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A J Rees

Publications and source records attributed to A J Rees.

At least 91 records · Page 5Linked to original sources
PubMed1989

Modulation of antibody-mediated glomerular injury in vivo by bacterial lipopolysaccharide, tumor necrosis factor, and IL-1.

We have investigated the effects of LPS, human rTNF (hrTNF) and human rIL-1 beta (hrIL-1 beta) pretreatment on the intensity of antibody-mediated injury in vivo by using a passive model of anti-glomerular basement membrane (GBM) antibody-mediated nephritis in rats. The experiments show that all three pretreatments exacerbate injury in this model whether judged by albuminuria or the prevalence of glomerular capillary thrombi. The effect on albuminuria was dose dependent with all three treatments. The lowest effective dose of LPS was 0.025 microgram while those for hrTNF and hrIL-1 beta were 0.4 microgram and 0.5 microgram, respectively. All three pretreatments also increased the prevalence of glomerular capillary thrombi which were rare in rats injected with anti-GBM antibodies without pretreatment. LPS pretreatment appeared to be more effective in causing glomerular capillary thrombi than hrTNF or hrIL-1 beta and this was reflected in the correlations between albuminuria and the proportion of glomeruli with capillary thrombi. This relation was linear for all three pretreatments but the slope was appreciably greater for rats pretreated with LPS (0.37) when compared with results from rats given either hrTNF (0.22) or hrIL-1 beta (0.29). Pretreatment of nephritic rats with both cytokines increased the slope to 0.42 demonstrating a synergistic effect. The synergism of hrTNF with hrIL-1 beta was also demonstrated by the effective doses needed to induce albuminuria which was evident in rats treated with 0.05 microgram of IL-1 beta and 0.4 microgram of TNF. Neither the cytokines nor LPS caused clinical, morphologic, or biochemical evidence of renal toxicity when given alone in the dose used here but they did cause a transient increase in the number of neutrophils marginated in glomerular capillaries. Pretreatment of rats with LPS or cytokines increased the glomerular neutrophil influx after anti-GBM antibodies by roughly sixfold. Our experiments show that TNF and IL-1 can increase the severity of glomerular injury in nephritis; they may be important in modulating glomerular injury clinically.

Albuminuria↗
PubMed1989

Exaggerated glomerular albuminuria after cobra venom factor in anti-glomerular basement membrane disease.

The mechanisms by which intercurrent bacterial infections are associated with increased tissue injury in some forms of glomerulonephritis may include complement activation by bacteria and subsequent increased glomerular neutrophil (PMN) infiltration. We have studied the effect of complement activation after cobra venom factor (CVF) in anti-glomerular basement membrane (GBM) antibody-mediated disease. A single injection of CVF 24 h before the administration of heterologous nephrotoxic globulin (NTG) to Sprague-Dawley rats resulted in greatly increased albuminuria in some animals on the second day of this model. This phenomenon was reproducible and depended on the presence of circulating PMN and complement. We have previously shown that the administration of CVF on days 9 and 11 of the HgCl2 model in inbred Brown Norway rats, resulted in increased albuminuria in all animals at day 17 (p less than 0.05). The administration of small amounts of CVF with consequent complement activation in antibody-mediated disease represents a model for the increased injury seen after infection in human disease.

Albuminuria↗
PubMed1989

Autoantibodies to glomerular antigens in patients with Wegener's granulomatosis.

Patients with Wegener's granulomatosis have autoantibodies to a neutrophil cytoplasmic antigen. As these patients often present with severe glomerulonephritis we investigated whether the same autoantigen was expressed in glomeruli by using both cultured human glomerular cells and frozen normal human kidney sections. Glomeruli were isolated from normal human kidney cortex by differential sieving and plated on to coverslips in growth medium containing various supplements. Cell types were identified by a series of markers and designated either epithelial, endothelial or mesangial. In single and double staining experiments, glomerular cells were incubated with a monoclonal antibody to the neutrophil cytoplasmic antigen (MCAW8), control mouse monoclonal IgG, sera from patients with Wegener's granulomatosis and control normal human serum. MCAW8 and Wegener's patient sera bound specifically to cultured epithelial and endothelial cells. MCAW8 was also found to bind to the glomerular epithelium in frozen sections. We conclude that autoantibodies to glomerular antigens are present in serum of patients with Wegener's granulomatosis and may be important in the pathogenesis of rapidly progressive glomerulonephritis.

Antibodies, Monoclonal↗
PubMed1988

Prednisolone and chlorambucil treatment in idiopathic membranous nephropathy with deteriorating renal function.

Eight patients with idiopathic membranous nephropathy whose renal function was deteriorating were given a 6-month course of alternating monthly cycles of prednisolone and chlorambucil. Proteinuria was reduced in all eight, from a mean (SD) of 15.3 (5.9) g/24 h at the start of treatment to 2.1 (1.5) g/24 h at follow-up (p less than 0.05). Creatinine clearance increased in six, and the rate of decline was reduced in the other two (group mean 51.6 [17.8] ml/min at the start of treatment and 81.4 [36.8] ml/min at follow-up; p less than 0.05). Adverse effects of chlorambucil were severe, and the daily dose had to be reduced. Prednisolone and chlorambucil treatment can change the natural course of membranous nephropathy even when renal function has started to deteriorate, so treatment can be reserved for high-risk patients.

Adult↗
PubMed1988

A prospective randomized controlled trial of perioperative antibiotic prophylaxis in renal transplantation.

We have carried out a prospective, randomized controlled trial of perioperative prophylaxis with cefuroxime and piperacillin in 53 recipients of renal allografts. Twenty-seven patients received antibiotic prophylaxis with three doses of cefuroxime 750 mg and piperacillin 4 g, and 26 patients received no prophylaxis. Risk factors for infection were well matched. Infection rates were analysed for the periods 0-5 days and 0-14 days post-transplant. In the first 5 days, patients receiving antibiotics had fewer infections (3 vs. 11, P = 0.04) but by 14 days this difference was no longer apparent (21 vs. 30, P = NS). There was a total of 15 wound infections, which were more common in the control group both at 5 days (1 vs. 5, P = NS) and at 14 days (4 vs. 11, P = 0.027). Urinary infections were unaffected by prophylaxis. We conclude that perioperative antibiotic prophylaxis results in a modest but worthwhile reduction in the incidence of wound infections after renal transplantation.

Adult↗
PubMed1988

Synergistic effects of recombinant tumour necrosis factor and interferon-gamma on rat thyroid cell growth and Ia antigen expression.

In this study, we have investigated the effects of tumour necrosis factor (TNF), interferon-gamma (IFN-gamma) and interleukin-1 (IL-1) on rat thyroid cells, using the continuously growing, differentiated FRTL5 cell line. No effect on cell growth was found with any cytokine alone, but the combination of TNF and IFN-gamma was cytostatic. These cells were not killed in a 18-hr assay for cytotoxicity, but prolonged incubation (4 days) with TNF and IFN-gamma produced cell detachment and death. Normal rat thyroid cells in primary culture were also susceptible to the combination of TNF and IFN-gamma for 4 days, but not 18 hr. In addition, IFN-gamma treatment induced class II (Ia) antigens on thyroid cells, and this was enhanced by TNF. TNF alone did not cause Ia expression on thyroid cells but did increase the constitutive expression of class I antigens. These results suggest that IFN-gamma and TNF, which are likely to be released by the lymphocytes and macrophages infiltrating the gland in thyroid autoimmunity, may synergize to impair cell growth and produce aberrant Ia antigen expression in thyroiditis. This could be an important mechanism for disease perpetuation.

Animals↗
PubMed1988

Kinetics of glomerular neutrophil influx after lipopolysaccharide in antibody-mediated injury.

Reconstitution experiments in the heterologous phase of nephrotoxic nephritis (HNTN) have shown that tissue injury is directly related to the number of polymorphonuclear neutrophils (PMN) infiltrating the glomeruli. Recent studies have indicated that endotoxin pretreatment in this model enhances tissue injury under certain conditions. The aim of this project was to investigate the relationship between glomerular PMN infiltration and tissue injury after endotoxin in HNTN. A dose of nephrotoxic globulin (NTG) that resulted in low levels of albuminuria was chosen. The administration of E. coli lipopolysaccharide (LPS) to Sprague-Dawley rats 24 h before the induction of HNTN resulted in the earlier appearance of larger numbers of glomerular PMN than in animals injected with nephrotoxic globulin alone (P less than 0.05 at 1/2 and 1 h). However there was no significant increase in albuminuria nor in renal histological damage. There was no difference in the amount or rate of glomerular deposition of the NTG or rat complement between the two groups of rats. The more rapid accumulation of glomerular PMN can, however, be accounted for by the LPS-induced activation of endothelium, since endotoxin was detected in the kidneys 24 h after the injection of LPS. No endotoxin was present in the serum at the time of injection of NTG. Thus we have demonstrated in a model of PMN-mediated tissue injury, that an increase in PMN influx is not necessarily associated with exaggerated injury.

Albuminuria↗
PubMed1987

Chronic renal failure after nephrotoxic nephritis in rats: contributions to progression.

In rats dietary protein restriction decreases the rate of progressive glomerulosclerosis and the development of renal failure after subtotal nephrectomies. The present experiments were designed to see whether dietary protein had similar effects on renal failure after nephrotoxic nephritis (NTN). Groups of rats were fed isocaloric diets containing 8%, 18% and 78% casein. Irrespective of whether the diets were introduced 7 days or 30 days after induction of nephritis by a single injection of rabbit anti-rat nephrotoxic globulin, rats on 8% casein and 78% casein had significantly lower plasma creatinines than rats fed with 18% casein. Semiquantitative scoring systems were used to assess glomerular sclerosis, tubular atrophy and tubular calcification. Rats on 8% protein had significantly lower glomerular sclerosis scores than the other two groups. Tubular atrophy scores were similar in rats on 8% and 78% casein and significantly lower than those of rats on 18% casein. All rats on 8% and 18% casein diets had tubular calcification whereas rats on 78% casein did not. This suggested that the normal relation between glomerular sclerosis and tubular atrophy after NTN was altered by a 78% casein diet. This was confirmed by the slopes of the regression equation for glomerular sclerosis on tubular atrophy (0.54 +/- 0.07) for rats on 78% casein compared to the slopes of the regression equations for the other two groups which were 1.12 +/- 0.10 and 1.00 +/- 0.12, respectively. This difference is highly significant statistically, P less than 0.1 X 10(-5) (one-way analysis of variance). These results show that dietary protein has a variable effect on the development of renal failure after nephrotoxic nephritis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Neutrophil-mediated pulmonary vascular injury. Synergistic effect of trace amounts of lipopolysaccharide and neutrophil stimuli on vascular permeability and neutrophil sequestration in the lung.

The pathogenesis of acute lung injury in humans is obscure, but lipopolysaccharide (LPS), complement activation, and neutrophils have been implicated. We investigated in rabbits the interaction of small amounts of intravascularly administered LPS (100 ng) with neutrophil chemotactic factors, the synthetic chemotactic peptide formyl-norleucyl-leucyl-phenylalanine (FNLP), and the biologically relevant chemotactic fragments of C5 (C5f). These neutrophil stimuli produce neutropenia when injected intravascularly in rabbits, reflecting neutrophil adherence to vascular endothelium. When LPS was injected with FNLP, the duration of neutropenia was enhanced. Studies with radiolabeled neutrophils infused in vivo demonstrated prolonged neutrophil sequestration within the lung in rabbits that were given FNLP plus LPS, an effect that was visible for 4 h after injection. Morphometric analysis of tissue sections 4 h after infusion confirmed the presence of greater numbers of neutrophils in the lungs of animals receiving LPS and FNLP. When a combination of LPS and chemotactic factors was infused at both zero and 6 h, we found a marked enhancement of lung vascular permeability at 24 h (as assessed by radiolabeled albumin accumulation), an effect not seen with either LPS or chemotactic factor alone. Ultrastructural studies revealed neutrophil sequestration and alteration in endothelial cells in the animals that received the combination of LPS and chemotactic factors. Neutrophil depletion with nitrogen mustard completely abolished the increased vascular permeability seen in animals that received LPS and chemotactic factors. This study suggests that small amounts of intravascularly administered LPS enhance the sequestration of neutrophils within the lung and increase lung vascular permeability and endothelial injury caused by neutrophils stimulated by intravascularly administered chemotactic factors. This mechanism may be relevant to the production of acute lung injury in human beings.

Albumins↗
PubMed1987

A single autoantigen in Goodpasture's syndrome identified by a monoclonal antibody to human glomerular basement membrane.

A mouse monoclonal antibody (P1) to the autoantigenic component of human glomerular basement membrane (GBM) was used to study the immunochemistry and tissue distribution of the Goodpasture antigen and the specificity of the human autoimmune response in Goodpasture's syndrome (anti-GBM disease). In solid phase assays, monoclonal antibody P1 bound to collagenase-solubilized human GBM (the ligand used in assays for human autoantibody), but not to other biochemically defined components of basement membrane. On Western blotting, P1 bound to the same 6 bands in solubilized GBM (between 26 and 58 kilodaltons with major bands at 26 and 54 kilodaltons) that were recognized by sera from all 42 patients studied with anti-GBM disease. Preincubation with sera from 8/8 patients blocked the subsequent binding of P1 from 83 to 89% on densitometer scanning of the Western blot; and preincubation with P1 blocked the binding of sera from 6/6 patients from 58 to 89%. Indirect immunofluorescence and immunoperoxidase studies revealed that the pattern of binding of P1 was identical to that of antibody eluted from the kidneys of a patient with Goodpasture's syndrome; there was linear binding to GBM, Bowman's capsule, and distal tubular basement membrane. In addition, P1 bound to basement membranes in lung and choroid plexus, and to membranes of the lens capsule, choroid, and retina of the eye and cochlea, but not to other organs studied. It is concluded that there is a single major autoantigenic component of human GBM (the Goodpasture antigen), which is present on fragments of different molecular weight in the collagenase digest. This antigen is distributed throughout well-defined basement membranes known to be involved in both Goodpasture's and Alport's syndromes. Human anti-GBM antibodies bind to the same (or closely related) determinants which are recognized by P1, demonstrating that the autoimmune response in Goodpasture's syndrome is of highly restricted specificity.

Anti-Glomerular Basement Membrane Disease↗
PubMed1986

Antiglomerular basement membrane antibody mediated disease in the British Isles 1980-4.

Clinical and pathological data on 71 patients from throughout the British Isles who developed antiglomerular basement membrane antibody mediated nephritis in the period 1980-4 were studied. Two principle patterns of disease were recognised: young men presenting in their 20s with Goodpasture's syndrome (glomerulonephritis and lung haemorrhage) and women presenting in their 60s with glomerulonephritis alone. The effect of treatment on prognosis of a total of 108 patients was also reviewed (the 71 patients plus patients seen before 1980 at Hammersmith Hospital). Treatment with prednisolone, cytotoxic drugs, and plasma exchange hastened the time to clearance of autoantibody and improved the outlook of patients who were not dependent on dialysis and those with lung haemorrhage.

Adolescent↗
PubMed1985

Pulmonary haemorrhage complicating Wegener's granulomatosis and microscopic polyarteritis.

The incidence and characteristics of pulmonary haemorrhage in a series of 89 patients with systemic vasculitis were analysed. Pulmonary haemorrhage occurred in 32 of these patients and was associated with haemoptysis in all 32, alveolar shadowing in the chest radiograph in 28, and a significantly raised transfer coefficient in 30. Pulmonary haemorrhage usually resolved with treatment by immunosuppressive drugs but was the cause of death in 11 patients. In contrast with patients with antibasement membrane antibodies there was no correlation between pulmonary haemorrhage and cigarette smoking. Pulmonary haemorrhage is a cause of serious morbidity in patients with systemic vasculitis.

Arteritis↗