Search

In the present review, the role of lipid disturbances is evaluated as a risk factor in the pathogenesis and the potential acceleration of atherosclerosis in uremic patients undergoing long-term hemodialysis. The alteration in high density lipoprotein composition with a decrease in high density lipoprotein cholesterol but a normal apoprotein AI content may have relevance to the atherogenetic process. Moreover, the accumulation of cholesterol-rich, very low density lipoproteins and intermediate density lipoproteins may play a major role in atherosclerosis since these degradation products of triglyceride-rich particles are considered as atherogenic. The hypothesis should be tested whether a correction of the abnormal catabolism of triglyceride-rich lipoproteins in uremic patients leads to a decrease in ischemic vascular events.

The following conclusions and speculations can be tentatively drawn from the changes in lipoprotein composition and metabolism: (1) The presence of apo B-48 in serum VLDL and the high serum apo A-IV concentrations indicate a greater than normal contribution of alimentary remnant particles to the hypertriglyceridemia of uremic patients, (2) The presence of apo E and C in triglyceride-enriched serum LDL, together with the triglyceride enrichment of all lipoproteins, probably stems from a deficiency of lipoprotein lipase (LPL) and hepatic lipase (HL) activity, (3) The decreased ratio of serum apo C-II/C-III in VLDL is at least in part responsible for the depressed activity of LPL, (4) The accumulation of lipoprotein particles with distorted apoprotein and lipid patterns (particularly beta-VLDL with enrichment in cholesterol) could be associated with an increased atherogenesis because a recent study has demonstrated a strong association between raised serum IDL and VLDL concentrations and the degree of coronary atherosclerosis, (5) The increased apo E content of VLDL and HDL in uremic patients could particularly point to a disturbed cholesterol metabolism because such lipoproteins could interact with LDL at apo B, E receptors, (6) The decrease in serum HDL-cholesterol has been shown to be strongly associated with atheromatous vascular disease, and this could also hold for uremic patients; however, it is probable that low serum HDL-cholesterol together with a diminished capacity to form cholesterol-rich, apo E containing HDL represents a decrease in the antiatherogenic defense of the organism rather than an increased atherogenic potential [21].

In this study we were able to evaluate the total lactate dehydrogenase activity of serum of children year by year. We also defined by electrophoresis the normal isozyme profile for each age group. We noted that the total activity was higher during the first years of life and that during this period, the isoenzymic profile was different from that of adults: higher percentage of LDH 5 (13% as against 8% in adults) and a lower percentage of LDH 1 (19% as against 24% in adults). Furthermore, it seemed to us preferable to determine the total LDH activity on fresh serum for a fall in activity is noted both after preservation at + 4 degrees C and -20 degrees C. Similarly, it is preferable to trace the isoenzyme profile on the same day rather than after preservation of the samples. The average differences show clearly the disappearance of certain fractions (isoenzymes 4 and 2 after six days preservation at + 4 degrees C). However, each serum seems to behave in a somewhat unforseeable manner and the dispersion of individual variations makes any statistical interpretation impossible.

We investigated serum lipoproteins in uraemic and kidney transplant patients, and compared the results with those from normal persons. In uraemic patients, with or without haemodialysis, and in kidney transplant patients, the ratio of HDL-cholesterol to total cholesterol minus HDL-cholesterol, the ratio of HDL-phospholipids to total phospholipids minus HDL-phospholipids, and the ratio of apolipoprotein A to apolipoprotein B are all decreased, though to different extents, when compared with healthy control subjects. Furthermore, important differences exist in the relative HDL composition between the 3 patient groups and healthy control subjects. Thus, the ratio of apolipoprotein A/HDL-cholesterol and that of HDL-cholesterol/HDL-phospholipids are significantly altered in uraemic haemodialyzed patients, while the ratio of apolipoprotein A/HDL-phospholipids is normal. By contrast, the 3 ratios are normal in uraemic undialyzed patients, and the 2 ratios, apolipoprotein A/HDL-cholesterol and apolipoprotein A/HDL-phospholipids are normal in renal transplant patients. The last ratio, HDL-cholesterol/HDL-phospholipids, is increased in this group of patients. Thus, it appears that HDL-cholesterol, HDL-phospholipids, and total apolipoprotein A represent different aspects of the same lipoprotein. The determination of all three parameters could lead to a different approach in the evaluation of the so-called cardiovascular risk, at least for uraemic patients and renal transplant patients.

The possible mechanisms of the increase in serum triglycerides (TG) and TG-rich lipoproteins were studied in chronically uremic (U) rats by comparison with either ad-lib fed control (C) rats or diet-restricted (DR), sham-operated pair-fed control rats. A first series of animals was studied in the fed state and a second series after a 16-hr fast. In U animals the concentration of serum TG and TG-rich particles was lower than that of C rats in the fed state but significantly higher than that of C and DR rats after a 16-hr fast. Serum glucose and lactate concentrations in the fed or fasted state were unchanged by uremia. Serum insulin concentration was significantly decreased in U rats as compared to C and DR rats in both series. The fast did not increase the concentration of serum nonesterified fatty acids (NEFA) in U or DR animals to the same extent as in C rats, whereas the serum concentration of beta-hydroxybutyrate (BOB), which was higher than that of C rats in the fed state, was significantly lower after a 16-hr fast. In U animals, as compared to control rats of either series, a significant decrease of epididymal lipoprotein lipase (LPL) activity was observed during both nutritional states when expressing the enzymic activity per number of cells. In conclusion, our data provide evidence against hepatic over-production of TG-rich lipoproteins in rats with chronic renal failure and strongly point to an LPL-mediated defect of their peripheral catabolism, probably related to the insulin deficiency state.

An in vivo atherogenic role of dietary vitamin D has been postulated. To address this hypothesis we sought to determine the in vitro effects of its active circulating metabolite, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on lipid metabolism in human monocyte-derived macrophages. When cultured 6 days in the presence of 10(-8) M 1,25(OH)2D3 monocyte-macrophages accumulated significantly more triglycerides than control cells: 987.6 +/- 26.8 vs. 779.3 +/- 24.1 micrograms/mg protein (P less than 0.001). Triglyceride accumulation was associated with a hormone-induced stimulation of triglyceride synthesis as determined by [3H]oleate incorporation into cellular triglycerides. The effect of the hormone was significant after 24 h and dose dependent [10(-11) to 10(-8) M 1,25(OH)2D3]. It was specific since 10(-7) M 25-hydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 did not stimulate triglyceride synthesis, and its magnitude decreased from 1 to 9 days of culture. 1,25(OH)2D3 (10(-8) M) modified the cholesteryl ester metabolism of monocyte-macrophages only in the presence of acetylated low-density lipoproteins (50 micrograms/ml); it induced a significant increase of cellular cholesteryl ester content (21.9 +/- 1.1 vs. 11.7 +/- 1.7 micrograms/mg protein; P less than 0.001) and of esterification rate of cholesterol measured by [3H]oleate incorporation into cellular cholesteryl esters (17.2 +/- 0.9 vs. 6.5 +/- 0.3 nmol.mg protein-1.24 h-1; P less than 0.001) by comparison with control cells. These results show that 1,25(OH)2D3 alters in vitro lipid metabolism in the human monocyte-macrophage and suggest a new in vivo role for the hormone.

The present study was performed to appreciate the potential role that thyroid deficiency could play in the energy homeostasis and lipid metabolism of experimental chronic renal failure. For this purpose, 12 uremic rats that were supplemented with T3 (0.4 microgram/100 g body weight/day) during 5 weeks by means of osmotically driven minipumps were compared to 12 unsupplemented uremic rats and 12 control rats. The chronic supplementation of uremic rats with T3 induced no significant change in body weight gain or in the serum concentration of insulin, glucose, glycerol, nonesterified fatty acids, total triglycerides (TG), total cholesterol, and total choline phospholipids. Similarly, the metabolism of TG-rich lipoproteins was not affected by the supplementation with T3 in these uremic rats as appreciated by TG production or TG degradation (adipose tissue lipoprotein lipase activity). T3 administration induced a significant decrease in serum beta-hydroxybutyrate concentration and an increase in serum lactate concentration. Furthermore, heparin-releasable hepatic TG lipase activity as expressed per total liver mass was decreased in uremic rats treated with T3. The latter changes were observed in the absence of modifications of serum glucose or TG concentration. We conclude from these observations that rats with a moderate degree of chronic uremia do not seem to have a cellular thyroid deficiency sufficient to disturb their energy or lipid metabolism.

Eleven patients with kidney stone disease and idiopathic hypercalciuria (urinary calcium above 4 mg/kg/j), without phosphorus renal leak and 6 control subjects have been put for 3 days on a diet containing 1 g calcium and 1 phosphorus daily (period A), and then for 4 days on a diet containing 1 g calcium, 450 mg phosphorus and 3 g aluminium hydroxyde daily (period B). During period A, no significant difference in blood calcium, phosphorus and magnesium, not in phosphaturia, rate of phosphorus reabsorption (RPR) and ratio maximum RPR/creatinine clearance was found between the two groups. After 2 days on a low phosphate diet (period B) the blood phosphorus decreased significantly in the hypercalciuric patients but not in the control subjects, thus revealing among the forme a latent abnormality in the retention of phosphates. This abnormality could play an important role in the pathogenesis of hypercalciuria.

The present study was performed to document factors playing a role in the age-related increase of serum total cholesterol, triglycerides, and phospholipids in male WISTAR rats. In 59 and 122 week old rats, serum concentrations of all three parameters were significantly higher than those determined in younger rats (15-17 weeks of age). Serum triglycerides and cholesterol concentrations were higher in post absorptive than in fasting state. In mature rats of same age (59 weeks), mean concentrations of cholesterol, triglycerides, and phospholipids were significantly higher in the heavier animals than in the others. A strong correlation could be established between body weight and serum cholesterol or triglycerides of these animals. The composition of diet appears to play a role in serum cholesterol concentration but not in serum triglycerides concentration in old rats (59-65 weeks of age). This effect is demonstrated even if daily caloric intake and daily body weight gain of old rats (40-50 weeks of age) were not significantly different with both diets tested (2900 and 3250 cal/kg). In conclusion old Wistar rats develop increased concentrations of serum lipids parameters.