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Biomedical subjects

D C Wheeler

Publications and source records attributed to D C Wheeler.

At least 55 records · Page 3Linked to original sources
PubMed1993

Simvastatin therapy for hypercholesterolemic patients with nephrotic syndrome or significant proteinuria.

Experimental evidence suggests that lipid lowering therapy could slow the progression of renal disease in humans. We have conducted a double-blind, placebo controlled trial of the HMG CoA reductase inhibitor simvastatin in patients with the nephrotic syndrome or significant proteinuria (> 1 g/day) and hypercholesterolemia (> or = 6.5 mmol/liter). Patients were placed on a lipid lowering diet for at least 10 weeks before randomization. After a four-week placebo run-in, 30 adults were randomized to simvastatin or placebo therapy (10 mg/day, increasing to 20 to 40 mg/day as required) for 24 weeks. There were seven dropouts, none of whom were "definitely" related to drug therapy. Total and LDL cholesterol levels fell by a mean of 33 and 31%, respectively, in simvastatin treated patients, compared with only 5 and 1% in patients on placebo (P < 0.001, P = 0.002, respectively). Apolipoprotein B100 levels fell by a mean of 31% in the simvastatin group but rose 0.3% in the placebo group (P = 0.014). There were no significant changes in HDL levels. There were no significant differences between the groups in their urine protein levels, their rise in plasma creatinine, or decline in plasma inulin clearance. Simvastatin is a safe, effective therapy for hypercholesterolemia in proteinuric states. A much larger trial is needed to show if potent lipid-lowering therapy slows progression of hypercholesterolemic proteinuric diseases.

Adolescent↗
PubMed1993

Interactions between lipoproteins, glomerular cells and matrix.

Lipid deposition, mononuclear cell infiltration and accumulation of mesangial matrix components are recognized as early events in the development of glomerulosclerosis whilst correction of plasma lipid abnormalities slows the progression of renal disease in experimental models. In vitro studies have demonstrated that low density lipoprotein (LDL) is bound and internalized by mesangial cells, acts synergistically with growth factors to stimulate cellular proliferation and modifies secretion of chemotactic mediators and matrix components. LDL incubated with mesangial cells becomes oxidized and in this modified from inhibits cell proliferation and causes cytotoxic injury. Oxidation of LDL also modulates its effects on cell secretory function. Since proteoglycans secreted by mesangial cells bind LDL particles, excess matrix accumulation may exacerbate lipoprotein-mediated injury. These findings suggest that lipoproteins deposited and oxidized in the glomerulus may promote inflammation, cell injury and sclerosis.

Animals↗
PubMed1991

Effects of dietary fatty acids in an animal model of focal glomerulosclerosis.

The obese Zucker rat develops hyperlipidemia, proteinuria and focal glomerulosclerosis without prior changes in renal hemodynamics. To study the effects of oral fatty acid intake on the development of renal injury in this model, rats were fed standard chow or chow supplemented with either 14% fish oil or 14% beef tallow after unilateral nephrectomy at the age of 10 weeks. At 32 weeks post-nephrectomy animals were sacrificed and renal tissue saved to assess histology and glomerular eicosanoid production. Fish-oil treated rats had lower mean plasma cholesterol levels and developed less proteinuria than control or tallow-fed animals although there was no difference in plasma creatinine or blood pressure. Histological analysis showed significantly fewer sclerosed glomeruli in the fish oil group (4.0 +/- 0.8% vs. control 19.4 +/- 4.1%, P less than 0.0005 and vs. beef tallow 10.8 +/- 1.9%, P less than 0.005). Glomeruli derived from rats on fish oil supplements produced smaller amounts of prostaglandin (PG)E2 and of the stable metabolites of PGI2 (6-oxo-PGF1 alpha), PGF2 (PGF2 alpha) and thromboxane (TX)A2 (TXB2) than those from tallow-fed animals. This study demonstrates that oral fatty acid intake may influence the development of glomerulosclerosis. The apparent beneficial effects of fish oil have not been fully defined, but may relate to favorable changes in plasma lipid concentration and renal eicosanoid production.

Animals↗
PubMed1991

Characterisation of the binding of low-density lipoproteins to cultured rat mesangial cells.

Mesangial cell lipid accumulation is a recognised feature of glomerular disease and has been implicated as a factor in the pathogenesis of renal injury. To investigate possible mechanisms of such accumulation, binding of 125I-labelled human low-density lipoprotein (LDL) to rat mesangial cells was studied in vitro. Experiments were performed at 4 degrees C to prevent ligand internalisation. LDL remained associated with the cells after repeated washing. Binding was time-dependent, was inhibited by addition of an excess of unlabelled LDL, but to a much lesser extent by apoprotein-A-rich high-density lipoprotein particles devoid of apoprotein E (HDL-A). Specific binding reached saturation at an LDL concentration of 21 micrograms/ml, required the presence of calcium, and was inhibited by heparin and dextran sulphate. Scatchard analysis suggested a single class of binding site (Kd 22.7 micrograms protein/ml). Higher binding affinities were obtained when rat LDL was substituted for human LDL (Kd 1.3 micrograms/ml) and when human fibroblasts were exposed to human LDL under identical experimental conditions (Kd 3.0 micrograms/ml). Further experiments at 37 degrees C demonstrated degradation of LDL by cells. These results suggest that mesangial cells possess apoprotein B, E receptors. Mesangial cell lipid accumulation may therefore result from receptor-mediated endocytosis of LDL particles.

Animals↗
PubMed1991

Experience with a new method for percutaneous renal biopsy.

Between January 1989 and August 1990 a new technique for percutaneous renal biopsy was evaluated in all patients undergoing native kidney biopsy in our hospital. The method combines the use of an automated biopsy device, disposable biopsy needles, and a needle guide attached to an ultrasound probe. This allows real-time ultrasound scanning throughout the procedure. All biopsies were performed by trainee nephrologists. The success of the technique was evaluated by analysis of histopathological data, and the complications of the procedure from case-notes and nursing records. During the study 192 biopsies were attempted, of which 188 (97.8%) were successful. For each biopsy a mean of 2.8 needle passes were required and 75% of these obtained cores of tissue. An average of 25 glomeruli (range 1-90) were seen per biopsy. Although microscopic haematuria was almost invariable, there were no episodes of frank haematuria and no blood transfusion or surgical intervention was required. The new method is simple, providing accurate localisation of the kidney coupled with direct visualisation of the biopsy, and results in a very high success rate. Intrarenal needle dwell time is kept to a minimum and there were only minor complications. This technique deserves more widespread use.

Adult↗
PubMed1990

Effects of low-density lipoproteins on mesangial cell growth and viability in vitro.

Recent animal studies suggest that abnormal lipid metabolism may play a role in the pathogenesis of glomerulosclerosis. In order to define mechanisms whereby lipoproteins could contribute to glomerular injury, the effect of Low-density lipoprotein (LDL) concentration on the proliferation of rat mesangial cells was studied in vitro. Human LDL was added to culture medium that had been rendered otherwise lipid free and proliferation rate was estimated by measuring incorporation of 3H-thymidine. When compared to standard medium, LDL-enriched medium stimulated cell division when present in protein concentrations of between 10 and 100 micrograms/ml. At greater concentrations (more than 200 micrograms/ml), cell proliferation was inhibited and above 500 micrograms/ml cells sustained visible morphological injury when assessed under phase contrast microscopy. Estimation of 51Cr release from prelabelled cells confirmed that LDL was cytotoxic in these greater concentrations. A similar pattern of proliferation and toxicity has been observed in vascular smooth muscle cell cultures over a corresponding range of LDL concentrations. These results strengthen the analogy between glomerulosclerosis and atherosclerosis and provide further evidence that lipoproteins may contribute directly to glomerular scarring.

Animals↗
PubMed1989

Glomerular structures and lipids in progressive renal disease.

In the last few years, remarkable advances have been made in the understanding of lipoprotein metabolism in the pathogenesis of renal disease in animal models and in vitro cell culture. Central to this work is the problem of the progression of renal disease in humans. This review recapitulates the theory (Lancet 1982; II: 1309-1312) that the progression of disease depends in part on the damage inflicted on the glomerulus by lipoproteins. The glomerular environment of high or low pressure, basement membrane damage, and destruction or damage of the mesangial and epithelial cells permits the filtration of protein, the consequence of which is hyperlipidemia. Whatever the therapeutic measures employed, if proteinuria persists, hyperlipidemia will follow. This suggest that lipoprotein toxicity may contribute to the final common path of renal damage in progressive renal disease. "Lipoprotein toxicity" in arteries is called atherosclerosis, but this term ignores the complexity of the glomerulus and the possible tubular damage that might be caused by filtered lipoprotein. It is clear there is insufficient knowledge of the metabolism of the damaged kidney to confidently attribute the pathology of progression of disease to any single process.

Animals↗
PubMed1989

Dietary fish oil supplements preserve renal function in renal transplant recipients with chronic vascular rejection.

The effect of dietary fish oil supplements on renal failure and lipid abnormalities was studied in 14 adult renal transplant recipients with chronic vascular rejection. The rate of decline of renal function (assessed by studying the slope of reciprocal plasma creatinine plots) slowed significantly during a 6-month period on fish oil supplements compared with the preceding 6-month control period (slope 1/cr during supplementation -3.6 X 10(-5) mumols/l per month compared with -13.5 X 10(-5) before, the difference in slope being -9.8 X 10(-5), 95% confidence interval (CI) -16.2 X 10(-5), -3.5 X 10(-5), P less than 0.05). Total plasma triglyceride concentrations decreased during supplementation (mean change -1.15 mmol/l, 95% CI -1.84, -0.47, P less than 0.003), but there was no change in total plasma cholesterol concentration or urinary protein excretion. Platelet function was studied in nine patients. Platelet aggregation induced by adrenaline and collagen was reduced by fish oils (median change in per cent aggregation), adrenaline 2 mumols/l, -36% (95% CI -68%, -8%, P less than 0.05), collagen 1 mg/1, -13% (95% CI -44%, -2%, P less than 0.05). Platelet thromboxane A2 release in response to these agents was also significantly reduced. These results demonstrate that fish oils preserve residual function in renal graft failure due to chronic vascular rejection.

Adult↗
PubMed1987

Radiation effects on cerebral white matter: MR evaluation.

The purpose of this study was to evaluate the white-matter changes associated with cranial radiation by MR imaging. The MR scans of 95 patients receiving conventional external beam radiation for a wide variety of central nervous system tumors were reviewed. Moderately T2-weighted spin-echo images with a 2000-msec repetition time and 56-msec-echo time were analyzed for white-matter abnormalities without knowledge of the patient's history. These were correlated with radiation dose, port, and time interval since completion of therapy, and then compared with an age-matched control group of 180 patients with nonirradiated, space-occupying, intracranial lesions. Radiation-related lesions were characterized as symmetric, high-signal foci in the periventricular white matter. Relative sparing of the posterior fossa, basal ganglia, and internal capsules was noted. In patients older than 20 years, these changes paralleled those seen in ischemia but were more prevalent (p less than .005). In 25 patients with sequential MR scans, these findings remained stable. In those patients with limited treatment fields, for example, pituitary adenomas, no statistical differences were seen between radiation-treated and nontreated groups. Cerebral white-matter changes that mimic deep white-matter infarction are frequently seen in response to therapeutic radiation. There is a variable incidence of radiation effects, becoming more marked in older patients. MR interpretation must consider the neuropathologic consequences of therapeutic radiation, which include demyelination, microvascular occlusion, and blood-brain barrier breakdown.

Adult↗
PubMed1987

Recurrent acute renal failure with interstitial nephritis due to D-penicillamine.

A 60-year-old man with rheumatoid arthritis, who developed acute reversible renal failure with nephrotic syndrome and tubulointerstitial nephritis in association with multiple-drug therapy, is described. The episode was ascribed to the nonsteroidal anti-inflammatory agent fenbufen, and the patient was reexposed to D-penicillamine within 6 months, reproducing the same renal lesion. There was no evidence of the glomerular lesions characteristically associated with D-penicillamine nephrotoxicity. D-penicillamine was the only drug therapy common to both episodes and it is concluded that it may cause tubulointerstitial nephritis with nephrotic syndrome.

Acute Kidney Injury↗
PubMed1987

Measurement of renal functional reserve of the single kidney in man.

The renal functional reserve capacity (RFRC) and response of the single kidney to a low protein diet (LPD) were investigated. Effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) were measured using a single injection of I125 Hippuran and Cr51 EDTA during a dopamine infusion (3 micrograms/kg/min) and after 2 weeks on a LPD (0.6 g/kg/day). Dopamine increased ERPF but the associated rise in GFR was not significant. There was a significant decrease in both ERPF and GFR on LPD. The change in GFR during dopamine infusion, but not during LPD, correlated inversely with baseline GFR. Dopamine and LPD had no effect on heart rate or blood pressure and LPD did not alter urinary sodium excretion. These results suggest that the single kidney lacks functional reserve capacity and that protein restriction may be useful in preserving long term function.

Adult↗
PubMed1986

High risk acute renal failure.

Acute renal failure carries a high mortality and little change in survival rate over the last three decades has been seen. Patients requiring intensive care, most of whom have developed acute renal failure following trauma or surgery, have a worse prognosis. The survival in this series of 100 consecutive patients admitted to one intensive care unit between 1976 and 1985 was 35 per cent. The only factors which differed significantly between the surviving and non-surviving patients were age, requirement for mechanical ventilation and maximum serum creatinine level before the first dialysis. It is difficult to predict outcome for an individual patient at the start of treatment and an aggressive approach to management is advocated.

Acute Kidney Injury↗