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Aims: The aim of our study was to demonstrate the efficacy of ultrasound-guidance compared with computed tomography (CT) guidance for coeliac plexus block in cancer patients., Methods: Coeliac plexus block (30 ml ethanol) was performed in 34 cancer patients (sex ratio: 10F, 24M), mean age: 54.8 years (range 26-67) under CT (n=21) and ultrasound-guidance (n=13). All patients had excruciating epigastric and generalized abdominal pain caused by cancer of the pancreas (n=13) or upper abdominal viscera (n=9) or a malignancy of extra-digestive origin (n=12). Feasibility and complication rates were analysed., Results: Notable pain relief was obtained in 27 (79%) of the patients. The technical success rate was 100% for CT-guidance and 93% (13/14) for ultrasound guidance. There were six minor complications (17%): chemical peritonitis (n=2), orthostatic arterial hypotension (n=2) and transient left shoulder pain (n=2), no major complications occurred. The target route was transhepatic in 6/13 of the ultrasound cases and mean length was 6 cm (range 3-12 cm). Colour Doppler sonography improved visualization of the 21 Gauge Chiba needle when the needle shaft was vibrated. Echogenic foci were observed around the origin of the coeliac trunk and superior mesenteric artery in all cases. CT coeliac block was successfully performed after failure of ultrasound guidance in one patient., Conclusion: Ultrasound guidance is safe and effective and should be attempted for coeliac plexus block whenever possible., (Copyright Harcourt Publishers Limited.)

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.

Background: 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., Methods: 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., Results: 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., Conclusion: 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.

Oxidative stress, which results from a rupture in the natural balance between pro- and antioxidant systems, is considered as a major factor in dialysis-associated morbidity and mortality. Emerging pharmacologic and dialytic antioxidant therapeutic and dialysis strategies should enable us to reduce the harmful consequences of oxidative stress in dialysis patients. Moreover, since there is increasing evidence of oxidative stress long before the initiation of maintenance dialysis, antioxidant therapeutic strategies should probably be developed very early in the course of renal failure.

No therapy is currently available for patients with recurrent vascular obstruction of the superior vena cava (SVC) caused by tumor regrowth after chemotherapy or radiation therapy. Intravascular stenting is a new option for the treatment of vena cava syndrome. Forty cancer patients with SVC syndrome (SVCS) were evaluated by computed tomography (CT) and venography. The SVC or its tributaries were stenosed or thrombosed in all patients. The etiology was malignant in all but 2 cases: non-small-cell lung carcinoma (n = 28), mediastinal nodal metastasis (n = 5), lymphoma (n = 2), pleural mesothelioma (n = 2), small-cell lung carcinoma (n = 1), and postradiation fibrous mediastinitis (n = 2). Stenting was achieved in 39 of the 40 patients, and clinical symptoms subsided in 92%. Stents remained patent in 36 of these 39 patients throughout a mean follow-up of 24 weeks (range 3 days to 24 months). SVC stenting is safe, effective and allows rapid cure of SVCS and port catheter implantation in patients in poor health.

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.

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.

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.

The aim of this retrospective study was to prove the effectiveness of percutaneous cementoplasty in pelvic bone metastases. We studied the data entered in a multicenter prospective database on 18 cancer patients (average age 58 years) who underwent percutaneous computed tomography (CT) or fluoroscopy-guided cementoplasty from September 1996 to September 1998. The metastatic sites were: acetabulum (n = 12), iliac bone (n = 2), and sacrum (n = 4). Indications were pain recurrence (n = 9) or no relief (n = 3) after radiotherapy, and 6 procedures were performed before radiation. Mean follow-up was 4.6 months, ranging from 11 days up to 24 months. Improvement in pain and walking was obtained in 81.8% cases, and it was generally maintained, except in 1 patient who experienced pain again at day 15 because of an acetabular fracture. Percutaneous cementoplasty is a safe and efficient technique, and is mandatory when radiotherapy fails or when rapid resolution of pain is requested.

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., (Copyright 2000 Academic Press.)

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., (Copyright 1999 Academic Press.)

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

Background: 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., Methods: 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., Results: 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., Conclusion: 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.

Background: 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., Study Design: 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., Results: 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., Conclusion: 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.

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.

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.

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 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).

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.

Background: Accelerated atherosclerosis resulting in an abnormally high incidence of coronary and cerebrovascular occlusive accidents has been repeatedly reported in dialysis patients, but incidence and risk factors of such complications in chronic renal failure (CRF) predialysis patients are debated., Methods: We prospectively assessed the incidence of first myocardial and cerebral infarction episodes in a cohort of 147 CRF patients (99 male) followed from January 1985 to December 1994. Relevant clinical and laboratory risk factors for atherogenesis were determined at yearly intervals. They included blood pressure, smoking, blood lipids, fibrinogen, and homocysteine which were compared in patients with (CVA+) or without (CVA-) occurrence of cardiovascular (CV) atherosclerotic accidents., Results: Incidence of CV accidents was nearly three times higher in CRF patients than in the French general population in both genders. In particular, incidence of myocardial infarction in male patients aged 45-55, 55-65 and > 65 years was 7.6, 18.2, and 27.8/1000 patient-years, respectively, compared to 3.4, 8.9, and 10.4/1000 subject-years in the general population. Although age and degree of renal failure at onset of CV events or at end of follow-up did not differ between CVA+ and CVA- groups, cigarette smoking (24.5 [SD 24.3] vs 8.2 [14.7] pack-years, P < 0.0001) and systolic blood pressure (159 [19] vs 148 [19] mmHg, P < 0.001) were markedly higher in CVA+ patients. Similarly, mean plasma HDL-cholesterol was lower, whereas LDL-cholesterol, triglycerides, apoB, Lp(a), fibrinogen, and homocysteine levels all were significantly higher in CVA+ than in CVA- patients. Multivariate Cox analysis identified cigarette smoking, systolic pressure, HDL cholesterol, and fibrinogen as independent risk factors for developing CV accidents., Conclusions: Incidence of atherosclerotic CV complications is abnormally high in predialysis CRF patients, suggesting that the uraemic state per se is associated with atherogenesis. As several of the identified clinical and metabolic risk factors for such accidents are potentially remediable by specific therapeutic interventions, prophylactic measures should be initiated long before start of renal replacement therapy.

Hyperhomocysteinemia has been shown to constitute an independent risk factor for premature occlusive arterial disease. Moderate hyperhomocysteinemia is present in chronic uremic patients, who often develop premature atherosclerosis, but no direct evidence of an association between the occurrence of atherosclerotic cardiovascular accidents (CVAs) and hyperhomocysteinemia has yet been reported in such patients. We serially determined total plasma homocysteine (Hcy) levels in a cohort of 93 consecutive chronic renal failure, undialyzed patients (57 males, 36 females) with creatinine clearance (Ccr) < 50 ml/min.1.73 m2 and age > or = 50 years at start of follow-up, together with serial assessment of Ccr and blood lipid parameters. From January 1989 to December 1995, 24 patients (group 1) experienced myocardial infarction (18 cases, 13 males) or cerebral infarction (6 cases, 3 males) while the remaining 69 (group 2) remained free of CVAs. Patients in groups 1 and 2 did not differ with respect to age (66 +/- 1.8 vs. 65 +/- 1.1 years, mean +/- Se) or serum creatinine (227 +/- 24 vs. 251 +/- 36 mumol/l) at onset of a CVA (group 1) or at the end of follow-up (group 2). The mean Hcy level was significantly higher in group 1 (20.7 +/- 1.6 vs. 12.8 +/- 0.5 mumol/l, p < 0.0001), as was the proportion of patients with Hcy in excess of 14 mumol/l, the upper limit in healthy controls (83 vs. 30%, p < 0.0001). Logistic regression analysis identified Hcy as an independent risk factor for CVA, with an odds ratio of 11.4 (95% confidence interval 3.5-37.7), which remained significant after adjustment on other variables. We conclude that an elevated Hcy level is associated with a risk of occlusive arterial accidents in patients with chronic renal failure and that hyperhomocysteinemia contributes to the accelerated atherosclerosis complicating chronic uremia.

The present study addresses the question of a possible linkage between the cystic fibrosis (CF) genetic autosomal recessive disorder and disturbance in neutrophil function. Neutrophil-dominated chronic airway inflammation is present at an early age in children with CF, even in the absence of detectable infection. As evidenced by extracellular superoxide anion release (measured by lucigenin luminescence) or intracellular hydrogen peroxide production (measured by 2',7'-dichlorofluorescein (DCF) fluorescence), no significant difference in the nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity of isolated neutrophils was observed in noninfected CF children (homozygotes), their mothers or fathers (CF heterozygotes), and controls. In contrast, both myeloperoxidase (MPO)-dependent oxygenation activity (measured by luminol luminescence) and chloramine release were increased significantly in both CF homozygotes and heterozygotes as compared with controls. In the presence of either amiloride (a sodium channel inhibitor and sodium/proton antiport blocker) or EIPA (5-ethyl-N-isopropyl-amiloride, a specific inhibitor of the antiport), or choline buffer, intracellular MPO activity was decreased significantly in controls and in the CF homozygotes and heterozygotes, thus bringing intracellular MPO-dependent activity in CF subjects back to the level of controls. Extracellular release of MPO, measured by an ELISA to provide an activity-independent assessment of the enzyme, was increased only in CF homozygotes, and was decreased by amiloride and choline buffer, but not by EIPA. We conclude that a modification of intracellular pH and/or ionic concentrations may be related to the altered MPO enzymatic activity observed in CF neutrophils.

Reflux nephropathy is one of the most prevalent renal diseases and a leading cause of chronic renal failure in women-of childbearing age. To evaluate the issue and possible complications of pregnancy in women with reflux nephropathy, we retrospectively analyzed fetal and maternal outcome in 158 women who had 375 pregnancies between 1965 and 1994. The overall fetal death rate was 10.2% and tended to decrease in the 1985 to 1994 decade as compared to the preceding period (8.4% vs. 12.6%). The relative risk of fetal death was 4.8 times greater hypertension was present at conception than in normotensive patients. Fetal death rate was also higher in patients with impaired renal function that in those with serum creatinine < 0.11 mmol/liter at conception (36.7% vs. 7.7%, P < 0.0001). Urinary tract infection accounted for frequent morbidity but seldom resulted in fetal mortality. Maternal renal disease was unaffected by pregnancy, excepted for 4 of the 21 patients with pre-existing renal failure who exhibited an irreversibly accelerated course after pregnancy. We conclude that pregnancy is essentially successful and uneventful in patients diagnosed with reflux nephropathy who have normal blood pressure and preserved renal function, whereas the fetal prognosis is more compromised and there is a risk of accelerated progression of maternal renal disease when serum creatinine concentration is in excess of 0.22 mmol/ liter. This suggests that women with reflux nephropathy should preferably conceive before having reached that stage of renal failure.

Objective: To determine the age- and gender-related incidence of chronic renal failure in a French urban area., Methods: Prospective study of adult patients newly identified as having established, chronic renal failure defined by serum creatinine (Scr) > or = 200 mumol/l, with the cooperation of all nephrology and dialysis units in the Ile de France district (10,660,000 inhabitants) during a 1-year period., Results: 2775 patients (1780 males, 995 females) were referred with Scr > or = 200 mumol/l between July 1991 and June 1992, an overall incidence of 260/million population. 847 had advanced renal failure (Scr > or = 500 mumol/l) and 541 patients (19.5%) were > or = 75 years of age. The age-related incidence was 92, 264, 523 and 619/million population in the age groups 20-39, 40-59, 60-74 and > or = 75 years old, respectively. The annual incidence was twice as high in males than in females up to 75 years and three times as high in patients > or = 75 years (1124 vs 356/million population). Based on the proportion of patients reaching end-stage renal failure within one year of referral, the minimal estimation of the need for supportive therapy is 81/million/year., Conclusions: This epidemiological study in a large French urban area indicates an incidence of 260 patients per million population annually referred to nephrology units for chronic renal failure defined by Scr > or = 200 mumol/l, with a marked preponderance of males and a dramatic increase of incidence with age in both genders.

Rationale: Advanced glycation endproducts (AGEs) contribute to the pathogenesis of vascular complications in diabetes, aging and end-stage renal disease (ESRD). Immune abnormalities in patients with chronic renal failure and those treated by dialysis contribute to high rates of morbidity and mortality. We therefore sought a relationship between a circulating marker of immune dysfunction and plasma levels of the AGE pentosidine., Method: We studied non-diabetic patients with mild to advanced renal failure (n = 60), and with ESRD treated by hemodialysis (HD) (n = 44) and peritoneal dialysis (PD) (n = 19). The plasma protein content of the well characterized AGE, pentosidine was measured using HPLC. In the same samples the monocyte activation product neopterin was measured by RIA., Results: Plasma levels of pentosidine and neopterin increased in parallel with the progression of renal failure. Pentosidine and neopterin were highly correlated in all patients even after adjustment for Ccr. This correlation was also present in patients with ESRD., Conclusion: These data suggest that the AGE pentosidine is associated with monocyte activation in renal failure, an interaction which may contribute to accelerated rates of complication and death by as yet unknown mechanisms.

Evidence suggests an imbalance between antioxidant and oxidant-generating systems resulting in oxidative stress in uremic patients. As plasma proteins are critical targets for oxidants, we developed a novel spectrophotometric assay which allows to detect advanced oxidation protein products (AOPP) in uremic plasma. By size-exclusion chromatography AOPP are retrieved in two distinct peaks at 600 and below 80 kDa in uremic plasma, while no such peaks are found in control plasma. Further biochemical characterization revealed that AOPP are carried by oxidized plasma proteins, especially albumin and do not have oxidant properties. AOPP increased in a dose-dependent manner following in vitro exposure of plasma or purified human serum albumin (HSA) to hypochlorous acid. Advanced glycation end products of human serum albumin (AGE-HSA) also increased AOPP levels. In vivo, plasma level of AOPP was the highest in patients on hemodialysis, followed by those on peritoneal dialysis and by undialyzed patients with advanced chronic renal failure. AOPP levels correlated with plasma concentrations of dityrosine and AGE-pentosidine, as indices of oxidant-mediated protein damage, but not with thiobarbituric reactive substances as lipid peroxidation markers. A close correlation was also found between AOPP and neopterin levels, suggesting that AOPP could be part in the monocyte-mediated inflammatory disorders associated with uremia. In conclusion, we propose the measurement of AOPP as a reliable marker to estimate the degree of oxidant-mediated protein damage in uremic patients and to predict the potential efficacy of therapeutic strategies aimed at reducing such an oxidative stress.

Recent knowledge into the pathophysiological mechanisms mediating the immune abnormalities characteristic of end-stage renal disease (ESRD) has focused on the dual activation versus deficiency state of immunocompetent cells. Despite major advances in renal replacement therapy, notably hemodialysis, no significant improvement in the immune status of uremic patients has been achieved. After a brief review of the role of T cells and B cells in the normal immune response, the functional and phenotypic T and B cell abnormalities observed in uremic patients are presented. Special emphasis is placed on our recent findings indicating that these abnormalities are observed at an early stage in the course of chronic renal failure, worsen with the progression of uremia, and are exacerbated by the dialysis procedure. The previous hypotheses that could reconcile the so-called Janus-faced behavior of T cells in uremia are updated in light of the recent findings obtained in the search of therapeutic strategies that could counteract the impaired responsiveness of patients with ESRD to vaccination against hepatitis B virus. Perspectives of research aimed at elucidating the respective role of T helper cell subpopulations (Th1 and Th2) could contribute to understanding of the mechanisms of the multifaceted process of uremia-related immune dysregulation and of the rationale for possible immunointervention strategies.

Using the baculovirus/insect cells system, we have expressed a recombinant proteinase 3 (PR3) -- the neutrophil-derived serine protease autoantigen in Wegener's granulomatosis -- as a glycosylated intracellular and membrane-associated protein. Oligosaccharides accounted for the difference in molecular weights between recombinant (34 kDa) and neutrophil-PR3 (29 kDa). Whereas rabbit-anti-PR3 IgG recognized both recombinant and neutrophil-derived PR3, autoantibodies from Wegener patient sera recognized only neutrophil-derived PR3. Although oligosaccharides were not involved in PR3 epitope recognition, autoantibodies did not recognize the amino acid primary structure of recombinant PR3. Improper disulfide bond formation and/or lack of post-translational events in insect cells, may affect the conformation and/or lack of post-translational events in insect cells, may affect the conformation of PR3, precluding its reactivity with sera from WG patients.

A profound imbalance between oxidants and antioxidants has been suggested in uremic patients on maintenance hemodialysis. However, the respective influence of uremia and dialysis procedure has not been evaluated. Circulating levels of copper-zinc superoxide dismutase (CuZn SOD), glutathione peroxidase (GSH-Px), and reductase (GSSG-Rd), total GSH and GSSG were determined in a large cohort of 233 uremic patients including 185 undialyzed patients with mild to severe chronic renal failure, and 48 patients treated by peritoneal dialysis or hemodialysis. Compared to controls, erythrocyte GSH-Px and GSSG-Rd activities were significantly increased at the mild stage of chronic uremia (p < .001), whereas erythrocyte CuZn SOD activity was unchanged, total level of GSH and plasma GSH-Px activity were significantly decreased, and GSSG level and GSSG-Rd activity were unchanged. Positive Spearman rank correlations were observed between creatinine clearance and plasma levels of GSH-Px (r = .65, p < .001), selenium (r = .47, p < .001), and GSH (r = .41, p < .001). Alterations in antioxidant systems gradually increased with the degree of renal failure, further rose in patients on peritoneal dialysis and culminated in hemodialysis patients in whom an almost complete abolishment of GSH-Px activity was observed. In conclusion, such disturbances in antioxidant systems that occur from the early stage of chronic uremia and are exacerbated by dialysis provide additional evidence for a resulting oxidative stress that could contribute to the development of accelerated atherosclerosis and other long-term complications in uremic patients.

We evaluated long-lived oxidant potential in the sputum of patients with cystic fibrosis (CF) by quantitating the methionine-inhibitable, long-lived oxidant fraction of sputum, referred to as the chloramines. Taurine, the preferred amino acid substrate for chloramine formation, and myeloperoxidase (MPO), the chlorinated oxidant-generating enzyme, were also quantitated. As compared with the sputum of asthmatic subjects, the sputum of CF patients contained high concentrations of chloramines along with high levels of taurine and active MPO. A negative correlation between chloramine and taurine was found in the sputum of CF patients. No correlation was found between the density of Pseudomonas aeruginosa and the level of chloramines, taurine, or MPO. In contrast, respiratory parameters (%FEV or %FVC) and a nutritional index correlated positively with chloramine levels, whereas negative correlations were observed with taurine and MPO. In addition, the effect of antibiotic therapy, which significantly increased chloramine and decreased taurine levels, supported a beneficial effect of chloramines on overall clinical status. Our findings support a dual role of long-lived oxidants at the site of airway inflammation in CF, one component of which is their ability to mediate oxidative stress and the other a beneficial effect that may be partly explained by their inhibitory effect on antiprotease defense systems.

According to some nephrologists, pregnancy has damaging effects on renal function in primary glomerulonephritis, but the evidence is conflicting. We evaluated the effect of pregnancy on the occurrence of end-stage renal failure (ESRF) in 360 patients with various histological forms of primary glomerulonephritis but with normal renal function (serum creatinine < or = 0.11 mmol/L) at presentation. In actuarial analyses, overall ESRF-free survival did not significantly differ between women who became pregnant after clinical onset of renal disease (n = 171) and those who did not conceive (n = 189). Furthermore, in a case-control study pregnancy did not emerge as a risk factor for progression to ESRF (odds ratio 1.15 [95% CI 0.61-2.18]), whereas the type of glomerulonephritis and hypertension were major determinants. We conclude that pregnancy does not affect the course of renal disease in patients who have normal renal function at conception.

Interaction of HIV with cultured human monocytes triggers not only cytokine production but also the release of natural cytokine inhibitors such as the soluble TNF receptors, levels of which are increased in the circulation of HIV-infected patients. We found that HIV-1 LAI induced the production by human monocytes from HIV-seronegative donors of another type cytokine inhibitor, the IL-1Ra receptor antagonist (IL-1Ra). HIV mainly induced the secreted form (83%) of IL-1Ra through de novo mRNA synthesis. IL-1Ra production was triggered at an early step of the infection process and involved the HIV envelope protein and the CD4 receptor. HIV-triggered IL-1Ra production occurred after a lag time, suggesting an indirect mechanism. Neutralizing Abs to IL-1 beta and IL-10 had no effect, while simultaneous treatment with anti-TNF-alpha, anti-granulocyte-macrophage CSF, and anti-TGF-beta nearly abrogated IL-1Ra release, supporting an indirect induction through the concerted action of the co-produced cytokines. IL-1Ra was induced by HIV in a mean 1,000-fold increase over IL-1 alpha beta, a ratio 20-fold higher than that obtained with LPS. This production masked 80% of IL-1 bioactivity in HIV-induced monocyte supernatants. These results suggest that the net balance between pro-inflammatory cytokines and their natural inhibitors could be critical in the control of the inflammatory process associated with HIV infection.

Background: Pulmonary aspergillosis is now the main cause of death in chronic granulomatous disease (CGD); it may occur before the age of one year and then often reveals CGD., Case Report: A male newborn was referred to hospital at 27 days of age for fever (39 degrees C), hemodynamic failure and biological inflammation syndrome caused by pulmonary infection. Chest CT scan revealed multiple and bilateral intraparenchymatous nodules. An open lung biopsy showed histiocystic granuloma with multinucleated giant cells. Culture of tracheal, bronchoalveolar lavage samples and lung biopsy grew positive for Aspergillus fumigatus. Impaired chemiluminescence production by neutrophils was detected, enabling the diagnosis of CGD. It was later confirmed by the study of neutrophils functions. The child recovered after 12 months of parenteral amphotericin B therapy., Conclusion: A febrile multifocal pneumopathy occurring in infancy should lead to consider the possibility of CGD which may be confirmed by the chemiluminescence test.

Administration of monoclonal antibodies to CD3 triggers acute and massive release of several cytokines, including tumor necrosis factor alpha (TNF-alpha), essentially T cell-derived. This cytokine release is responsible for the spontaneously reversible acute clinical syndrome observed in most OKT3-treated patients. We found that the first OKT3 injection in human renal allograft recipients led to the release in significant amounts of soluble TNF receptors (TNF-sR55 and TNF-sR75) that are considered main natural inhibitors of TNF bioactivity. As for OKT3-induced TNF-alpha, peak TNF-sR levels were observed 1 hr postinjection, and this release was limited to the first monoclonal antibody injection. A distinct regulation of OKT3-mediated release of TNF-sR75 and TNF-sR55 was observed, since (1) in clear contrast with OKT3-mediated TNF-sR75 induction, TNF-sR55 release was completely blocked by a high dose of corticosteroids prior to OKT3 injection and (2) secretion of TNF-sR75 but not TNF-sR55 correlated with immunoreactive TNF-alpha release. In hemodialyzed patients prior to transplantation and OKT3 treatment, a condition characterized by chronic TNF-alpha release, TNF-sR efficiently block TNF bioactivity. In contrast, the system is overwhelmed by the massive acute TNF-alpha release that follows the first OKT3 injection: in such a condition TNF-sR looses its capacity to counteract TNF bioactivity.

Concomitant immune deficiency and activation of immuno-competent cells, together with a disequilibrium between inflammation-inducing cytokines and their specific natural inhibitors is the basis of our current understanding of immune system dysregulation in patients with chronic uraemia. These anomalies may even be accentuated by dialysis. Clinically, bacterial infections, viral hepatitis and amyloidosis all play important roles. Humoral factors include abnormal immunoglobulin response to specific antibodies and complement activation. The response of T lymphocytes, long sought as the origin of the immunodeficiency associated with chronic uraemia, is also significantly decreased in these patients. The decreased antibody responses to specific stimuli may be related to B cell dysfunction. Monocyte and polymorphonuclear cell reactions are also perturbed. A deficiency in natural killer cells is observed although the mechanisms involved and the consequences are still debated. The factors determining the anomalies leading to immune system dysregulation in chronic uraemia and dialysis and their relationship with the reduction in active nephron mass as well as their metabolic and/or endocrine consequences remain to be fully described. A better understanding of the mechanisms involved should lead to new strategies for immuno-intervention in patients with chronic renal failure and help in optimizing haemodialysis.

Patients with end-stage renal disease present an immunodeficiency that paradoxically coexists with activation of most immunocompetent cells, and the roles of chronic uremia and maintenance dialysis are poorly understood. We determined circulating levels of IL-1 beta and IL-1Ra, TNF-alpha and its soluble receptors (TNF-sR55 and TNF-sR75), and activation markers of T cells (soluble CD25), B cells (soluble CD23), and monocytes (neopterin) in a large cohort of undialyzed patients at various stages of chronic renal failure and in dialyzed patients on maintenance hemodialysis or chronic peritoneal dialysis. The progression of uremia was associated with a gradual increase in soluble CD25, CD23, and especially neopterin levels. Although IL-1 beta could not be detected, IL-1Ra levels were significantly increased from the earliest stage of renal failure. Plasma levels of TNF-alpha, TNF-sR55, and TNF-sR75 progressed with the severity of renal failure and correlated with soluble CD25, CD23, and neopterin levels, whereas IL-1Ra levels correlated exclusively with TNF-sR55 levels. Compared with undialyzed patients, levels of IL-1 beta were higher in patients on maintenance hemodialysis, whereas those of IL-1Ra were lower and decreased further at the end of dialysis sessions. In contrast, both TNF-sR55 and TNF-sR75 levels were significantly higher than in undialyzed patients and increased further at the end of dialysis sessions in the absence of an increase of TNF-alpha. Such an imbalance between cytokines and their inhibitors may play a pivotal role in the multifaceted process of immune dysfunction.

Background: The respective contribution of the type of nephropathy, gender, and proteinuria, and of the potentially alterable factors blood pressure level and daily protein intake on the rate of progression in non-diabetic renal diseases is debated., Methods: We retrospectively analysed the influence of primary renal disease, gender, urinary protein excretion, mean arterial pressure (MAP), and dietary protein intake on the rate of decline in creatinine clearance (delta Ccr) in 159 adult patients with well-defined nondiabetic kidney diseases. All patients had been followed from a baseline Crr of 40-50 ml/min/1.73 m2 until endstage renal disease and need for dialysis., Results: Mean (+/- SD) delta Ccr (ml/min/1.73 m2/year) was 9.9 +/- 6.5 in 51 patients (45 males) with chronic glomerulonephritis, 6 +/- 2.5 in 50 patients (26 males) with polycystic kidney disease, 5.5 +/- 2.4 in 17 patients (16 males) with hypertensive angionephrosclerosis, and 3.9 +/- 2 in 41 patients (21 males) with chronic tubulointerstitial nephritis. delta Ccr was higher in males than in females (7.5 +/- 5.2 versus 4.8 +/- 2.5; P < 0.001). Linear regression analysis of the whole population disclosed a strong relationship between delta Ccr and proteinuria (r2 = 0.23; P < 0.001), and a weak relationship between delta Ccr and protein intake (r2 = 0.03; P = 0.02), but no relationship between delta Ccr and MAP (r2 = 0.01; P = 0.23). Stepwise multiple regression analysis identified the type of nephropathy, gender, and proteinuria as independent predictive factors of progression; however, these factors together accounted for only 36% of the variation in delta Ccr, suggesting the contribution of other yet unidentified factors., Conclusions: Primary kidney disease and urinary protein excretion (reflecting the severity of renal disease in individual cases) appear as the major determinants of the rate of progression, with faster progression in males in all types of nephropathy, whereas potentially alterable factors such as blood pressure and protein intake had only a modest influence in the range of values observed in our patients.

Soluble tumor necrosis factor (TNF) receptors were recently detected in the circulation of patients with early HIV-induced disease, at significantly higher levels than in control subjects. They were proposed as markers of disease progression and of the degree of immunodeficiency. We report that adsorption of heat-inactivated HIV-1 LAI to isolated human monocytes triggers the release of both TNF-alpha and its natural specific inhibitor, the soluble TNF receptor (sTNF-R)75, but not that of sTNF-R55. Only limited inhibition of sTNF-R release was obtained in the presence of a fully neutralizing anti-TNF-alpha monoclonal antibody, suggesting that stimulation by TNF-alpha was only partially responsible for sTNF-R release. HIV-1 LAI induced a higher sTNF-R/TNF ratio than lipopolysaccharide, a well-known monocyte activator. Monocytes thus represent a cellular source of sTNF-R that can be detected in the circulation of HIV-infected patients from seroconversion onwards. The release of sTNF-R could be of great significance in the control of HIV infection via the cytokine network and especially TNF-alpha.

The low-affinity receptor for IgE (CD23) is cleaved into biologically active soluble fragments (sCD23), some of which have been reported to exhibit pleiotropic activities. However, it is not known whether the sCD23 fragments contribute to the induction and/or regulation of pro-inflammatory cytokine production. In this study, this possibility was tested using interleukin (IL)-1-stimulated human whole blood as an ex vivo model of cytokine cascade production. We show that human recombinant 25-kDa sCD23 significantly enhanced the production of IL-6 in whole blood stimulated by IL-1, but had only little or no effect in the absence of IL-1. The potentiating effect of sCD23 was concentration dependent within the range of plasma levels occurring during various inflammatory processes in man. These results prompted us to study whether sCD23 and IL-1 together also enhance the production of regulating factors exhibiting anti-cytokine activities. Our data indicate that sCD23 augments the release of IL-1 receptor antagonist induced by IL-1. Finally, examining the effect of sCD23 on human peripheral monocytes stimulated by IL-1, we confirmed the capacity of sCD23 to potentiate cytokine production. We suggest that sCD23 can modulate monocyte functions, thereby contributing to the amplification and regulation of immune and inflammatory processes.

Neutrophils generate potent microbicidal molecules via the oxygen-dependent pathway, leading to the generation of reactive oxygen intermediates (ROI), and via the non-oxygen dependent pathway, consisting in the release of serine proteinases and metalloproteinases stored in granules. Over the past years, the concept has emerged that both ROI and proteinases can be viewed as mediators able to modulate neutrophil responses as well as the whole inflammatory process. This is well illustrated by the oxidative regulation of proteinase activity showing that oxidants and proteinases acts is concert to optimize the microbicidal activity and to damage host tissues. ROI and proteinases can modify the activity of several proteins involved in the control of inflammatory process. Among them, tumour necrosis factor-alpha and interleukin-8, are elective targets for such a modulation. Moreover, ROI and proteinases are also able to modulate the adhesion process of neutrophils to endothelial cells, which is a critical step in the inflammatory process.