Mechanism for elevated plasma lipoprotein(a) concentrations in patients on dialysis: turnover studies.

Plasma concentrations of lipoprotein (a) [Lp(a)] are increased in patients on renal replacement therapy. Lipoprotein (a) is increasingly being recognized as an independent cardiovascular risk factor. In an effort to explore the mechanism for elevation of Lp(a) in patients on dialysis we have performed turnover studies of Lp(a) with radioactive iodine. Lp(a) was isolated from 1 patient on hemodialysis (HD) and 1 patient on continuous ambulatory peritoneal dialysis (CAPD); the protein was labeled with 125I and returned to each patient. Lipoprotein (a) was subsequently isolated from the patients over a 15-day period and the decay of the specific radioactivity of Lp(a) was used to determine the fractional catabolic rate (FCR), which was 0.27 (pool/day) for the HD patient and 0.28 (pool/day) for the CAPD patient. These rates are indistinguishable from those measured in 4 patients with hypercholesterolemia (0.29, SEM = 0.01) and in 4 other familial hypercholesterolemic patients (0.29, SEM = 0.02) studied previously using the same method by Knight et al. (7). We found no difference in the FCR of patients on dialysis when compared to patients with hyperlipidemia and normal renal function. Increased plasma concentration of Lp(a) in our patients on renal replacement therapy is not due to decreased catabolism, but is caused by increased synthesis.

Six-month prospective cross-over study to determine the effects of 1.1% amino acid dialysate on lipid metabolism in patients on continuous ambulatory peritoneal dialysis.

OBJECTIVE: To evaluate the effect of 1.1% amino acid dialysate (AAD) (Nutrineal, Baxter, Castlebar, Ireland) on lipid metabolism in hyperlipidemic patients on continuous ambulatory peritoneal dialysis (CAPD). DESIGN: Patients were alternately assigned to receive AAD in the first (group A), or the second (group B), 6 months of a prospective cross-over study. SETTING: University teaching hospital. PATIENTS: Eighteen stable CAPD patients with a serum cholesterol 5.5 mmol/L or greater. INTERVENTIONS: One post prandial exchange of AAD during a 24-hour period for 6 months. MAIN OUTCOME MEASURES: A significant change in serum lipid levels. RESULTS: Patients in group A (n = 10) received a single daily exchange of AAD in place of their post prandial dextrose exchange for the first 6 months, and then crossed over to the dextrose phase. Patients in group B (n = 8) continued their usual dextrose dialysis for the first 6 months and then crossed over to receive AAD in the latter 6 months. Measurements of serum lipids and lipoproteins along with other biochemical parameters were made at regular intervals. Although a downward trend in mean serum total cholesterol was seen on AAD in group A, no significant change in total cholesterol, low-density lipoprotein cholesterol, or high-density lipoprotein cholesterol was observed in any group. Mean serum triglycerides fell on AAD in both groups, but were not statistically significant. Serum lipoprotein(a) [Lp(a)] and apolipoprotein B were elevated in both groups but did not change on AAD or with time. No change was observed in serum apoprotein A1 levels. Serum Lp(a) was not correlated to dialysate protein excretion. No change in mean serum albumin was observed, in either group, on AAD. KT/V urea, total weekly creatinine clearance, net ultrafiltration, and dialysate protein excretion remained unchanged on AAD. CONCLUSIONS: The use of AAD, although clinically safe and without side effects, had no effect on the dyslipidemia in our group of CAPD patients.

The effect of change of renal replacement therapy on serum lipoprotein (a) concentration.

Lipoprotein (a) [Lp(a)] is an independent atherogenic risk factor. Lp(a) levels are elevated in patients on renal replacement therapy (RRT). This study looked at the effect of change of RRT on serum lipid and Lp(a) levels. Three groups were identified: (1) patients on dialysis who were transplanted; (2) those who had lost their transplants through immunorejection; (3) those who changed from continuous ambulatory peritoneal dialysis (CAPD) to hemodialysis (HD). All Lp(a) measurements were taken at least 3 months after the change of therapy. Our results were as follows: Group A (n = 21): 8 CAPD and 13 HD patients were transplanted. Median Lp(a) levels fell posttransplantation in the CAPD group (15.6 mg/dL vs 11.4 mg/dL, p = 0.04). The HD group showed a rise in cholesterol, low-density (LDL) and high-density lipoprotein (HDL) levels, with no change in Lp(a) levels. Group B (n = 11): 7 patients started CAPD and 4 HD. Overall, there was a marked increase in Lp(a) levels: median 38.2 mg/dL vs 55.9 mg/dL (p = 0.04), reflecting an increase in those starting CAPD (27.8 mg/dL vs 60.0 mg/dL, p = 0.01), with little change in the HD group (40.45 mg/dL vs 40.05 mg/dL). However, there was a decrease in cholesterol (7.4 mmol/L vs 5.1 mmol/L, p = 0.002) and LDL (5.5 mmol/L vs 3.3 mmol/L, p = 0.004). Group C (n = 16): 16 patients changed from CAPD to HD. Lp(a) levels were higher while on CAPD, as compared to when on HD (58.9 mg/dL vs 49 mg/dL, p = 0.03). Cholesterol (6.62 mmol/L vs 5.26 mmol/L, p = 0.006) and LDL (4.48 mmol/L vs 3.40 mmol/L, p = 0.004) were also higher when on CAPD. In conclusion, serum Lp(a) levels are clearly affected by the mode of the RRT, being highest in CAPD, and decline after transplantation or conversion to HD. Atherogenic risk is thus likely to differ between the modes of RRT and may be greatest for those on CAPD.

Energy balance in asymptomatic HIV infection.

OBJECTIVES: Body weight is regulated by the balance between energy intake and energy expenditure, but the influence of HIV infection on energy balance has not been fully examined. The main objectives of this study were (1) to assess the effect of HIV on energy balance, (2) to examine the relationship of parameters of immunodeficiency to energy balance, and (3) to examine the interrelationship of different components of energy balance in asymptomatic HIV-seropositive men. DESIGN: A cross-sectional study of nutrition and metabolism in asymptomatic HIV-seropositive men METHODS: Components of energy balance were examined in 104 asymptomatic HIV-seropositive men (CD4 count 4-482 x 10(6)/l) and 57 age-matched HIV-seronegative male controls. Energy and protein intake were measured using 5-day diaries, and small bowel absorption and permeability was assessed using four sugar probes. Resting energy expenditure was calculated from indirect calorimetry and nitrogen loss estimated from 24 h urine collection. Four methods were used to assess the effect of HIV infection on body composition (anthropometry, dual energy X-ray absorptiometry, bioelectrical impedance and 24 h urine creatinine). RESULTS: Resting energy expenditure per kilogram of fat-free mass was raised (P < 0.0001), fat mass was decreased (P = 0.001), fat-free mass was increased (P = 0.05), energy intake was higher (P = 0.05), absorption of L-rhamnose (P = 0.01) and 3-O-methyl-D-glucose was decreased (P = 0.003), and small bowel permeability was increased (P < 0.0001) in HIV-seropositive men compared with HIV-seronegative controls. HIV-seropositive subjects with a CD4 count less than 100 x 10(6)/l had decreased absorption of L-rhamnose (P < 0.05), D-xylose (P < 0.05) and 3-O-methyl-D glucose (P < 0.05) compared with HIV-seropositive subjects at higher CD4 counts, and had a similar resting energy expenditure to HIV-seronegative controls. Protein intake, carbohydrate, fat and protein oxidation. 24 h nitrogen excretion and appendicular muscle mass were similar in HIV-seropositive men and controls. CONCLUSION: HIV infection exerts a direct effect on parameters of energy balance that varies with the severity of immunosuppression.

Nutritional effects of amino acid dialysate (Nutrineal) in CAPD patients.

The use of amino acid dialysate (AAD) has been shown to improve the nutritional status of malnourished continuous ambulatory peritoneal dialysis (CAPD) patients. We report on a randomized, prospective, cross-over study evaluating the effects of a single, daily, postprandial 2-L exchange of 1.1% AAD (Nutrineal) on a nutritionally unselected group of 18 stable CAPD patients. Patients in group A (n = 10) were randomized to receive AAD in the initial six months, whereas group B (n = 8) patients received AAD in the final six months of the study. Regular biochemical, hematological, and anthropometric measurements were made. A computerized nutrition score(1) combined anthropometry, serum albumin, and total lymphocyte count. Improved nutritional status was indicated by a decreased score. Mean serum albumin and transferrin did not show a significant rise in either group. However, patients in group A, with a mean serum albumin of less than 30 g/L, showed a significant rise at two months, which persisted at six months (26.8 g/L on entry, 29.0 g/L at two months, 30.1 g/L at six months; p < 0.05 and p < 0.01, respectively). Treatment with AAD showed a trend towards improvement in midarm muscle circumference in both groups (22.9 -23.5 cm, group A; 22.9-23.7 cm, group B). The nutrition score improved in both groups but was significant only in group A (14.6 to 13.1; p = 0.02). These effects of AAD on the nutritional status of CAPD patients need validation in a long-term study to evaluate the effects on morbidity and mortality.

Lipids and lipoprotein(a) as risk factors for vascular disease in patients on renal replacement therapy.

A large cohort of patients on renal replacement therapy were screened for the presence of symptomatic arterial disease affecting the coronary, cerebral or peripheral circulations. Ninety-two of 325 patients were found to have vascular disease. Those with vascular disease had significantly higher median lipoprotein(a) [Lp(a)] levels than those without (38.4 vs 14.2 mg/dl, P < 0.001), with a preponderance of Lp(a) levels greater than 30 mg/dl (58% vs 25% P < 0.001). Apolipoprotein(a) [apo(a)] isoform distribution was similar between the groups, but those with vascular disease had higher Lp(a) levels in the S2, S3/S4 and S4 isoform types. Comparison of 76 matched pairs of patients confirmed elevated Lp(a) levels in those with vascular disease. These patients also had significantly higher total cholesterol (6.66 vs 6.02 mmol/l) and low-density lipoprotein cholesterol (4.49 vs 3.86 mmol/l). Only Lp(a) was independently associated with vascular disease (P = 0.02). Elevated Lp(a) levels are significantly associated with the presence of vascular disease in patients on renal replacement therapy and may constitute another risk factor for the development of such disease in these patients.

Prevalence of intermittent claudication and risk factors for its development in patients on renal replacement therapy.

The prevalence of symptomatic intermittent claudication (IC) was assessed using a standard cardiovascular questionnaire in a cohort of 325 patients on renal replacement therapy (RRT). IC was found in 19% of patients, 77% of whom were smokers and 22% diabetic. It was more common in men than women and in smokers than non-smokers (p < 0.001). Those with IC were significantly older (61 years vs. 50 years p < 0.001), smoked more (23 pack years vs. 12 pack years p = 0.002), had higher median systolic blood pressures (143 mmHg vs. 140 mmHg p = 0.041) and median triglyceride levels (2.07 mmol/l vs. 1.60 mmol/l p = 0.023) than those renal patients without IC. A case control study matching for age, sex and treatment revealed patients with IC to have higher median systolic blood pressure (147 mmHg vs. 140 mmHg p = 0.031), cholesterol (6.70 mmol/l vs. 5.90 mmol/l p = 0.029), LDL cholesterol (4.64 mmol/l vs. 3.86 mmol/l p = 0.011), and contained a greater proportion of smokers (78% vs. 50% p < 0.001). IC is common in patients on RRT. Whilst smoking was prevalent among those with IC it was much less frequent than in the general population with IC. Other factors such as hypertension, lipid abnormalities or the uraemic state itself may also be important in the development of IC in these patients.

Effect of insulin-dependent diabetes mellitus on lipids and lipoproteins: a study of identical twins.

1. Forty-five identical twin pairs, discordant for insulin-dependent diabetes mellitus, were studied with respect to their serum lipid (high-density lipoprotein, low-density lipoprotein, total cholesterol and triacyl-glycerol) and apoprotein [apoprotein A-I, apoprotein B and lipoprotein (a)] concentrations and apoprotein (a) phenotypes. The twins were compared with an age- and sex-matched non-diabetic control group. 2. A significantly higher value was found only for high-density lipoprotein cholesterol in the diabetic twins of the female twin pairs. 3. Highly significant correlations existed between the twin pairs for all lipids and lipoproteins measured, particularly lipoprotein (a), for which identical apoprotein (a) isoforms were also found. 4. Correlations existed between the non-diabetic twins and the control subjects for high-density lipoprotein cholesterol and apoprotein A-I, probably due to the rigorous matching of control subjects. 5. The similarity between values for lipids and lipoproteins in the non-diabetic twins and control subjects suggested no effect of a genetic susceptibility to insulin-dependent diabetes mellitus. The differences in lipoproteins we describe for the identical twins discordant for insulin-dependent diabetes mellitus, in whom there was no evidence of a raised urinary albumin excretion rate, does not appear to explain the excess mortality from cardiovascular disease reported in patients with this disease.

Does cyclosporin increase lipoprotein(a) concentrations in renal transplant recipients?

Cyclosporin, the immunosuppressant of choice for renal transplant recipients, has been implicated as the cause of abnormalities in serum lipid concentrations in these patients. We have measured serum lipoprotein(a) concentrations and analysed the distribution of apoprotein(a) isoforms in 90 renal transplant recipients receiving cyclosporin and prednisolone (with or without azathioprine), 59 patients receiving azathioprine and prednisolone alone, and 146 non-hyperlipidaemic controls. Cyclosporin-treated patients had significantly higher lipoprotein(a) concentrations (median 170 [interquartile range 55-382] mg/L) than those receiving azathioprine and prednisolone (64 [10-204] mg/L, p = 0.001) or the healthy controls (94 [18-280] mg/L, p = 0.008). The difference between the azathioprine and prednisolone group and the controls was not significant. Although the time since transplantation was significantly shorter for the cyclosporin-treated group, there was no correlation between lipoprotein(a) concentration and time since transplantation (r = -0.13, p = 0.18). Apoprotein(a) phenotyping showed no significant differences in the distribution of apoprotein(a) isoforms between the treatment groups or between patient and control groups. Lipoprotein(a) concentrations are higher in renal transplant recipients treated with cyclosporin than in those maintained on azathioprine and prednisolone. The mechanisms underlying this abnormality remain to be elucidated.

Lipoprotein (a) in patients on maintenance haemodialysis and continuous ambulatory peritoneal dialysis.

Lipoprotein (a) concentrations and apoprotein (a) isoforms were measured in 99 haemodialysis and 79 peritoneal dialysis patients and compared with a normal population. Peritoneal dialysis patients demonstrated a threefold and haemodialysis a twofold increase in median Lp(a) values compared to controls (P < or = 0.001). The peritoneal dialysis group had significantly more patients with Lp(a) values greater than 30 mg/dl compared to controls, (53% versus 22% P < or = 0.001). In addition both patient groups demonstrated significant hypertriglyceridaemia (P < or = 0.001), reduction in HDL (P < or = 0.001) and elevation of the cholesterol/HDL ratio (P < or = 0.001) compared with controls. Peritoneal dialysis patients also demonstrated significant hypercholesterolaemia (P < or = 0.003). Lipoprotein (a) concentrations are considerably elevated in patients on maintenance dialysis and this occurs in addition to the typical lipoprotein disturbances. This elevation may increase vascular risk, particularly in the peritoneal dialysis group who also have hypercholesterolaemia and reduced HDL.

Lipid and lipoprotein (a) concentrations in renal transplant patients.

Lipid and lipoprotein concentrations, including lipoprotein (a), were measured in 67 clinically stable renal allograft recipients and compared with age- and sex-matched controls. Median lipoprotein (a) concentrations were significantly elevated in the transplant group (P = 0.048), with the distribution of apoprotein (a) isoforms being similar between the two groups. The transplant group also demonstrated significant elevations in cholesterol (P less than 0.0001), triglycerides (P = 0.0007) and low-density lipoprotein cholesterol (P less than 0.0001). There was no significant difference in high-density lipoprotein cholesterol concentrations between the groups although there was the expected tendency for higher values in females. Lipoprotein abnormalities are common following renal transplantation and these patients also demonstrate elevated lipoprotein (a) values. This unique lipoprotein is known to be atherogenic and may contribute to the development of vascular disease, which is a common mode of death in these patients.

Amino acid clearances and daily losses in patients with acute renal failure treated by continuous arteriovenous hemodialysis.

OBJECTIVE: To determine daily amino acid and total protein losses in patients with acute renal failure receiving total parenteral nutrition (TPN) during treatment by continuous arteriovenous hemofiltration with hemodialysis (CAVHD). DESIGN: Prospective, nonrandomized study. SETTING: Patients in the ICU of a regional nephrology referral center. PATIENTS: Eight clearance studies of individual amino acids were performed in six patients with acute renal failure receiving TPN. Daily nitrogen intake was 9 g (one patient), 14 g (two patients), and 18 g (three patients). The clearances of individual amino acids were measured at two dialysis flow rates to calculate daily amino acid and total proten losses. RESULTS: Amino acid clearance rates ranged from 7.8 +/- 2.2 (glutamic acid) to 25.2 +/- 4.8 mL/min (3-methylhistidine) at a dialysate flow rate of 1 L/hr and from 13.6 +/- 1.7 (tryptophan) to 33.7 +/- 4.3 mL/min (3-methylhistidine) at a dialysate flow rate of 2 L/hr. These results represent daily amino acid losses of 1.5 +/- 0.4% (glutamic acid) to 111.6 +/- 16.6% (tyrosine) of the nutritional input at a dialysate flow rate of 1 L/hr and 2.1 +/- 0.6% (glutamic acid) to 145.8 +/- 17.8% (tyrosine) at a dialysate flow rate of 2 L/hr. Total losses would represent 8.9 +/- 1.2% and 12.1 +/- 2.2%, respectively, of the daily protein input. CONCLUSIONS: These studies confirm that amino acid clearances are relatively high during CAVHD and daily losses should therefore be considered.

High lipid parenteral nutrition improves portasystemic encephalopathy.

We have conducted a randomized double crossover study over 4 days in six parenterally fed patients with portasystemic encephalopathy (PSE) in which the nonprotein energy source of otherwise identical feeds was alternately all glucose or predominantly fat. Concentrations of plasma branched chain amino acids (BCAA), plasma insulin, and blood glucose were measured after an initial fast and subsequently after each of the four 24-hr periods of isonitrogenous feeding. The grade of PSE was assessed clinically and by the number connection test, BCAA concentrations were significantly lower during the glucose infusion than during fasting or the lipid infusion. PSE was significantly less with the lipid than with the glucose infusion. Trials testing the effect of infused BCAA must take account of the opposing effect on BCAA concentrations of simultaneous glucose infusion. A high lipid feed may have advantages in the short-term treatment of PSE.

High lipid parenteral feeds raise plasma branched chain amino acid concentrations--a possible therapeutic approach to portasystemic encephalopathy?

The effect of varying the calorie source of parenteral feeding from an all glucose source to a high fat source has been studied in seven patients with normal liver function by randomised crossover trial. 'Intralipid' used as the major non-nitrogen calorie source (except for 400 kcal as glucose) was associated with significantly lower plasma concentrations of insulin and glucose, significantly higher plasma concentrations of the three branched chain amino acids, and a significantly higher urinary excretion of sodium. If these effects of a high fat parenteral feed were repeatable in patients with liver failure and portasystemic encephalopathy they might be of therapeutic benefit.

Some enzymic activities and chemical properties of the mesosomes and cytoplasmic membranes of Bacillus licheniformis 6346.

1. The liberation of the vesicles of the mesosomes from protoplasts of Bacillus licheniformis strain 6346 is controlled by the Mg(2+) concentration present during the removal of the walls by lysozyme. 2. The functioning of the cytoplasmic membranes is also critically controlled by the Mg(2+) concentration. 3. The isolated mesosomes and the cytoplasmic membranes differ in their enzymic activities. Both succinate dehydrogenase and NADH oxidase activities are very low or absent from the mesosomes. 4. The cytoplasmic membranes can also be separated into materials of different density. 5. Distribution of the membranes between these fractions is controlled by the Mg(2+) concentration and the growth conditions of the microorganisms.