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Biomedical subjects

Z Varghese

Publications and source records attributed to Z Varghese.

At least 55 records · Page 3Linked to original sources
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

Short report: plasma aluminium concentration and 24-hour urinary aluminium excretion before, during and after treatment with sucralfate.

Ten dyspeptic patients were treated with 1 g sucralfate q.d.s. for six weeks. The plasma aluminium concentration and 24-h urinary aluminium excretion were measured at 3-weekly intervals before, during and after treatment with sucralfate. Compared with before treatment, there were significant rises in the median plasma aluminium concentration at 3 and 6 weeks during treatment with sucralfate (6 micrograms/L to 13 and 12 micrograms/L). The median 24-h urinary aluminium excretion rose significantly from a pretreatment level of 20 micrograms to 71 and 78 micrograms after 3 and 6 weeks of treatment; the significant increase of urinary aluminium excretion persisted for three weeks after cessation of treatment (52 micrograms/24 hours), but thereafter urinary excretion was not significantly different from pretreatment. The results are consistent with significant absorption and tissue accumulation of aluminium during standard treatment with sucralfate in individuals with normal renal function.

Adult↗
PubMed1991

Partial lecithin:cholesterol acyltransferase (LCAT) deficiency in Balkan endemic nephropathy.

The role of lipid abnormalities has been also implicated in the progression of renal diseases. The search for lipid abnormalities in Balkan endemic nephropathy (BEN) has roused sporadic interest and has not been fully elucidated. This study was performed in 54 healthy subjects from the families affected with BEN (group A), 18 members from non-affected families living in the same location (group B), and 25 control subjects (group C). Lipid profiles and lecithin:cholesterol acyltransferase (LCAT) were determined in each subject. The most striking distinction between the groups was that of the LCAT activity, which was abnormally low in group A (39 +/- 2), significantly different (P less than 0.0001) from that of the other groups. Thirty individuals from group A were those accounting for the low LCAT activity (A1). This group had a significantly lower total cholesterol and free cholesterol than all of the other subjects. The entire group A subjects had a significantly lower percentage of free cholesterol than the other two groups. There was no significant difference in HDL cholesterol between any of the groups, but group A1 had significantly higher HDL than group C (P less than 0.04). What emerges from our study is that a certain proportion of subjects from BEN families have a peculiar form of lipid abnormalities associated with an abnormal LCAT activity. At present we have no explanation for these findings. We believe that these changes may have an important role in the pathogenesis of BEN.

Adult↗
PubMed1990

Conversion of stable renal allografts at one year from cyclosporin A to azathioprine: a randomized controlled study.

Seventy-seven stable, nondiabetic, cadaveric renal transplants were randomized at 1 year to convert from cyclosporin A to azathioprine or to continue on cyclosporin A. Prednisolone was increased twofold during the period of conversion, and there was a 3-week overlap period during which azathioprine and cyclosporin A were given. No grafts were lost due to rejection related to conversion, but 9 of the 33 patients who were randomized to convert experienced rejection episodes and 6 were returned to cyclosporin A. Conversion to azathioprine resulted in a drop in creatinine and improvement in blood pressure control. In the group randomized to stay on cyclosporin A, 6 patients had to be subsequently converted to azathioprine because of cyclosporin A toxicity in spite of well-controlled plasma levels. The creatinine levels after successful conversion remained stable whereas those of the patients continuing on cyclosporin A showed a progressive decline. We conclude that conversion from cyclosporin A to azathioprine can be achieved safely. Progressive deterioration in graft function with continuing cyclosporin A therapy does occur and should be taken as an indication for conversion.

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↗
PubMed1990

Cyclosporin-induced renal magnesium leak in renal transplant patients.

Renal transplant patients (n = 116) attending an outpatients clinic were screened for hypomagnesaemia. No azathioprine-treated patients (n = 46) but 24% (17 of 70) of the cyclosporin treated patients were hypomagnesaemic. The hypomagnesaemia in all cases was associated with a renal magnesium leak. This leak did not correlate with plasma bicarbonate, urate, calcium, cyclosporin or creatinine concentrations, nor did it correlate with the use of loop diuretics or duration of the transplant. A renal magnesium leak is common in renal transplant patients treated with cyclosporin and it is independent of other markers of nephrotoxicity.

Adult↗
PubMed1990

Newcastle bone disease in Hong Kong: a study of aluminum associated osteomalacia.

We measured serum aluminum concentrations in 104 haemodialysis patients from 3 centres in Hong Kong. We found that the 52 patients dialyzed in unit A had much higher mean aluminium levels (100 micrograms/L) than those from the other two units (61 and 39 micrograms/L respectively). In unit A, where water treatment by reverse osmosis had been introduced only recently, 30.8% of patients had fractures/looser zones, 46.2% had rugger-jersey spine and 28.8% had skeletal erosions. When these patients were divided into two groups according to whether their serum aluminium concentration was below or above 100 micrograms/l, the latter patients had significantly lower alkaline phosphatase, serum phosphate, and higher total prescribed dose of aluminium hydroxide. It was concluded that both dialysate aluminium and oral aluminium intake seemed to have contributed to the high incidence of osteomalacic fractures among Unit A patients. In eight of these patients serum aluminium increased by more than 150 micrograms/L after four weeks of receiving 1.5 g desferrioxamine twice weekly. Serial X-rays showed that the mean time after dialysis for the appearance of fractures/Looser zones was 72 months. Three patients developed fractures/Looser zones after successful renal transplantation; and it was postulated that the prompt excretion of aluminium permitted increased osteoclastic activity, resulting in fractures in these patients.

Adult↗
PubMed1989

An in vitro model of nephrocalcinosis using rabbit inner medullary collecting tubular cell culture.

In order to investigate the pathogenesis of medullary nephrocalcinosis, rabbit inner medullary collecting duct cells were grown in media containing different Ca++, PTH and pH levels. It was found that high Ca++ (7.8mM) only reduced growth slightly and that crystalline deposits were found under the cells. This suggests that high Ca++ is not severely toxic to the cells but can lead to deposition of calcium beneath the basement membrane. PTH did not effect cell growth even in the presence of high Ca++ implying that it has an indirect effect on tubular cells in medullary nephrocalcinosis associated with hyperparathyroidism. In renal tubular acidosis these cells are subjected to a persistently high urinary pH and low interstitial pH. Raising the pH reduced the cell growth in normal Ca++ medium whereas lowering the pH increased cell growth in vitro. Our results show that nephrocalcinosis is not due to the direct effect of raised pericellular Ca++ or PTH alone and that persistently alkaline tubular fluid may play a role.

Animals↗
PubMed1989

Logistic regression model for the assessment of microalbuminuria and microproteinuria in insulin-dependent diabetic patients at risk.

Diabetic microalbuminuria, which predisposes to the irreversible macroproteinuria and terminal renal failure, has been shown to be reversible by stringent metabolic control. In this study, using logistic regression, 23 patients with insulin-dependent diabetes mellitus were evaluated. Basing on the reported biochemical changes in patients with diabetes mellitus, the relationship between microalbuminuria and serum biochemistries was assessed. Four biochemical parameters were shown to be significantly related to the amount of microalbuminuria and microproteinuria. The microalbuminuria as assayed by rocket immunoelectrophoresis is closely correlated with the microproteinuria as measured by the Coomassie dye binding method and both have a significant relationship with plasma creatinine, bicarbonate, albumin and globulin as assessed by the Minitab computer program and the Biomedical Data Package--Logistic Regression computer program. The relationship with bicarbonate and creatinine can be due to a decrease in glomerular filtration rate associated with more advanced microproteinuria. The relationship with albumin and globulin is the result of impaired albumin synthesis by the liver in diabetes mellitus. From these data, two simple equations which can provide a relative risk factor with rough quantitative assessment for microproteinuria and microalbuminuria are derived. Thus, from these four parameters available from relatively simple blood biochemistries, assessment can be made of the severity of coexisting diabetic proteinuria. The measurement of the latter is not readily available and is more costly and tedious. This assessment together with the finding of a decrease in albumin, slight increase in creatinine and decrease in bicarbonate associated with the more severe microalbuminuria can be used to alert the diabetologist in implementing tighter metabolic control and other interventional methods before irreversible macroproteinuria develops.

Adult↗
PubMed1989

Low-dose vs high-dose intravenous methylprednisolone therapy for acute renal allograft rejection in patients receiving cyclosporin therapy.

Three mg/kg bodyweight per day of intravenous methylprednisolone for 3 consecutive days is as effective as 15 mg/kg bodyweight per day of methylprednisolone in reversing acute renal allograft rejection (80% vs 68%; 95% confidence intervals of the difference are -8% to 32%). This dose was not associated with an increased incidence of further rejection episodes. It may not be necessary to continue with the common practice of administering high-dose intravenous methylprednisolone for acute renal graft rejection.

Clinical Trials as Topic↗
PubMed1989

In vitro cyclosporine toxicity. The effect of verapamil.

The epithelial cell line LLC-PK1, which expresses many proximal tubular characteristics, was used to investigate the relationship between calcium, the calcium channel blocker verapamil, and cyclosporine toxicity. The LLC-PK1 cells took up cyclosporine when this was added in a concentration of 2 micrograms/ml, and this uptake was maximal at 30 min (112 +/- 3 ng cyclosporine/mg cell protein). At 12 micrograms/ml it inhibited the sodium glucose cotransporter, as assessed by phlorizin-inhibitable 14C-alpha-methyl glucopyranoside (alpha-MG) uptake (control 37.2 +/- 6.3, 12 micrograms/ml 21.2 +/- 1.1 mumol/hr/mg protein). Cyclosporine at 2 micrograms/ml did not affect cell growth after 5 days (control 945 +/- 60 micrograms cell protein per 25 cm2 flask, 2 micrograms/ml cyclosporine/ml 1046 +/- 32 micrograms protein/flask), even in the presence of 7.6 mM ionized calcium (862 +/- 37 micrograms protein/flask). Cyclosporine at 12 micrograms/ml inhibited cell growth (286 +/- 27 micrograms protein/flask), and raising the ambient ionized calcium concentration to 7.6 mM reduced cell growth further (91 +/- 6 micrograms protein/flask). Cyclosporine at concentrations of 2 and 12 micrograms/ml produced increasing cell vacuolation, as seen in vivo. Short-term uptake of 2 micrograms/ml cyclosporine could be inhibited by 1.0 mM and 0.5 mM verapamil (49 +/- 9.5 and 71 +/- 6.4 ng cyclosporine/mg cell protein, respectively, at 30 min). However, in the presence of 2 micrograms/ml cyclosporine 0.1 mM verapamil was toxic to the cells grown over five days (44 +/- 5 micrograms protein/flask). At 0.01 mM verapamil was not toxic to cell growth (921 +/- 29 micrograms protein/flask), but raising the medium calcium to 7.6 mM reduced cell growth (652 +/- 96 micrograms/ml). Inhibition of cyclosporine uptake did not occur with 0.01 mm verapamil (control 145.6 +/- 12.3 vs. 0.01 mM verapamil 150.4 +/- 3.8 ng cyclosporine/mg cell protein). The LLC-PK1 cell line represents a good in vitro model for cyclosporine renal tubular toxicity, as the in vivo observation of glycosuria and proximal tubular cell vacuolation in cyclosporine nephrotoxicity can be reproduced. In vitro this is shown to be associated with inhibition of sodium-dependent glucose cotransport. Verapamil inhibited cyclosporine uptake, but only at concentrations that were toxic to the cells. Verapamil potentiated rather than reduced the increased cyclosporine toxicity produced by increasing the medium calcium concentration. The suggested protective effect of verapamil against cyclosporine nephrotoxicity is therefore unlikely to be due to inhibition of cyclosporine uptake or of calcium entry into proximal tubular cells.

Calcium Channels↗
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↗
PubMed1989

Apolipoprotein B turnover in dialysis patients: its relationship to pathogenesis of hyperlipidemia.

Exogenously labelled Iodine-125-VLDL (very low density lipoprotein) was given intravenously to twelve dialysis patients and four normal controls. Specific activities of I-125-VLDL apoB (apolipoprotein B) and I-125-IDLapoB (intermediate density lipoprotein apolipoprotein B) were measured for forty-eight hours. Synthesis rates (flux) and fractional catabolic rates (FCRs) of VLDLapoB and IDLapoB for hyperlipidemic (n = 8), normolipidemic (n = 4) dialysis patients and controls (n = 4) were calculated. Dialysis patients had lower VLDLapoB FCRs than controls (p less than 0.05); hyperlipidemic dialysis patients had marginally raised VLDLapoB flux over normolipidemics (p = 0.0508), suggesting apoB production might play a greater role in the pathogenesis of hyperlipidemia. Hyperlipidemics had lower IDLapoB FCRs than controls (p = 0.01). IDLapoB flux was similar in all three groups. The discrepancy in VLDLapoB fluxes between hyperlipidemics and normolipidemics with similar IDLapoB fluxes suggested that VLDLapoB could be directly catabolized in hyperlipidemics. ApoB concentration was increased in VLDL, IDL of hyperlipidemics when compared with normolipidemics (p less than 0.05) and controls (p = 0.01). Hyperlipidemic VLDL plasma levels were relatively enriched with cholesterol when compared with controls, p less than 0.01, and normolipidemics, p less than 0.05. These factors might all contribute towards accelerated atherogenesis in hyperlipidemic dialysis patients.

Adult↗
PubMed1988

Effects of diets with high carbohydrate content on diabetic hyperlipidaemia and microalbuminuria.

Recent dietary recommendations for patients with diabetes mellitus have focussed on the liberalisation of carbohydrate intake to at least 50% of total calories. However, there are reports that this diet may cause adverse metabolic effects as a result of high intake of carbohydrate. Whether this high-carbohydrate diet will exacerbate hypertriglyceridaemia, which increases the risk of atherosclerosis, and diabetic microalbuminuria, which predisposes to progressive renal failure, is unknown. The dietary intake of 28 patients with insulin-dependent diabetes mellitus was assessed by diet histories with both questionnaire surveys and 3-day recall methods. The dietary contents of different constituents were graded according to the type and amount of food typically eaten, and the frequency of their consumption in the past 6 months. Twelve patients were found to have a high dietary intake of carbohydrate and this was confirmed by detailed assessment of food intake records over a 3-day period. The carbohydrate intake of these 12 patients amounted to at least 55% of total calories. Total calorie intake, body weight, mean blood pressure, glycaemic control, and glomerular filtration rate were similar between the 12 patients with high intake of carbohydrate and the other 16 patients with low intake. Urinary protein and albumin appearance as measured by dye binding and immunoassay, fasting cholesterol, triglyceride and high-density lipoprotein cholesterol were also comparable between the two groups. This study provides evidence that a high-carbohydrate diet in the treatment of diabetes mellitus is not associated with significant alterations in the amount of microalbuminuria or in hypertriglyceridaemia.

Adult↗