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Biomedical subjects

J F Moorhead

Publications and source records attributed to J F Moorhead.

At least 19 recordsLinked to original sources
PubMed1996

Do glomerular atherosclerosis and lipid-mediated tubulo-interstitial disease cause progressive renal failure in man?

The nephrotic syndrome presents the kidney with a new environment in which blood vessels, glomerular structures and tubules are exposed over substantial periods of time to lipoproteins. LDL has charge affinity with glomerular basement membrane glycosaminoglycans, so potentially increases or maintains albumin loss. This in turn stimulates LDL synthesis. HDL is small enough to be passed by the glomerular filter in substantial amounts and has been found to stimulate endothelin-1 production by human proximal tubular cells in culture. LDL also inhibits nitric oxide vasodilatory responses, an action which when added to that of endothelin-1 may result in decreased renal tissue oxygenation. Taken together, these aspects of the nephrotic syndrome broaden conventional definitions of atherosclerosis and offer a number of targets for therapy in progressive renal disease.

Arteriosclerosis↗
PubMed1994

Tubular lipidosis: epiphenomenon or pathogenetic lesion in human renal disease?

Tubular lipidosis is a commonly observed histological lesion in proteinuric renal diseases. We have studied the interaction between native and modified human lipoproteins and human renal proximal tubular cells to investigate whether lipoproteins could be injurious to tubular cells in culture. Human renal proximal tubular cells were cultured and characterized by established methods. Preliminary studies showed that these cells could take up and degrade normal human lipoproteins by high affinity (HDL) and low affinity (LDL) pathways. In subconfluent culture, native lipoproteins, that is, LDL, HDL2 and HDL3, had markedly different effects on cell growth as measured by 3H-thymidine uptake and total cell protein as compared to modified lipoproteins such as minimally modified and oxidized LDL. In addition, we found that renal tubular cells could oxidized native LDL in the presence of copper largely by a superoxide-mediated mechanism. Finally, cellular accumulation of lipid was demonstrated in vitro by incubating cultured cells with varying lipoprotein concentrations for up to 48 hours. Notably, cell detachment was observed only with high concentrations of modified LDL especially with minimally modified LDL. We speculate that uptake and oxidation of filtered LDL by tubular cells may lead to tubular injury in nephrotic states.

Cell Division↗
PubMed1994

Human high density lipoproteins stimulate endothelin-1 release by cultured human renal proximal tubular cells.

The vasoconstrictive and mitogenic actions of endothelins have been implicated in the pathogenesis of progressive renal disease. In the present study, we have assessed whether plasma high density lipoproteins (HDL), the major filtered urinary lipoprotein in nephrotic states, can influence endothelin-1 (ET-1) production by cultured human renal proximal tubular cells. Human HDL was found to stimulate ET-1 secretion up to fourfold in a dose- and time-dependent manner; the effect was greater in subconfluent cultures than in confluent ones. There was little difference between the stimulatory effect of HDL2 and the major HDL subclass, HDL3. Preincubation of the cells with albumin did not abolish the HDL effect, while partially- or fully-delipidated HDL3 largely reproduced the effect of whole HDL3. These findings suggest that stimulation of ET-1 secretion was not simply due to protein or lipid repletion of the cells. Rather, the effect was mediated by HDL apolipoproteins, although binding to the HDL receptors involved in cellular cholesterol homeostasis was not required as tetranitromethane-modified HDL3 was an equally effective agonist of ET-1 release. Apolipoprotein (apo) A-I was indirectly implicated in the process since modified HDL3 in which apoA-II largely replaced apoA-I was less potent than HDL3. A one hour exposure of the cells to HDL3 was sufficient to activate ET-1 production for the following 12 hours, although maximum activation required six hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaloids↗
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

Lipiduria in renal disease.

This article reviews the published data on lipiduria in both health and disease. Small amounts of lipid appear in the urine under normal circumstances but, in the nephrotic syndrome in humans, there is also a considerable amount of high-density lipoprotein in the urine as well as smaller amounts of other lipoproteins. Potential tubular re-uptake mechanisms for lipoproteins have been demonstrated in both animal and cell-culture models. In humans, there is no direct evidence for these specific re-uptake mechanisms--it is only through specific staining of renal biopsies for apolipoproteins that the presence of such mechanisms in intracellular vesicular structures is suggested. It is possible that lipoprotein filtration and re-uptake by the tubule are important mechanisms in tubular injury.

Animals↗
PubMed1993

Oxidation of low-density lipoproteins by rat mesangial cells and the interaction of oxidized low-density lipoproteins with rat mesangial cells in vitro.

Glomerulosclerosis and atherosclerosis share common pathobiological mechanisms. Experiments carried out in vitro over the past decade using cells thought to be involved in the atherosclerotic process such as endothelial cells, smooth muscle cells, and monocyte/macrophages have shown that postsecretory modifications such as oxidation increase the atherogenicity of LDL. Animal experiments employing antioxidant therapy have also been shown to slow the progression of atherosclerotic lesions. We set out to investigate the interactions between oxidized LDL (oxLDL) and rat mesangial cells (RMC) that might be of importance in the glomerulosclerotic process. Our results show that RMC have the ability to oxidize LDL, that oxLDL binding was 2-3-fold greater than native LDL (nLDL), and that oxLDL was more cytotoxic to these cells than nLDL. We speculate that cell-mediated oxidation of LDL in vivo may play a role in the progression of the glomerulosclerotic process.

Animals↗
PubMed1993

Effect of cyclosporin A on endothelin synthesis by cultured human renal cortical epithelial cells.

We report here for the first time that human renal proximal tubular cells secrete endothelin, clear evidence of de-novo endothelin synthesis by these cells and the effect of cyclosporin A (CsA) on endothelin synthesis both in short-term (24 h) and medium-term (5-day) culture. Human renal cortical epithelial cells were cultured and shown to possess proximal tubular characteristics. These cells produced endothelin in culture in a time-dependent manner, as measured by radioimmunoassay (291.6 +/- 51.4 pg/well/24 h). Furthermore, endothelin production by these cells was significantly decreased by up to 80% by cycloheximide (1051.8 +/- 54.9 pg/mg cell protein/24 h versus 253.2 +/- 12.6 pg/mg cell protein/24 h), showing that these cells actively synthesize endothelin. In short-term culture (24 h), CsA significantly inhibited endothelin synthesis at a medium concentration of 10,000 micrograms/l. No change in endothelin synthesis was seen at lower CsA concentrations. In contrast, over a 5-day period, a non-significant increase in endothelin synthesis was observed at CsA concentrations of 2000 micrograms/l (152.5 +/- 20.4%); however, cell growth was significantly decreased at this concentration (71.33 +/- 6.39%). Using a newly developed two-site immunoradiometric assay specific for endothelin-1 (ET-1), we demonstrate that ET-1 is the major endothelin isoform produced by human renal proximal tubular cells.

Animals↗
PubMed1993

Serum cholesterol falls spontaneously in nephrotic patients with progressive renal disease.

Total cholesterol (TC) levels were lower than expected in some patients with advanced renal disease and nephrotic-range proteinuria. Studies of 35 clinically stable nonuremic patients and of 12 nephrotic patients with advancing renal failure were therefore performed. Analysis of pooled biochemical data from 35 patients who were hypercholesterolemic on entry to the clinic revealed a positive correlation between TC and reciprocal creatinine (l/Cr) while serum albumin (ALB) was negatively correlated with l/Cr and TC. In the 12 nephrotic patients with negative reciprocal creatinine slopes there was a strong correlation between the slopes of l/Cr and TC. These data suggest that plasma cholesterol falls in the nephrotic hypercholesterolemic patients in whom renal disease progresses, and that the slopes of plasma cholesterol and reciprocal creatinine are closely related.

Cholesterol↗
PubMed1993

Low-dose simvastatin is safe in hyperlipidaemic renal transplant patients.

Hyperlipidaemia is common after renal transplantation, and because of its association with atherosclerosis, interest has increased in the use of lipid-lowering drugs in transplant patients. Dietary approaches have not been consistently successful, and multiple pharmacotherapy and drug interactions have led to difficulties in establishing lipid-lowering drug regimes. The statins reduce plasma cholesterol by inhibiting the rate-limiting step in cholesterol synthesis, and although some side-effects have been reported in their use after transplantation, the efficacy and safety of low doses has not been formally established. A randomized single-blind placebo crossover study designed to determine the safety and effectiveness of simvastatin in a single daily 5-mg evening dose was therefore conducted in 26 stable renal transplant patients, 14 of whom were receiving cyclosporin A. The results demonstrated no difference between total cholesterol levels in the baseline simvastatin and placebo periods: 7.97 +/- 1.2 and 7.59 +/- 1.5 mmol/l respectively. After 8 weeks of simvastatin, the total cholesterol declined significantly to 6.72 +/- 0.87 mmol/l (P < 0.001). A significant difference was found when the placebo and simvastatin cholesterol levels were compared at 4 and 8 weeks (P < 0.01). LDL cholesterol decreased from 4.74 +/- 0.87 to 3.78 +/- 0.78 mmol/l after 8 weeks on simvastatin (P < 0.001), and apo B fell from 142 +/- 31 to 112 +/- 22 mg/dl (P < 0.001). The difference in LDL cholesterol and apo B after 8 weeks of simvastatin when compared with the corresponding values on placebo was also significant (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Cervical myelopathy presenting as a genu recurvatum gait disorder.

A 49-year-old man presenting with a genu recurvatum gait disorder was found to have a cervical myelopathy, probably on the basis of cervical spondylosis and a cervical disc herniation compromising a congenitally narrow cervical spinal canal. Satisfactory resolution of abnormal hyperextension of the knee was achieved through the use of an ankle-foot orthosis. A genu recurvatum gait disorder as the presenting sign of cervical myelopathy does not appear to have been reported previously.

Cervical Vertebrae↗
PubMed1993

Calcium set point progressively worsens in hemodialysis patients despite conventional oral 1-alpha hydroxycholecalciferol supplementation.

Calcium set point was measured in 12 patients on chronic hemodialysis. Dialysate calcium concentration was 1.65 mmol/l. Calcium carbonate (CaCO3) was used as the phosphate binder and oral 1-alpha hydroxycholecalciferol (alfacalcidol) was administered in a dose of 0.25-1.0 micrograms/day for 12 months. Comparing base line and post study values, there were no significant changes in ionized calcium (ICa++), intact immunoreactive parathyroid hormone (iPTH), plasma total calcium (TCa++), plasma phosphate (P), alkaline phosphatase (ALP), or aluminum (Al). However, the relative calcium set point significantly worsened (shifted to the right). Three patients developed hypercalcemia (25%) with a total calcium > 2.65 mmol/l. Total bone mineral content (BMC) fell suggesting demineralization. We conclude that this dose of oral alfacalcidol, CaCO3, and a dialysate calcium concentration of 1.65 mmol/l are not sufficient to halt the progression of secondary hyperparathyroidism in chronic hemodialysis patients. Measurement of calcium set point may be the best early measure of failure to prevent worsening of hyperparathyroidism.

Administration, Oral↗
PubMed1992

Lipoprotein(a) in patients with proteinuria.

Lipoprotein(a) (Lp(a)) has recently been recognized to be a risk factor for coronary heart disease. Lp(a) median values in the absence of renal disease are around 10 mg/dl. Higher levels (greater than or equal to 30 mg/dl) correlate with the occurrence of coronary heart disease, particularly in the presence of elevated cholesterol. We have studied Lp(a) in 76 adults with proteinuria. Fifty had glomerular diseases and 26 non-glomerular diseases, with renal function varying from normal to advanced chronic renal failure. Lp(a) values were shifted to the right, with a median of 21.0 mg/dl, and 25% of patients had values of 30 mg/dl or more. Lp(a) did not correlate with cholesterol, age, lipoprotein subclasses, apoproteins A-I or B-100, albumin, creatinine, or creatinine clearance. Median Lp(a) values did not differ significantly comparing men versus women, or glomerular versus non-glomerular disease. Lp(a) may inhibit fibrinolysis, and is deposited in atherosclerotic lesions. Although the cause of these elevated Lp(a) levels is uncertain, we propose that they contribute to the increased risk of coronary heart disease in the nephrotic syndrome, and may play a role in progressive renal disease.

Adolescent↗
PubMed1992

Screening for renovascular disease with captopril-enhanced renography.

Changes in renal function caused by angiotensin-converting-enzyme (ACE) inhibitors can be detected on 99mTc-DTPA renography so that DTPA scanning before and after a single dose of captopril can be used to screen for renovascular disease. We have performed captopril-DTPA scans with renal arteriography on 104 patients, of whom 27 had renal artery stenosis, all due to atheroma. Using a 5% fall in divided function or a delay of greater than 15 min in time to peak activity on one side after captopril, or the finding of greater than 90% divided function on one side before captopril as criteria for a positive scan, a sensitivity of 93% and specificity of 70% was achieved. The negative predictive value of the test in our population was 93%. Bilateral improvement in renographic function after captopril was seen in patients with accelerated phase hypertension. The presence of bilateral renal artery disease did not reduce the sensitivity of the test, but sensitivity was reduced (75%) in patients with renal impairment. Clinical characteristics in our patients most strongly associated with renal artery stenosis were abdominal bruit, recurrent left ventricular failure, and peripheral vascular disease. In view of the well-publicized risks of ACE inhibitor therapy, care should be exercised in the use of these agents in such patients.

Adult↗
PubMed1992

Effect of 24,25-dihydroxycholecalciferol on intestinal absorption of calcium and phosphate and on parathyroid hormone secretion in chronic renal failure.

Twelve patients with chronic renal failure (CRF) requiring dialysis, 7 of whom were hypercalcaemic, were treated with 24,25-dihydroxycholecalciferol [24,25(OH)2D3; 10 micrograms daily for 3 months] or placebo and the treatment then crossed over for a further 3 months. Treatment with 24,25(OH)2D3 was associated with small but significant increments in the fractional rates of absorption of calcium (p less than 0.01) and phosphate (p less than 0.05) measured by a combined radioisotope test, but even during treatment, the absorption of both calcium and phosphate remained subnormal. A significant fall in immunoreactive parathyroid hormone (i-PTH) levels occurred during treatment (p less than 0.05) in the absence of significant changes in plasma ionised calcium and plasma phosphate levels. In 7 patients, treatment with 24,25(OH)2D3 converted parathyroid glands which were non-suppressible by calcium infusion before treatment to suppressible ones (greater than 50% suppression of i-PTH levels) at similar levels of ionised calcium. 24,25(OH)2D3 may have a role in the treatment of renal osteodystrophy, especially in patients with hypercalcaemic hyperparathyroidism.

Adult↗