M.K. Chan

LIPID NEPHROTOXICITY IN CHRONIC PROGRESSIVE GLOMERULAR AND TUBULO-INTERSTITIAL DISEASE

It is hypothesised that chronic progressive kidney disease may be mediated by abnormalities of lipid metabolism. A series of self-perpetuating secondary events follows an initial glomerular injury. Increased glomerular basement membrane permeability leads to loss of lipoprotein lipase activators, resulting in hyperlipidaemia. Circulating low-density lipoprotein binds with glycosaminoglycans in the glomerular basement membrane and increases its permeability. Filtered lipoprotein accumulates in mesangial cells and stimulates them to proliferate and produce excess basement membrane material. The proximal tubular cells metabolise some of the filtered lipoprotein and the remainder are altered on passage down the nephron. Luminal apoprotein precipitates, initiating or aggravating tubulo-interstitial disease, if the intraluminal pH is close to the isoelectric point of the apoprotein. The hypothesis offers new approaches to the study of chronic progressive kidney disease by proposing a major pathogenetic role for lipid abnormalities.

Hyperlipidaemia in untreated nephrotic syndrome, increased production or decreased removal?

The relative importance of increased lipoprotein synthesis and decreased lipoprotein catabolism is examined in 13 patients with untreated nephrotic syndrome by the use of intravenous fat tolerance tests analysed in relation to other parameters of lipid metabolism. Increased lipoprotein synthesis in nephrotic patients was indicated by the fact that at a given fractional clearance rate of Intralipid (K2), nephrotic patients had higher serum TG concentrations than did control subjects. A defect in lipoprotein catabolism was also suggested by the frequent finding of intermediate density lipoproteins on electrophoresis and the marginally low (p = 0.05) mean K2 in nephrotic patients. A highly significant (p less than 0.001) positive correlation between HDL-cholesterol concentrations and postheparin fractional clearance rates (K2) of Intralipid led to the speculation that in the severe nephrotic state (albumin less than 20 g/l) the loss of high density lipoproteins may contribute to the hyperlipidaemia.

Plasma lecithin-cholesterol acyltransferase activities in uraemic patients

Plasma lecithin-cholesterol acyltransferase (LCAT) activity was measured in 43 haemodialysis and 15 peritoneal dialysis (CAPD) patients. LCAT activities in both groups of patients were significantly lower than those of normal subjects and did not correlate with any of the other biochemical parameters studied. The effect of intravenous administration of 100 U/kg of heparin on LCAT activity was examined in 21 haemodialysis patients and 19 normal subjects. Heparin inhibited LCAT activity by increasing plasma free fatty acid concentrations. LCAT remained inhibited throughout a dialysis session and returned towards pre-dialysis levels an hour after haemodialysis was discontinued. The cause of the low LCAT activities in the patients was not certain, but did not appear to be due to the presence of inhibitors in the uraemic plasma. The significance of these findings is discussed.

Plasma LCAT activities in renal allograft recipients

Plasma LCAT activities were measured in 51 renal allograft recipients as well in 18 patients before and after successful renal transplantation. The mean plasma LCAT activity of the 51 patients did not differ significantly from that of 27 normal subjects. When the patients were separated into two groups according to whether they had normal or impaired renal function, there was no significant difference in their mean LCAT activities. Plasma LCAT activities correlated significantly with total cholesterol and total triglyceride concentrations. The sequential study demonstrates that the low plasma LCAT activities in uraemic patients rose towards normal after successful transplantation. At the same time, total cholesterol and HDL-cholesterol concentrations also increased. The increase in LCAT activity after renal transplantation is due to increased concentrations of the enzyme and probably reflects increased turnover of triglyceride-rich lipoproteins.

Fat clearance before and after heparin in chronic renal failure—Haemodialysis reduces post-heparin fractional clearance rates of intralipid

The effect of heparin on the kinetics of fat removal was studied in 15 subjects and it became apparent that the fat tolerance test could be performed after the administration of heparin. Therefore, fractional clearance rates of Intralipid were determined before and after heparin in three groups of patients: 18 in chronic renal failure, 11 on peritoneal dialysis and 17 on haemodialysis. Patients on peritoneal dialysis and on haemodialysis had similar serum triglyceride concentrations and comparable fractional clearance rates of Intralipid before heparin was given. However, the latter had significantly smaller increases in fractional rates of Intralipid clearance after the administration of heparin. Either gradual diminution of releasable releasable enzymes by regular heparinisation or activator concentrations becoming rate-limiting could be responsible for the low post-heparin fractional clearance rates observed in haemodialysis patients.

Response Patterns to DL-Carnitine in Patients on Maintenance Haemodialysis

10 hypertriglyceridaemic hemodialysis patients were given dl-carnitine, 600 mg daily, for 8 weeks and then 1.2 g daily for 12 weeks. Serum total cholesterol, total triglyceride, high-density lipoprotein cholesterol and plasma free fatty acid (FFA), glucose, and immunoreactive insulin concentrations were measured at regular intervals during the treatment. Intravenous fat tolerance tests were performed in 9 patients. Plasma FFA concentrations fell and the post-heparin fractional clearance rate of Intralipid increased significantly after all-carnitine administration. While overall no clear-cut effect of dl-carnitine on serum lipids was found, two patterns of response to dl-carnitine could be distinguished: the paradoxic response with a rise in serum triglyceride concentrations and the dual response to two different dosages of dl-carnitine.

Fat clearances and hyperlipidaemia in renal allograft recipients — the role of insulin resistance

The mechanism of hyperlipidaemia in renal allograft recipients was investigated in 19 patients randomly selected from a cohort of 54 patients with functioning renal allografts. Serum cholesterol, triglyceride and high-density lipoprotein cholesterol concentrations as well as plasma immunoreactive insulin levels were measured in fasting blood samples. Intravenous fat tolerance tests were performed before and 15 min after heparin administration. Renal allograft recipients had reduced fractional clearance rates of Intralipid and a positive correlation was demonstrated between plasma immunoreactive insulin levels and serum triglyceride concentrations. Plasma immunoreactive insulins also correlated inversely with fractional clearance rates of Intralipid. It was concluded that both increased production and decreased removal of lipoproteins contribute to the hyperlipidaemia and that insulin resistance due to corticosteroids was the centre of the problem.

Cefuroxime Pharmacokinetics in Continuous and Intermittent Peritoneal Dialysis

Pharmacokinetics of cefuroxime was studied in patients on continuous ambulatory or intermittent peritoneal dialysis. A single intravenous bolus (15 mg/kg) of cefuroxime provided a mean serum concentration of 86 mg/litre 5 min, 40 mg/litre 1 h, 163 mg/litre 24 h after the injection. The peritoneal clearance of cefuroxime varied widely among different individuals, ranging from 1.45 to 6.17 ml/min with a mean of 3.59 ml/min during 4-hour exchanges, and from 0,52 to 11.3 ml/min during 2-hour exchanges. A single injection (15 mg/kg) of the antibiotic could not provide satisfactory antibiotic concentrations in peritoneal effluent during peritoneal lavage. When cefuroxime had been added to peritoneal dialysis solution before the solution was instilled into the peritoneal cavity, a significant decrease in cefuroxime concentration occurred in the peritoneal effluent even after a short equilibration time. Furthermore, cefuroxime concentrations measured in residual dialysis solutions in the plastic bags ranged from 44.3 to 1,351% of the concentration of cefuroxime calculated from the added doses, indicating that despite great care, mixing of the antibiotic with dialysis solutions in plastic bags was far from uniform.