The effect of vitamin B12 on total plasma homocysteine concentration in folate-replete hemodialysis patients.

AIM: Results from several studies indicate that the total homocysteine (tHcy) concentration in plasma is an independent risk factor for cardiovascular disease in hemodialysis patients. Folic acid is the established mainstay of homocysteine-lowering treatment, but since such treatment does not normalize plasma tHcy concentration in hemodialysis patients, it is of importance to search for additional therapy. METHODS: Twenty-eight folate-replete hemodialysis patients were randomized to 2 equally sized groups, a treatment group and a control group. The treatment group received vitamin B12 tablets at a dose of 2 mg 3 times a week for 6 weeks (after each dialysis session) while the control group received no such treatment. Blood samples were collected before and at the end of the treatment period for analysis of tHcy in plasma and vitamin B12, methylmalonic acid as well as folate in serum. RESULTS: At the end of the study period, serum vitamin B12 concentrations were significantly higher in the treatment group than in the control group. Plasma tHcy concentrations decreased significantly in both groups during the study period. However, there was no difference between the responses of the 2 groups. CONCLUSION: The results of this open, randomized controlled study did not support the hypothesis that treatment with oral vitamin B12 has considerable homocysteine-lowering effect in folate-replete hemodialysis patients.

Effects of short-term treatment with corticotropin on the serum apolipoprotein pattern.

Treatment with adrenocorticotrophic hormone (ACTH) has a well-documented cholesterol-lowering effect. Increased uptake of low-density lipoprotein (LDL) by HepG2 cells in response to incubation with ACTH has been demonstrated but the precise cholesterol-lowering mechanism has resisted elucidation. Since apolipoproteins are important determinants of lipoprotein metabolism, we sought to extend the knowledge of the effect of ACTH treatment on the serum apolipoprotein (apo) pattern. Twelve healthy individuals and 14 dyslipoproteinemic hemodialysis patients were recruited. The two groups responded similarly to ACTH1-24 at the dose of 1 mg daily for four days. In accordance with previous results, serum concentrations of total cholesterol decreased by 18% and 17%, LDL cholesterol by 25% and 30%, and apo B by 20% and 19%, respectively, while there were no significant changes in the serum concentrations of triglycerides, high-density lipoprotein cholesterol and apo AI. Novel findings were that the serum concentrations of total apo E increased by 48% and 31%, and apo B-associated apo E by 69% and 46%, respectively. Moreover, in the healthy individuals, the serum concentrations of apo CIII did not change in response to ACTH, whereas in the hemodialysis patients, those of apo CIII not associated with apo B increased significantly by 44%. Since apo E binds strongly to the LDL receptor, the present results suggest that the cholesterol-lowering effect of ACTH may be mediated by facilitated hepatic uptake of apo E-enriched apo B-containing lipoproteins. Thus, the findings stimulate further research.

Plasma total homocysteine concentration in nephrotic patients with idiopathic membranous nephropathy.

BACKGROUND: The atherothrombotic risk pattern of the nephrotic syndrome resembles that of hyperhomocysteinemia. However, the effect of nephrotic range proteinuria on homocysteine metabolism has never been studied. METHODS: The study included 11 male nephrotic patients with idiopathic membranous nephropathy who underwent a treatment trial with adrenocorticotrophic hormone and 11 male non-nephrotic, renal function-matched control subjects. The nephrotic patients were studied before and after the treatment, which induced a marked reduction in urinary protein excretion and a moderate improvement in renal function in all cases. RESULTS: Plasma total homocysteine (tHcy) concentration did not change significantly during treatment, whereas the nephrotic patients had significantly lower tHcy than the non-nephrotic patients (14.2 +/- 3.4 micromol/l vs 19.0 +/- 5.4 micromol/l). tHcy correlated significantly with serum concentrations of creatinine (r = 0.53, P < 0.05) and albumin (r = 0.43, P < 0.05), glomerular filtration rates (GFRs) (iohexol clearances) (r = -0.42, P < 0.05) and urinary albumin excretion (r = -0.47, P < 0.05). CONCLUSION: The expected tHcy-lowering effect of improved renal function may have masked a tHcy-elevating effect due to reduced proteinuria leading to no net change in tHcy during treatment. The notion of an increase in tHcy associated with remission of the nephrotic syndrome is in accordance with the significantly lower tHcy in the nephrotic renal patients compared with the non-nephrotic renal function-matched patients, and the relationships between tHcy and serum albumin concentrations as well as urinary albumin excretion. Thus, the results of this small study suggest that nephrotic range proteinuria directs homocysteine metabolism towards a decrease in tHcy. However, the findings need to be confirmed in larger patient populations and in different varieties of the nephrotic syndrome.

Adrenocorticotrophic hormone exerts marked lipid-lowering effects in simvastatin-treated patients.

OBJECTIVE: Recently, it was reported that treatment with adrenocorticotrophic hormone (ACTH) has a strong lipid-lowering effect in healthy individuals. The mechanism behind this has not been established. The aim of the present investigation was to study the effect of ACTH on the plasma lipoprotein pattern in patients treated with a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor. DESIGN: The ACTH treatment was given to 10 patients who were on long-term treatment with simvastatin 40 mg daily. ACTHI-24 was administered at the dose of 1 mg daily for four consecutive days. Blood samples for analyses of lipids, lipoproteins and apolipoproteins were collected before and after treatment. Second baseline was obtained 2 weeks after the end of treatment. RESULTS: The serum concentrations of cholesterol, triglycerides, low density lipoprotein (LDL) cholesterol, apolipoprotein B and lipoprotein(a) fell significantly by 16, 23, 23, 10 and 38%, respectively. The serum apolipoprotein E concentration increased significantly by 39%; the fraction that was not associated with apolipoprotein B increased by 47% whereas the fraction that was did not change significantly. There were no changes in the serum concentrations of high density lipoprotein (HDL) cholesterol and apolipoprotein AI. At the second baseline, the lipid variables had generally returned to previous levels. CONCLUSIONS: In patients on long-term simvastatin treatment, ACTH had marked lowering effects on the lipoproteins that contain apolipoprotein B. Moreover, the serum apolipoprotein E concentration increased significantly in response to ACTH treatment.

Cutaneous infection caused by Paecilomyces lilacinus in a renal transplant patient: treatment with voriconazole.

Moulds belonging to the genus Paecilomyces are rare opportunistic pathogens. About 100 cases have been reported in immunocompromised hosts or in relation to surgical procedures. We describe here a cutaneous infection due to P. lilacinus in a renal transplant patient, which responded to voriconazole treatment.

Treatment with different doses of folic acid in haemodialysis patients: effects on folate distribution and aminothiol concentrations.

BACKGROUND: Hyperhomocysteinaemia is highly prevalent among haemodialysis patients and may contribute to their increased cardiovascular risk. Treatment with pharmacological doses of folic acid lowers the plasma homocysteine concentration in these patients. The purpose of the present study was to expand the knowledge about such treatment by testing the effects of stepwise increases in the dose of folic acid on the concentrations of plasma and red blood cell folate as well as the total plasma concentrations of homocysteine (tHcy), cysteine (tCys), and glutathione (tGSH) in patients on chronic hemodialysis. METHODS: Fourteen stable haemodialysis patients completed the study which consisted of four consecutive periods, each of 6 weeks duration: (i) no treatment with folic acid (control period); (ii) 5 mg of folic acid three times per week (15 mg/week); (iii) 5 mg of folic acid daily (35 mg/week); (iv) 10 mg of folic acid daily (70 mg/week). RESULTS: Neither plasma or red cell folate nor plasma aminothiol concentrations changed significantly during the control period. The mean red cell folate concentration doubled during the administration of folic acid at the dose of 15 mg/week but at higher doses the further rise was only marginal. The mean folate concentration in plasma increased steeply especially at the higher doses of folic acid. During treatment with 15 mg/week of folic acid, tHcy fell by a mean of 36%, tGSH increased by a mean of 34%, but tCys was unaffected. Increases in the dose of folic acid did not augment these responses. CONCLUSIONS: The maximal effect on tHcy seemed to be obtained already at the lowest given dose of folic acid (15 mg/week). At that dose, the red blood cells approached folate saturation, which may reflect the situation in other cells that participate in homocysteine metabolism and explain why further increases in the dose of folic acid are not effective from a tHcy-lowering point of view.

Beneficial effects of ACTH on the serum lipoprotein profile and glomerular function in patients with membranous nephropathy.

BACKGROUND: Previous studies have shown that short-term treatment with adrenocorticotrophic hormone (ACTH) has a strong and rapid lipid-lowering effect. In this long-term study of nephrotic patients with idiopathic membranous nephropathy, the influence of ACTH on the serum lipoprotein profile and glomerular function as well as the dose-effect relationship was investigated. METHODS: Fourteen patients received ACTH intramuscularly at increasing doses during 56 days. Serum concentrations of lipids, lipoproteins, and apolipoproteins as well as variables of glomerular function were analyzed, and the side-effects were recorded. ACTH treatment, in the estimated optimal dosage, was then continued in five patients with severe steroid-resistant nephrotic syndrome. In these five patients, the total treatment period was 12 months, and the follow-up time after discontinuing treatment was 18 months. RESULTS: Taking both the statistically significant therapeutic effects and the modest side-effects into consideration, the optimal dosage of ACTH was estimated to be 1 mg twice per week. At that dose, reductions by 30 to 60% in the serum concentrations of cholesterol, triglycerides, apolipoprotein B, and lipoprotein(a) were observed, whereas the serum concentrations of high-density lipoprotein cholesterol and apolipoprotein AI rose by 30 to 40%. In addition, the urinary albumin excretion decreased by 90%, and the glomerular filtration rate increased by 25%. Deterioration was observed in all cases when ACTH was discontinued after a treatment duration of 56 days. However, the five patients in whom ACTH therapy was resumed were still in remission 18 months after discontinuance of treatment. CONCLUSIONS: In nephrotic patients with idiopathic membranous nephropathy, treatment with ACTH 1 mg twice per week was associated with significant long-term improvements in serum lipoprotein pattern and glomerular function.

Influence of haemodialysis on plasma total homocysteine concentration.

BACKGROUND: The high prevalence of hyperhomocysteinaemia in uraemic patients is of interest because of the cardiovascular risk associated with increased plasma total homocysteine (tHcy) concentration. Treatment with folic acid lowers tHcy in haemodialysis patients, however, in most patients not to normohomocysteinaemic levels. With possible tHcy-lowering modifications in mind, we studied the influence of standard haemodialysis on tHcy. METHODS: In 56 folate-loaded haemodialysis patients, tHcy and parameters of dialysis adequacy were measured. In six patients, interdialytic curves of tHcy and serum creatinine concentrations were obtained and in five patients, the amount of homocysteine (Hcy) in dialysate was determined. RESULTS: tHcy (21.8+/-14.4 micromol/l) correlated significantly with Kt/V (r=0.32, P<0.05), total Kt/V (r=0.29, P<0.05), nPCR (r=0.30, P<0.05) and serum concentrations of albumin (r=0.28, P<0.05) and cobalamines (r=-0.27, P<0.05). In a multiple linear regression analysis, only serum albumin concentrations significantly predicted tHcy (r=0.34, P < 0.05). During dialysis, tHcy decreased by 28% and remained constant for at least 8 h after treatment. The amount of Hcy recovered in dialysate was 63 micromol (12-158 micromol). There was no difference in tHcy between those who had residual renal function and those who had not. CONCLUSIONS: The direct relationship between tHcy and Kt/V seemed to be mediated by the serum albumin concentration. The shape of the interdialytic tHcy curve suggested facilitated Hcy removal for at least 8 h after dialysis possibly due to reduced levels of inhibitory activities against relevant enzyme(s). The dialysed amount of Hcy did not seem to contribute significantly to Hcy removal. Thus, modifications of standard dialytic regimens are not likely to be effective from a tHcy-lowering point of view whereas convective procedures such as haemofiltration or haemodiafiltration might be more effective.

Corticotropin-induced reduction of plasma lipoprotein(a) concentrations in healthy individuals and hemodialysis patients: relation to apolipoprotein(a) size polymorphism.

Lipoprotein(a) [Lp(a)], a strong independent cardiovascular risk factor, consists of the unique apolipoprotein(a) [apo(a)] covalently linked to a low-density lipoprotein particle. Apo(a) contains a widely differing number of the plasminogen-like kringle IV, a size polymorphism that is codominantly inherited. In addition to powerful genetic control, renal failure is known to influence the plasma Lp(a) concentration. There is still a lot to be learned about the mode and site of catabolism of Lp(a), and there is no readily applicable Lp(a)-lowering treatment available. Therefore, it was of interest to study further the Lp(a)-lowering effect of corticotropin (ACTH) that has been demonstrated in small studies. The main purpose of the present study was to investigate the influence of ACTH on different apo(a) isoforms. Short-term treatment with ACTH decreased the plasma Lp(a) concentration in all 26 study participants. The two study groups (12 healthy individuals and 14 hemodialysis patients) responded similarly, with a median decrease in plasma Lp(a) of 39% and 49%, respectively. In subjects with two clearly separable apo(a) bands, apo(a) phenotyping and densitometric scanning of the bands before and after treatment with ACTH revealed a change in the proportion of apo(a) isoforms, ie, a shift toward the isoform with lower molecular weight. This was observed in seven of nine investigated subjects (four of five healthy individuals and three of four hemodialysis patients).

Serum total homocysteine concentration does not predict outcome in renal transplant recipients.

Established cardiovascular risk factors such as hypercholesterolemia have been claimed to adversely influence the outcome of renal transplants. The aim of the present study was to assess the effect of another risk factor, hyperhomocysteinemia, on graft outcome. This was relevant for two reasons; hyperhomocysteinemia is by now recognized as an independent risk factor for the development of atherosclerosis and it is highly prevalent in both dialysis patients and renal transplant recipients. The serum concentration of total homocysteine (tHcy) was analyzed in samples collected before transplantation in 81 patients and at 6 months after transplantation in 57 of these patients. Before transplantation, mean tHcy was 33.2 +/- 19.2 mumol/L and the prevalence of hyperhomocysteinemia was 94%. Six months after transplantation, mean tHcy was 27.7 +/- 14.6 mumol/L and the prevalence of hyperhomocysteinemia was 88%. The patients were followed up for 5 yr. Six months and 5 yr after transplantation, serum creatinine concentration and endogenous creatinine clearance were determined. After 6 months, allograft biopsy was evaluated. Neither pre- nor post-transplant tHcy was found to influence patient or graft survival, graft function or histopathology. Thus, tHcy does not seem to predict either short-term or long-term outcome of renal transplantation.

Serum total homocysteine concentration before and after renal transplantation.

BACKGROUND: Hyperhomocysteinemia is by now an established risk factor for the development of atherosclerosis. Total homocysteine concentration (tHcy) correlates inversely with glomerular filtration rate, and it is roughly three times as high in hemodialysis patients as in healthy individuals. Therefore, tHcy would be expected to fall markedly after successful renal transplantation. The aim of the present study was to assess the changes in tHcy associated with renal transplantation. METHODS: tHcy was analyzed in samples collected before renal transplantation and at six months after transplantation in 55 stable patients, all of whom were treated with cyclosporine (CS). tHcy was also analyzed in samples from 55 controls characterized by markers of renal function that matched those of the post-transplant state. RESULTS: At six months after transplantation, tHcy was significantly decreased as compared with pretransplant tHcy (27.7 +/- 14.8 vs. 36.9 +/- 21.3 micromol/liter, P < 0.001). Post-transplant tHcy was markedly higher than the tHcy of the control group (27.7 +/- 14.8 vs. 16.0 +/- 5.3 micromol/liter, P < 0.0001). The post-transplant change in tHcy ranged widely, the average change being a reduction of 14%. Sixteen patients (29%) actually manifested an increase in post-transplant tHcy. The post-transplant changes in tHcy correlated inversely with pretransplant tHcy (r = -0.66, P < 0.0001) and directly with the changes in serum albumin concentrations (r = 0.35, P < 0.05) and CS trough concentrations (r = 0.29, P < 0.05). A multivariate analysis, including the post-transplant changes in serum concentrations of folate and albumin as well as creatinine clearances explained 21% of the change in tHcy (P < 0.05). After inclusion of the CS concentration, an independent predictor, the model accounted for 28% of the post-transplant change in tHcy (P < 0.01). CONCLUSION: The post-transplant reduction in tHcy was far smaller than expected with respect to renal function, and the post-transplant changes in the major biochemical determinants of tHcy contributed relatively little to explain the change in tHcy. Thus, the results suggest the post-transplant introduction of one or more factors that induce an increase in tHcy. Treatment with CS appears to be such a factor.

Pathogenesis of dyslipoproteinemia in renal insufficiency: the role of lipoprotein lipase and hepatic lipase.

The lipoprotein pattern, observed in patients with renal failure, suggests impaired catabolism of triglyceride-rich lipoproteins. This is supported by the findings of numerous studies addressing the pathogenesis of the dyslipoproteinemia of uremia. Aberrant lipoprotein composition, resulting in disturbed substrate characteristics for lipoprotein lipase and unfavourable receptor ligand function, probably constitutes the primary pathology. The structural details of the lipoproteins that are responsible for this dysfunction are not yet established. In this regard, abnormal apolipoprotein pattern and, possibly more important, biological modifications must be taken into consideration. Low activity of lipoprotein lipase does not seem to be a primary pathogenetic factor. However, there is little doubt that it plays a contributory part. The role of hepatic lipase is controversial.

Adrenocorticotrophic hormone lowers serum Lp(a) and LDL cholesterol concentrations in hemodialysis patients.

Previously, we have shown that short-term administration of adrenocorticotrophic hormone (ACTH) results in reduced concentrations of apolipoprotein B-containing lipoproteins, including lipoprotein(a), and reduced activities of hepatic lipase. These effects were observed in steroid-treated patients suffering from iatrogenic ACTH deficiency and in healthy individuals. The direct nature of the influence of ACTH on hepatic lipoprotein metabolism was confirmed by in vitro experiments. The aim of the present investigation was to study the effects of ACTH treatment on uremic patients, who exhibit disturbed lipoprotein pattern due to the slow removal of triglyceride-rich lipoproteins and who probably are ACTH resistant. Eight patients on chronic hemodialysis were studied. After one intramuscular injection of Synacthen Depot (a synthetic ACTH1-24 preparation from Ciba Geigy AG, Basel, Switzerland) 1 mg, the only change noted was a significant reduction of 26% in median lipoprotein(a) concentration. After five injections, a further decrease (65%) was found in the lipoprotein(a) concentration. Also, reductions in median concentrations of total cholesterol, low density lipoprotein cholesterol and apolipoprotein B were observed. The magnitude of these changes was 15 to 30%. In contrast to previously studied groups, no changes were observed regarding triglyceride metabolism. Significantly increased median concentration of apolipoprotein CIII was found. However, the excess apolipoprotein CIII was confined to the fraction that was not associated with apolipoprotein B. Thus, administration of ACTH to uremic patients improved their atherogenic lipoprotein profile, a fact that may have future therapeutic implications. In comparison to previously studied groups, the uremic patients responded rather slowly and not at all regarding triglyceride metabolism.

[Hyperhomocysteinemia, a cardiovascular risk factor.].

The rare syndrome of homocystinuria is characterized by very high plasma concentration of the amino acid homocysteine. Homocystinuric patients are at greatly increased risk of atherosclerotic complications independent of the underlying cause of the syndrome. Based on these observations, the homocysteine theory of atherosclerosis was formulated 20 years ago proposing that homocysteine as such was responsible for the vascular damage. It was also proposed that the mild hyperhomocysteinemia, commonly found in the general population, constituted a cardiovascular risk factor. The homocysteine theory of atherosclerosis is supported by the results of a few large prospective investigations and many small retrospective studies which showed significantly higher plasma homocysteine concentrations in patients suffering from atherosclerotic complications than in controls. Moreover, according to multiple regression analyses of these study results, the risk associated with hyperhomocysteinemia is independent of other cardiovascular risk factors. The mechanism is unclear but clinical studies and animal experiments indicate that homocysteine induces endothelial damage and influences blood coagulation. Treatment with folic acid effectively lowers plasma homocysteine concentration. To date, it is not known whether such treatment lowers the incidence of atherosclerotic complications.