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Biomedical subjects

G Mourad

Publications and source records attributed to G Mourad.

At least 55 records · Page 3Linked to original sources
PubMed1998

Oxidative stress and lipid abnormalities in renal transplant recipients with or without chronic rejection.

BACKGROUND: The histological picture of chronic rejection with endothelial lesions and vascular hyperplasia resembles the early arteriosclerotic lesions. As increasing evidence suggests a role for oxidative stress in arteriosclerosis, we examined whether chronic rejection in renal transplant recipients was associated with increased oxidative stress markers. METHODS: We investigated lipid metabolism and oxidative stress in 77 renal transplant recipients. Group I patients (n=34; 48+/-2 years old, 12 women, 22 men) had no clinical or histological signs of chronic rejection, whereas group II patients (n=43; 47+/-3 years old, 15 women, 28 men) had histologically proven chronic rejection. All patients were treated with cyclosporine and steroids. Lipid metabolism was evaluated by determining total cholesterol, triglycerides, high-density lipoprotein cholesterol, apolipoproteins AI and B, and lipoprotein (a). Oxidative stress was evaluated by determining: (i) the end product of lipid peroxidation, malonyldialdehyde (MDA), and erythrocyte polyunsaturated fatty acids; (ii) the nonenzymatic antioxidant system: erythrocyte alpha-tocopherol and glutathione; and (iii) the enzymatic antioxidant system: erythrocyte superoxide dismutase and plasma glutathione peroxidase. Results were compared with those of a control group (38 healthy volunteers). RESULTS: Compared with controls, renal transplant recipients had significantly increased total cholesterol, triglyceride, and apolipoprotein B levels; they also had, in association with these lipid abnormalities, a significant increase in MDA and a significant decrease in erythrocyte polyunsaturated fatty acids, as well as a significant decrease in enzymatic and nonenzymatic antioxidant defense mechanisms. In contrast to lipid disturbances, where no difference was observed between groups I and II, markers of oxidative stress were significantly higher in group II compared with group I (MDA: 1.87+/-0.43 and 1.62+/-0.31 nmol/ml, respectively, P<0.05). The red blood cell antioxidative defense mechanisms were significantly decreased in group II compared with controls (erythrocyte alpha-tocopherol: 0.61+/-0.38 and 1.08+/-0.31 mg/L, respectively, P<0.01; superoxide dismutase: 1.08+/-0.2 and 1.32+/-0.31 U/mg Hb, respectively, P<0.01). CONCLUSION: Our data show that oxidative stress with a decrease in antioxidant defenses is associated with kidney transplantation. In addition, oxidative stress markers are particularly increased in transplant recipients with chronic rejection, which suggests that oxidative stress may participate in the development and/or progression of vascular lesions observed in these patients.

Adult↗
PubMed1998

Long-term improvement in renal function after cyclosporine reduction in renal transplant recipients with histologically proven chronic cyclosporine nephropathy.

BACKGROUND: Chronic cyclosporine (CsA) nephropathy, which has been unequivocally documented in recipients of heart, heart-lung, liver, or bone marrow transplants, as well as in nontransplant situations, usually results in a progressive deterioration of renal function. In this study, we assessed the potential reversibility of chronic CsA nephropathy in renal transplant recipients. PATIENTS AND METHODS: Twenty-three renal transplant patients with biopsy-proven CsA nephropathy associated with long-term CsA administration (27+/-4 months) were followed up for more than 2 years after CsA reduction (18/23 patients) or withdrawal (5/23 patients) and addition of azathioprine. Changes in effective renal plasma flow and glomerular filtration rate were assessed before and 2 years after CsA reduction, whereas serum creatinine, proteinuria, blood pressure, and CsA concentrations were monitored up to 5 years. RESULTS: At 2-year follow-up, glomerular filtration rate increased from 40+/-3 to 47+/-4 (P<0.05) and effective renal plasma flow from 217+/-23 to 244+/-24 ml/min/1.73 m2 (NS). Mean arterial pressure significantly decreased from 98.7+/-2.9 to 93.1+/-2.7 mmHg (P<0.05). There was no significant change in renal vascular resistance, filtration fraction, or albumin excretion. A significant decrease in serum creatinine was also observed during the whole follow-up (73+/-6.5 months). CsA reduction was followed by only one episode of acute reversible rejection; chronic rejection developed in three patients 2 years or later after CsA reduction. CONCLUSIONS: These data suggest that CsA nephropathy participates in graft dysfunction in a small group of renal transplant recipients. In addition, graft dysfunction may be reversible when CsA dosage is reduced early after diagnosis of chronic CsA nephropathy.

Adult↗
PubMed1997

Disposition of basiliximab, an interleukin-2 receptor monoclonal antibody, in recipients of mismatched cadaver renal allografts.

BACKGROUND: Basiliximab is an interleukin-2 receptor (IL-2R; CD25) chimeric monoclonal antibody for immunoprophylaxis against acute rejection in renal transplantation. Its pharmacokinetics were characterized in a multicenter open-label, prospective dose-escalation study to identify a single-dose regimen providing IL-2R-saturating serum concentrations in the critical first posttransplant month. METHODS: Thirty-two recipients of primary, mismatched cadaver kidneys were enrolled: 20 men and 12 women, who were 47+/-11 years old and weighed 65+/-12 kg. The immunosuppression regimen consisted of steroids and azathioprine from day 0 and cyclosporine from day 10. Basiliximab was infused over 30 min as a single dose preoperatively. RESULTS: Thirty patients were evaluable for basiliximab pharmacokinetics: 24 received 40 mg and 6 received 60 mg. Basiliximab was well tolerated without evidence of cytokine-release syndrome, hypersensitivity reactions, or anti-idiotype antibody response. Peak concentration and area under the concentration curve increased proportionally with dose. Postinfusion concentrations declined in a biphasic manner with a terminal half-life of 6.5+/-2.1 days. Weak, widely dispersed correlations were noted between body weight versus distribution volume (r=0.29) and versus clearance (r=0.45), suggesting no clinical relevance for weight-adjusted dosing. There were no apparent gender-related differences in basiliximab disposition. Previous phase II data indicated that serum concentrations in excess of 0.2 microg/ml are sufficient to saturate IL-2R epitopes on circulating T lymphocytes. Concentrations were above this threshold for 26+/-8 days (range 16 to 46) at the 40-mg dose level and for 32+/-11 days (range 22 to 51) at the 60-mg dose level. CONCLUSIONS: Total basiliximab doses of 40-60 mg were well tolerated, nonimmunogenic, and estimated to provide immunoprophylaxis to cover the first posttransplant month.

Adult↗
PubMed1997

Alpha 2-macroglobulin protects some of the protein constituents of dialysis-associated amyloidosis from protease degradation.

A crucial point to know in the prevention and treatment of beta 2-microglobulin (beta 2-m) amyloidosis is the putative resorption of amyloid fibrils in vivo. Although still controversial, long term clinical studies suggest that there is no resorption of amyloid fibrils in vivo, even after the suppression of the primary cause of amyloidosis. Two in vitro studies on murine and human AA amyloidosis as well as Alzheimer's disease suggest that protein constituents of amyloid fibrils may be resorbed. Protein resorption can be inhibited by the antiprotease amyloid P component. We extended these in vitro studies on beta 2-m amyloidosis, and assessed the effect of alpha 2-macroglobulin (alpha 2-M), a serum antiprotease previously found in this type of amyloidosis, on the putative protease induced protein resorption. Here, we show that amyloid proteins, beta 2-m and light chains of immunoglobulins, were degraded by trypsin. Preincubation of the amyloid proteins with alpha 2-M significantly inhibited the trypsin induced protein degradation of lambda chains. These data add further support to the hypothesis proposing a role for alpha 2-M and other antiproteases in the formation and/or persistence of beta 2-m amyloidosis.

Amyloid↗
PubMed1997

Molecular and cellular events implicated in local tolerance to kidney allografts in miniature swine.

Long-term tolerance to class I-mismatched renal allografts can be induced in miniature swine by treatment with a short course of cyclosporine (CsA). Kidney recipients treated with CsA and untreated control kidney recipients both demonstrated infiltration of the transplanted kidney by mononuclear cells, which reached a maximum between postoperative days 8 and 11. Recipients that did not receive the tolerizing regimen rejected their grafts between postoperative days 8 and 12 in this model. The kinetics of cytokine gene expression, including interleukin (IL)-1alpha, IL-1beta, IL-2, IL-6, IL-10, tumor necrosis factor, and interferon-gamma (IFN-gamma), within the grafted kidney of rejector and acceptor animals, were determined using Northern blot hybridization. A strong correlation between rejection and up-regulation of the IFN-gamma gene was observed, whereas animals with long-term tolerance showed low levels of IFN-gamma, but high levels of IL-10 gene transcription. None of the other cytokine genes demonstrated a reproducible pattern of expression that correlated with acceptance/rejection of allografts. Analysis of transcription patterns of cytokine genes in mononuclear cells purified from renal grafts confirmed the initial observations made on biopsies. The phenotype of graft-infiltrating cells (GIC) showed a dominance of CD8+ cells, with an average of 66% single-positive cells and 19% CD4/CD8 double-positive cells, compared with 30% and 14%, respectively, for peripheral cells. Predominance of CD8+ GIC was dictated neither by the MHC antigen disparity nor the rejector/acceptor status. These results, therefore, suggest that GIC represent a regulated combination of mononuclear cells producing local immune mediators that, in part, control the fate of allografts in this large animal model.

Animals↗
PubMed1997

Monomeric and dimeric beta 2-microglobulin may be extracted from amyloid deposits in vitro.

BACKGROUND: There is a controversy as to whether beta 2-microglobulin (beta 2M amyloid deposits may be degraded resulting in regression and cure of amyloidosis. We have recently reported a long-term clinical study involving transplanted patients suggesting that there is no resorption of amyloid deposits in vivo, even after correction of the primary cause of amyloidosis. To progress in the study of the solubility of amyloid fibrils we performed an in vitro study with the intent to remove protein constituents from amyloid fibrils and amyloid deposits. METHODS: Amyloid fibrils were prepurified from three amyloid deposits surgically obtained from carpal tunnel. They were incubated for 2 h with a phosphate-buffered saline (PBS) solution containing trypsin, collagenase, kallikrein, the three of them, or PBS alone. The experiments were repeated in the presence of the antiprotease alpha 2 macroglobulin (alpha 2M). RESULTS: Several bands were observed when the supernatants were run through SDS-PAGE. Western blotting identified in these bands the presence of alpha 2M, light chains of immunoglobulins and beta 2M in mono- and dimeric form. The same proteins were solubilized with PBS alone. Equivalent results were obtained with crude amyloid deposits; however, beta 2M presented almost exclusively in monomeric form. CONCLUSIONS: These results show that the protein constituents may be recovered from amyloid fibrils in vitro. They also show that even the more insoluble beta 2M dimers are resuspended by the action of PBS, with no need for proteases to cleave their attachment to the amyloid deposits.

Amyloid↗
PubMed1997

Diffuse pulmonary calcinosis without calcium metabolism abnormalities in a renal transplant recipient.

Eighteen years after an uneventful renal transplantation, the chest radiograph of an asymptomatic 50 year old man showed diffuse bilateral infiltrations, predominately at the right apex. Computed tomography (CT) scan demonstrated a diffuse alveolar pattern, the alveoli being filled with a very dense material, with some tracheal calcifications. Bronchoalveolar lavage fluid analysis was normal, but bronchial and transbronchial biopsies revealed calcium deposits in the bronchial mucosa and in the alveolar septa. The diagnosis of diffuse pulmonary calcinosis was established, despite normal blood calcium, phosphorus and magnesium levels, based upon computed tomography scan and pathological findings at fibreoptic bronchoscopy, without the need for an open lung biopsy.

Biopsy↗
PubMed1997

[Secondary hyperparathyroidism and multiple vertebral brown tumors: cure after parathyroidectomy].

A 46 year old man was referred for severe left cruralgia and multiple vertebral cystic defects on CT-scan. He was treated by hemodialysis since 1987 for chronic renal failure secondary to focal and segmental glomerulosclerosis, diagnosed in 1960 on renal biopsy. Dialysis schedule consisted of 3 x 4 h/week with a polysulfone dialyser and 1.75 mMol Ca containing bicarbonate dialysate. On early 1995, the patient complained of back pain and cruralgia, which gradually worsened. Vertebral column CT-scan and MRI showed multiple lytic lesions expanding into the medullary canal. Biological hyperparathyroidism was present. To differentiate between hyperparathyroidism with brown tumors, malignancy and amyloid deposition, an iliac biopsy and a biopsy of a corporeal vertebral cyst were done. They showed florid hyperparathyroidism and brown tumors. The patient was submitted to surgical parathyroidectomy. Six months after surgery, cruralgia resumed, CT-scan and MRI showed refilling of the cysts by calcic material.

Glomerulosclerosis, Focal Segmental↗
PubMed1996

[Intraglomerular hypertension. Physiopathology and therapeutic implications].

It is now well-established in experimental models in rodents that increased glomerular pressure results in the development of focal and segmental glomerulosclerosis, proteinuria and progressive renal functional deterioration. In humans, direct measurement of glomerular capillary pressure is impossible. However, it is widely accepted that glomerular hypertension is present in different clinical situations, like diabetic nephropathy, chronic renal failure associated with glomerulonephritides, some forms of essential hypertension and cadaveric kidney transplantation. Many studies were performed on the effects of protein-restricted died and/or angiotensin converting enzyme inhibition on the rate of progression of renal failure in these renal diseases. Although controversial, the overall results suggest that these therapeutic strategies may reduce the rate of progression, particularly in diabetic nephropathy.

Animals↗