide new insights into the still unclear mechanisms governing airway inflammation in cystic fibrosis. Although the genetic basis of cystic fibrosis as well as the molecular structure of cystic fibrosis transmembrane regulator (CFTR), the mutated protein which causes the disease, have been well defined, a clear relationship between the genetic defect and the pulmonary pathophysiology, especially chronic infections and neutrophil-dominated airway inflammation has not been established. Cystic fibrosis is thus a unique pathological situation in that neutrophils can be depicted as both an antiinfectious and a proinflammatory cell. In cystic fibrosis there is an emerging picture of an imbalance between these two roles with both a reduction in the antiinfectious efficacy and an augmentation of the proinflammatory functions. Better knowledge of fundamental defects in neutrophil function in cystic fibrosis as well as a novel cellular function of CFTR, which will be reviewed, will allow identification of potentially new clinical targets and aid selective therapeutic action aimed at counteracting the lethal neutrophil-induced airway inflammation. The rationale for colchicine therapy is a significant example of a drug which might act both at the molecular levels on CFTR expression in epithelial cells and on neutrophils to mediate antiinflammatory effects. Preliminary results are presented in this issue (Med Inflamm 1999; 8: 13-15).
Mediators of Inflammation 02/1999; 8(1):7-11. · 3.26 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Cystic fibrosis (CF) lung disease is characterized by persistent inflammation. Antiinflammatory drugs, such as corticosteroids and ibuprofen, have proved to slow the decline of pulmonary function although their use is limited because of frequent adverse events. We hypothesized that colchicine could be an alternative treatment because of its antiinflammatory properties and upregulatory effect on cystic fibrosis transmembrane regulator (CFTR) closely related proteins. We herein present results obtained in an open study of eight CF children treated with colchicine for at least 6 months. Clinical status was better in all patients and respiratory function tests significantly improved in five. Median duration of antibiotherapy decreased significantly. These preliminary results support our hypothesis of a beneficial effect of colchicine in CF patients and stress the need for a controlled therapeutic trial.
Mediators of Inflammation 02/1999; 8(1):13-5. · 3.26 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Blood phagocyte opsonin receptor CR1 (CD35) and CR3 (CD11b) functions were examined in cystic fibrosis (CF) patients with endobronchial Staphylococcus aureus or Pseudomonas aeruginosa chronic infection, CF patients without infection, heterozygous, non-CF patients with chronic pulmonary infection, and healthy controls. Circulating and platelet-activating factor (PAF)-primed phagocyte luminol luminescence responses to complement-opsonized zymosan were increased in both groups of infected CF and non-CF children relative to uninfected CF children and healthy control children and adults. The ratio between circulating and PAF-primed phagocyte responses was significantly elevated in all children with CF, and in these, the ratio could serve as an indicator of response to antibiotic treatment. The ratios of circulating and PAF-primed phenotypic expression for CR1, CR3, and FcgammaRIII (CD16), but not FcgammaRII (CD32), correlated with the functional ratios. Phagocyte opsonin receptor response capacity might be used for evaluation of inflammation and infection in CF patients.
The Journal of Infectious Diseases 02/1999; 179(1):151-62. · 6.41 Impact Factor
-
Nephrology Dialysis Transplantation 02/1999; 14 Suppl 1:76-8. · 3.40 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We previously demonstrated the presence of advanced oxidation protein products (AOPP), a novel marker of oxidative stress in the plasma of uremic patients receiving maintenance dialysis. The present study in a cohort of 162 uremic patients showed that plasma concentrations of AOPP increased with progression of chronic renal failure and were closely related to advanced glycation end products (AGE)-pentosidine (r = 0.52, p < 0.001), taken as a marker of AGE. In vivo, the relevance of AOPP and AGE-pentosidine in monocyte-mediated inflammatory syndrome associated with uremia was evidenced by close correlations between AOPP or AGE-pentosidine and monocyte activation markers, including neopterin, IL-1R antagonist, TNF-alpha, and TNF soluble receptors (TNF-sR55 and TNF-sR75). To determine the mechanisms by which AOPP and AGE could be directly involved in monocyte activation, AOPP-human serum albumin (HSA) and AGE-HSA were produced in vitro by treating HSA with oxidants or glucose, respectively. Spectroscopic analysis confirmed that AOPP-HSA contains carbonyls and dityrosine. Both AOPP-HSA and AGE-HSA, but not purified dityrosine, were capable of triggering the oxidative burst of human monocytes in cultures. The AOPP-HSA-induced respiratory burst was dependent on the chlorinated nature of the oxidant and on the molar ratio HSA/HOCI. Collectively, these data first demonstrate that AOPP act as a mediator of oxidative stress and monocyte respiratory burst, which points to monocytes as both target and actor in the immune dysregulation associated with chronic uremia.
The Journal of Immunology 10/1998; 161(5):2524-32. · 5.79 Impact Factor
