Influence of Oral Vitamin E Therapy on Micro-Inflammation and Cardiovascular Disease Markers in Chronic Hemodialysis Patients

Background. The aim of this study was to evaluate the influence of oral vitamin E therapy on serum concentrations of several markers of micro-inflammation and cardiovascular disease in chronic hemodialysis (HD) patients. Methods. 29 HD patients were randomized into two groups: 15 patients were treated orally with 400mg of vitamin E daily for a period of five weeks, and 14 patients received no antioxidant supplementation. Before and after vitamin E therapy, serum concentrations of vitamin E (high-performance liquid chromatography), pregnancy-associated plasma protein-A (immunochemical – TRACE assay), C-reactive protein (nephelometry), intercellular adhesion molecule-1 (ELISA), and E-selectin (ELISA) were measured. HD patients were compared with 16 healthy controls. Results. Baseline serum concentrations of PAPP-A and CRP were significantly higher in HD patients than in healthy controls (PAPP-A: 26.23±11.94 vs. 11.41±1.94 mIU/L, p<0.001; CRP: 5.20±3.50 vs. 3.40±3.80 mg/L, p<0.05). After five weeks of oral vitamin E intake, serum PAPP-A, CRP, ICAM-1, and E-selectin concentrations remained unchanged in both groups of HD patients. Conclusion. Chronic micro-inflammation in HD patients is documented by the elevation of CRP and PAPP-A. A daily oral dose of 400 mg of vitamin E does not seem to be able to reduce enhanced oxidative stress and micro-inflammation in chronic HD patients.     

Procalcitonin as a marker of micro-inflammation in hemodialysis

In searching for a rapid and sensitive test to detect micro-inflammation in patients on hemodialysis (HD), we measured serum procalcitonin (PCT) levels and made a comparison with other traditional markers such as C-reactive protein (CRP), serum amyloid (SAA) and homocysteine, considered related to vascular damage. We investigated 51 HD patients, without signs of infection, in basal conditions (during standard bicarbonate dialysis and unselected filters: X) and after 4 months of possibly more biocompatible treatments (on-line hemofiltration (HF) or HD with ultra-pure dialysate and biocompatible membranes: Y). Serum PCT (measured by immunoluminometric assay), CRP and SAA (nephelometric assay) and plasma homocysteine (measured by high performance liquid chromatography) concentrations were assessed at the beginning of dialysis (T0) and after 4 hr (T4). Patients on unselected dialysis displayed mean PCT values significantly increased after 4 hr of dialysis in comparison to those at the start of the sessions (XT4 1.56 +/- 3.93 vs. XT0 0.4 +/- 0.34 ng/mL; p < 0.05). The PCT levels detected after 4 hr of biocompatible treatments were significantly lower than those detected after 4 hr of unselected treatments (YT4 0.78 +/- 0.34 ng/mL; p < 0.05), even though the percentage of patients with positive PCT values (> 0.5 ng/mL) remained almost unchanged. No significant modification in mean levels or in the frequency of positive values was observed for CRP, SAA and homocysteine. After 4 months of highly biocompatible treatments, a reduction in intradialytic enhancements of all inflammation markers was detected. Our data support the conclusion that PCT is a more precise marker than other traditional tests to evaluate micro-inflammation and biocompatibility in HD.     

Effects of vitamin supplementation on microcirculatory disturbance in hemodialysis patients without peripheral arterial disease

AIMS: Dysfunctional endothelium caused by oxidative stress is thought to play a role in pathogenesis of a variety of conditions including atherosclerosis. We investigated whether a microcirculatory disturbance in hemodialysis (HD) patients was associated with increased oxidative stress and endothelial injury. PATIENTS AND METHODS: Transcutaneous oxygen tension (TcPO2) on the dorsum of the foot at rest was measured as a marker of microcirculation in 33 patients undergoing HD without clinical manifestations of peripheral arterial disease and 20 healthy controls. Furthermore, in order to examine whether TcPO2 was affected by antioxidants, oral supplementation with a combination of vitamin C (200 mg daily) and vitamin E (600 mg daily) was administered for 6 months to 8 patients with microcirculatory disturbance (TcPO2 values of 50 mmHg or less). Serum biochemical parameters including vitamins were also measured. RESULTS: Mean TcPO2 value was significantly lower in HD patients than in control subjects (47.9 +/- 13.5 mmHg versus 62.4 +/- 11.9 mmHg, p < 0.001). After vitamin supplementation, TcPO2 values remarkably increased (40.6 +/- 10.0 mmHg versus 57.4 +/- 6.5 mmHg, p < 0.005). Serum vitamin C and vitamin E levels increased significantly as well, while serum levels of thrombomodulin, a marker of endothelial injury, and thiobarbituric acid reactants, a marker of lipid peroxidation, were significantly decreased in comparison with those before supplementation. CONCLUSIONS: Our results suggest that the microcirculatory disturbance in HD patients seems to be associated with endothelial damage caused by oxidative stress. Combined supplementation with vitamin C and vitamin E may be of clinical benefit in improving the cutaneous microcirculation by reducing oxidative stress.     

Influence of parenteral iron therapy and oral vitamin E supplementation on neutrophil respiratory burst in chronic hemodialysis patients

BACKGROUND: Bioincompatibility of hemodialysis (HD) membranes is responsible for neutrophil activation leading to oxidative stress, which can be further increased by intravenous (IV) iron (Fe) administration. The aim of our study was to monitor neutrophil respiratory burst during HD and to find out whether this process is influenced by IV Fe and oral vitamin E administration. METHODS: Within four HD sessions, blood samples were taken from seven chronic HD patients at time 0 (before HD), 60, 70, and 130 min of HD session. Neutrophil respiratory burst was assessed by luminol-enhanced chemiluminescence (CL). Plasma advanced oxidation protein products (AOPP) concentration was measured spectrophotometrically. During the second and the fourth HD, 62.5 mg of sodium ferric gluconate was applied IV in the 65th minute of HD. Before the last two HD, the patients were given orally 200 mg of vitamin E daily for 7 days. Patient's results were compared with healthy controls. RESULTS: Predialysis CL is higher in patients than in controls (1,926 +/- 436 vs. 1,083 +/- 325 RLU, p<.01). CL decreases in the 60th min of HD (1,926 +/- 436 vs. 1,220 +/- 599 RLU, p<.05); thereafter, it remains stable. After Fe application, CL increases at time 130 compared with CL at time 60 (1,303 +/- 269 vs. 877 +/- 292 RLU, p<.05). AOPP concentration is higher in patients than in controls (137.5 +/- 42.7 vs. 88.9 +/- 24.8 micromol/L, p<.01) and remains unaffected by vitamin E supplementation. After vitamin E intake, predialysis CL remains significantly higher than in controls, and changes in CL during HD are minimal despite Fe administration. CONCLUSION: HD patients' neutrophils generate more oxygen radicals than in healthy individuals. This production decreases during HD and then increases after IV Fe administration. Short-term vitamin E administration attenuates this fluctuation of neutrophil oxidative metabolism, without affecting the total degree of oxidative stress.     

Differential diagnosis of bacterial infection and inflammatory response in kidney diseases using procalcitonin

BACKGROUND: Early diagnosis of bacterial infection in renal patients remains difficult. Common laboratory parameters, such as white blood cell (WBC) count, erythrocyte sedimentation rate, and C-reactive protein (CRP) may be affected by the underlying disease, uremia or its extracorporeal treatment, or by immunosuppressive drugs. Procalcitonin (PCT) may be useful for the detection of systemic bacterial infections in patients with end-stage renal disease (ESRD) undergoing renal replacement therapy, but elevated PCT concentrations have also been found in a significant number of uremic patients without signs of infection. METHODS: We tested whether measurements of PCT levels help distinguish the chronic inflammation in renal diseases from invasive bacterial infections. Serum levels of PCT were compared with the corresponding serum C-reactive protein (CRP) concentrations and WBC counts in 197 patients with different stages of renal disease: Group I) 32 patients with chronic renal failure (serum creatinine 2-6 mg/dL); group II) 31 patients with a functioning renal transplant receiving standard immunosuppressive regimens; group III) 76 clinically stable patients with ESRD undergoing hemodialysis (HD); group IV) 23 patients with chronic renal failure (CRF) due to systemic autoimmune disease; group V) 35 patients with proven systemic bacterial infection and CRF. RESULTS: PCT levels were within the normal range (< 0.5 ng/mL) in patients with CRF and renal transplant patients without any clinical evidence of bacterial infection, regardless of the degree of renal failure and the underlying disorders. In 22 out of 76 stable HD patients, PCT levels were above the upper limit of normal, but 97% of these values were below the proposed cut-off for chronic HD patients of < 1.5 ng/mL. CRP levels were elevated in 17 of 32 patients with CRF (mean +/- SD: 0.57 +/- 0.49 mg/dL), in 10 of 31 renal transplant patients (0.41 +/- 0.55 mg/dL), in 16 of 23 patients with autoimmune disorders (2.78 +/- 3.21 mg/dL) and in 42 of 76 patients treated by HD (0.64 +/- 0.58 mg/dL). In patients with CRF and systemic bacterial infections, both PCT and CRP were markedly elevated (PCT 61.50 +/- 115.4 ng/mL, CRP 14.50 +/- 10.36 mg/dL), but in contrast to PCT, CRP values overlapped in infected and non-infected patients. CONCLUSIONS: Our data indicate that PCT levels are not significantly affected by loss of renal function, immunosuppressive agents or autoimmune disorders. Thus, significantly elevated PCT concentrations offer good sensitivity and specificity for the early diagnosis of systemic bacterial infection in patients with CRF or patients with ESRD treated by HD. CRP concentrations may be useful indicators for inflammation in patients with renal diseases, but have low specificity for the diagnosis of bacterial infection.     

Effect of vitamin E therapy on oxidative stress and erythrocyte osmotic fragility in patients on peritoneal dialysis and hemodialysis

BACKGROUND: Several medications have been tested with the aim of decreasing oxidative stress and erythrocyte osmotic fragility in patients on dialysis. The aim of the present study was to assess the influence of vitamin E therapy on oxidative stress and erythrocyte osmotic fragility in patients on hemodialysis (HD) and peritoneal dialysis (PD). METHODS: This was a placebo-controlled study. The study was performed on 34 HD patients, 13 PD patients and 22 healthy volunteers with a mean age of 45.57 +/- 8.54 years. HD patients were divided into 2 groups: treatment (n=19) and control (n=15). Vitamin E was administered, 300 mg/day, to the HD treatment group and PD patients for 20 weeks. Lipid peroxidation, antioxidant condition and erythrocyte osmotic fragility (EOF) were examined before and after treatment. RESULTS: Before the treatment, the levels of EOF (p<0.001) and malondialdehyde (MDA) (p<0.001) were significantly lower, and erythrocyte superoxide dismutase (SOD) (p=0.001) and vitamin E levels (p<0.001) were significantly higher in the healthy group than PD and HD groups. Serum vitamin E increased from 0.93 +/- 0.16 to 1.09 +/- 0.14 mg/dL (p=0.001), EOF decreased from 0.49% +/- 0.03% to 0.42% +/- 0.04% NaCl (p<0.001), and plasma MDA values decreased from 2.77 +/- 0.87 to 2.20 +/- 0.767 nmol/mL (p=0.018) in the HD treatment group after vitamin E treatment. Levels of EOF decreased from 0.51% +/- 0.09% to 0.43% +/- 0.03% NaCl in the PD treatment group after vitamin E treatment (p=0.021). CONCLUSION: Vitamin E therapy is effective in decreasing the levels of EOF in patients on HD and PD, and it is also effective in decreasing lipid peroxidation in patients on HD.     

Pretransplant pregnancy-associated plasma protein-a as a predictor of chronic allograft nephropathy and posttransplant cardiovascular events

BACKGROUND: Cardiovascular disease and chronic allograft nephropathy (CAN) are two of the main complications observed in patients after renal transplantation. Both appear to be manifestations of the same process, in which inflammation plays a determinate role. Pregnancy-associated plasma protein A (PAPP-A) has been shown to be a marker of acute coronary syndrome and cardiovascular pathology. The objective of this study was to demonstrate whether or not serum concentration of pretransplant PAPP-A is a marker of CAN and a predictor of posttransplant cardiovascular events. METHODS: In all, 178 renal transplants (65% males; 53+/-12 years of age) followed up over the course of 49.3+/-33.6 months were used in this study. During the follow-up period, 19 patients developed CAN (diagnosed by renal biopsy) and 27 patients had a cardiovascular event. Previous to transplantation, the following were determined: ultrasensitive C-reactive protein (CRP) (nephelometry); interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) (immunofluorimetric automatized method), and ultrasensitive PAPP-A (ELISA). RESULTS: A positive correlation was found between PAPP-A and the inflammatory markers (PAPP-A vs. CRP, r=0.218; P=0.004; PAPP-A vs. IL-6, r=0.235; P<0.001; PAPP-A vs. TNF-alpha, r=0.372; P<0.001). The multiple regression analysis showed PAPP-A (relative risk [RR]: 6.4; 95% confidence interval [CI]:1.24-33.11; P=0.027) and CRP (RR: 6.05; 95% CI:1.21-29.74; P=0.028) to be predictors of posttransplant cardiovascular events and PAPP-A (RR: 4.27; 95% CI: 1.03-17.60; P=0.044) and TNF-alpha (RR: 5.6; 95% CI: 1.43-21.83; P=0.013) to be predictors of CAN. CONCLUSIONS: PAPP-A correlated with the inflammatory markers studied (CRP, IL-6 and TNF-alpha). Pretransplant serum concentration of PAPP-A is a predictor of posttransplant cardiovascular events and CAN.     

Intravenous iron gluconate administration increases circulating PAPP-A in hemodialysis patients

BACKGROUND: Pregnancy-associated plasma protein-A (PAPP-A) is a proatherosclerotic molecule, interrelated with oxidative stress in hemodialysis (HD) patients. As intravenous (IV) iron might enhance oxidative stress in HD patients, this study investigates circulating PAPP-A during HD session and after IV iron administration. METHODS: In 20 HD patients, plasma PAPP-A concentration was assessed immunochemically during 2 HD sessions (prior to HD and at 60, 130, and 240 min of HD session). Sodium ferric gluconate (62.5 mg) was given IV to all patients 65 min after the start of the second HD. RESULTS: Sixty-five min after IV iron application, there was a significant increase in plasma PAPP-A (from 36.0+/-9.9 to 79.6+/-28.9 mU/L, p<0.0001). At the end of this HD session, PAPP-A decreased significantly (p<0.0001), but still remained 1.5-fold greater compared with predialysis levels (p<0.0005). CONCLUSION: IV iron increases circulating PAPP-A, and in this way, it might contribute to more pronounced cardiovascular complications in HD patients.     

The effect of long-term intravenous high dose B-complex vitamins with or without folic acid on serum homocysteine in hemodialysis patients

BACKGROUND: Many regimens using different doses of folic acid (FA) alone or with supplementation of B-complex vitamins (BCV) have been tested for the reduction of total homocysteine (tHcy) levels in hemodialysis (HD) patients. BCV are usually administered orally and for a short period. In the present study, we assessed the effect of long-term intravenous (IV) BCV on serum tHCy levels in HD patients, and the effect produced by moderate oral supplementation with FA. METHODS: In a cohort of 37 patients under chronic HD treatment for a mean of 50.2 +/- 46.7 months, serum concentrations of tHcy, folate and vitamin B12 were determined at the end of four sequential periods: (A) three months without any FA supplementation, (B) three months with oral supplementation of 5 mg of FA three times weekly, (C) six months without FA supplementation, and (D) three months without BVC or FA supplementation. From the start of HD treatment and throughout the study until the beginning of period D, patients received a standard IV dose of BCV (B1 250 mg + B6 250 mg + B12 1.5 mg) three times per week, post-dialysis. RESULTS: At the end of period B, mean serum tHcy levels were significantly lower than in periods A and C (13.7 +/- 3.6 micromol/L vs 19.6 +/- 10.8 micromol/L and 21.3 +/- 9.4 micromol/L, respectively, p < 0.001) and mean serum folate levels were significantly higher (20.7 +/- 7.4 ng/mL vs 5.0 +/- 2.8 ng/mL and 4.5 +/- 1.4 ng/mL, respectively, p < 0.01). At the end of period D, mean serum tHcy levels were significantly higher than in all the previons periods (29.3 +/- 13.5 micromol/L, p < 0.001). Twenty-six of the 37 patients (70.2%) had normal (< 15 micromol/L) serum tHcy levels at the end of period B and only one (2.7%) had normal tHcy at the end of period D. Mean serum vitamin B12 levels at the end of periods A, B and C were 100 times the usual normal values. At the end of period D, although significantly lowered (p < 0.001), they remained above the normal range. CONCLUSIONS: Long-term high-dose BCV IV three times a week post-dialysis reduced serum tHcy levels only when combined with oral FA supplementation.     

Homocysteine and lipid peroxidation in haemodialysis: role of folinic acid and vitamin E.

BACKGROUND: Cardiovascular diseases are the leading cause of death in haemodialysis patients. Hyperhomocysteinaemia is an independent risk factor. Basic research has provided strong evidence that oxidation of low-density lipoprotein (LDL) plays an important role in the pathogenesis of atherosclerosis. Oxidative stress, lipid metabolism alterations, and hyperhomocysteinaemia observed in haemodialysis patients could induce increases in LDL oxidation. This study was designed to determine the effect of folinic acid on hyperhomocysteinaemia and to assess the antioxidant efficacy of folinic acid. The antioxidant effect of folinic acid was compared with that of vitamin E. METHODS: Sixteen stable patients (11 men, five women; mean age 54.3+/-6.32 years) on standard haemodialysis received 400 mg of vitamin E, orally, at the end of each haemodialysis session for 3 months. After a 1-month wash-out, they received 10 mg of folinic acid, intravenously, at the end of each haemodialysis session for an additional 3 months. Blood samples were drawn in the morning after an overnight fast and before dialysis. Plasma vitamin E was analysed by high-pressure liquid chromatography. Malondialdehyde (MDA) was determined using a fluorimetric method and plasma copper oxidized anti-LDL antibodies (Ab-LDLox) were measured with an ELISA method using native LDL and oxLDL as antigens. Plasma homocysteine was determined by an FPIA method. RESULTS: Folinic acid supplements significantly reduced hyperhomocysteinaemia (-44%), MDA concentrations (-40%), and IgG-LDLox titres (-13%). CONCLUSIONS: Treatment with folinic acid lowers plasma homocysteine levels and, like vitamin E, affords antioxidant protection, which prevents lipid peroxidation. This lowering of lipid peroxidation may reduce the risk of atherosclerosis and prevent or delay cardiovascular complications in HD patients.     

IL-10 genotype predicts serum levels of adhesion molecules, inflammation and atherosclerosis in hemodialysis patients

BACKGROUND: Hemodialysis (HD) patients suffer from inflammation and accelerated atherosclerosis that accounts for a large number of premature deaths. The anti-inflammatory interleukin (IL)-10 gene is polymorphic and potential direct effects of IL-10 gene polymorphisms on the circulating serum levels of adhesion molecules, inflammation and atherosclerosis in HD patients still have to be elucidated. METHODS: In a cross-sectional study, circulating serum levels of vascular cell adhesion molecule-1 (VCAM-1), E-selectin (E-selectin), and intracellular adhesion molecule-1 (ICAM-1), serum albumin and C-reactive protein (CRP) were measured in 121 HD patients (70 male and 51 female, with mean age 49 +/- 18 yrs). Carotid artery intima media thickness (IMT) was evaluated by Doppler ultrasonography. Patients were genotyped for the polymorphic base at position -1082 of the IL-10 promoter sequence by polymerase chain reaction (PCR). RESULTS: Circulating serum levels of all three adhesion molecules were higher in patients with -1082/AA genotype (p = 0.001). Higher serum albumin levels together with lower CRP levels were observed in patients with -1082/GG genotype (p < 0.05). Prevalence of atherosclerosis was higher in patients with -1082/AA genotype compared to heterozygous and -1082/GG genotype (41, 34 and 26%, respectively, p = 0.018). CONCLUSIONS: These results suggest that IL-10 gene polymorphism has an effect on inflammatory process and atherosclerosis in HD patients. Endothelial protective functions of IL-10 can modulate the circulating serum levels of adhesion molecules. Therefore, IL-10 gene polymorphism could lead to high or low inflammatory process and consequently, to atherosclerosis. IL-10 genotyping can define a high-risk group for atherosclerosis among HD patients.     

Effect of oral vitamin E and C therapy on calcineurin inhibitor levels in heart transplant recipients.

BACKGROUND: A recent prospective trial demonstrated that oral vitamins C and E retard the early progression of transplant-associated coronary arteriosclerosis; as a result, a number of centers have added these agents to their maintenance regimens. This study reviewed the impact of vitamin E and C supplementation on calcineurin inhibitor trough concentrations. METHODS: A retrospective chart review of the first 29 heart transplant patients prescribed anti-oxidant agents was performed. Twenty-two patients taking cyclosporin A (CsA) and 7 patients taking tacrolimus were prescribed vitamin C (500 mg twice a day) and vitamin E (400 IU twice a day). Serum chemistries and drug levels were measured before and after vitamin therapy was initiated. RESULTS: The baseline CsA trough concentration (mean +/- SD) was 137 +/- 39 ng/ml and it declined to 99 +/- 54 ng/ml (p = 0.007) after anti-oxidant therapy was initiated. The average percentage decrease in the CsA trough concentration was 30%. No significant changes were seen in the patients taking tacrolimus. CONCLUSIONS: These data demonstrate that supplementation with the anti-oxidant agents vitamin C and vitamin E decreases CsA concentrations but does not appear to effect tacrolimus concentrations. Although more detailed pharmacokinetic analysis is necessary to clarify the exact mechanism of this interaction, physicians who take care of transplant recipients should be aware that more frequent CsA concentration monitoring is warranted after initiating these anti-oxidant agents.     

Growth hormone treatment in hemodialysis patients--a randomized, double-blind, placebo-controlled study

OBJECTIVE: Renal failure and hemodialysis (HD) affect the anabolic growth hormone (GH)-insulin-like growth factor (IGF) axis. A positive correlation between serum IGF-I and normalized protein catabolic rate (PCRn) in HD patients has been reported, and the aim of this study was to assess the metabolic impact of recombinant human (rh)GH in these patients. MATERIAL AND METHODS: In a randomized, double-blind, placebo-controlled study, rhGH was given to 35 HD patients for 8 weeks: 0.025 IU/kg/day for 1 week, increasing to 0.05 IU/kg/day. Patients with diabetes, malignancy or clinical signs of infection and those receiving steroid treatment were excluded. RESULTS: All patients completed the study. Side-effects were rare and equally distributed between the two groups. Post-treatment, serum IGF-I and IGF-I standard deviation score (IGF-I SD) increased in the rhGH group compared to the placebo group: 283+/-33 vs 151+/-16 mg/l (p = 0.001) and 1.8+/-0.6 vs -0.2+/-0.6 (p = 0.002), respectively. IGF binding protein-3 was higher in the rhGH group compared to the placebo group: 5859+/-285 vs 4369+/-321 mg/l (p = 0.002). PCRn was significantly higher in the rhGH group compared to the placebo group: 1.09+/-0.06 vs 0.90+/-0.06 g/kg/day (p = 0.029). No differences were found in body weight, serum albumin or leptin between the two groups. There was no change in C-reactive protein (CRP) in the rhGH group compared to the placebo group: 17.4+/-9.0 vs 12.3+/-4.6 mg/l (p = NS). When the patients were subgrouped according to the CRP level (< or > 10 mg/1), the effect on PCRn persisted only in rhGH-treated subjects with a normal CRP level: 1.10+/-0.08 vs 0.81+/-0.09 g/kg/day (p = 0.025). CONCLUSION: Treatment of HD patients with rhGH at a moderate dose causes augmentation of PCRn which is considered to indicate a higher dietary protein intake. The anabolic effect of rhGH seems to be abolished by subclinical inflammation.     

Treatment of refractory hyperparathyroidism in patients on hemodialysis by intermittent oral administration of 1,25(OH)2vitamin D3

Intermittent oral administration of high dose 1,25(OH)2vitamin D3 was conducted in 7 patients associated with treatment-resistant secondary hyperparathyroidism (2nd HPT) on hemodialysis (HD) therapy. Each patient had a long history of HD therapy (range: 101-181 months, 145 +/- 29 months). Although serum calcium levels were maintained under the upper limit of the normal range with the appropriate dose of 1 alpha(OH)vitamin D3 every day before the present therapy, 2nd HPT could not have been controlled. The dose of 2-3 micrograms of 1,25(OH)2vitamin D3 3 times a week could successfully suppress serum levels of parathyroid hormone (iPTH) in all 7 patients after 20-32 weeks. The vitamin was given in the evening before each HD session and the dose and frequency of administration were dependent of the serum calcium level in each patient. After 20 weeks the iPTH-C and iPTH-intact levels decreased significantly from 35.0 +/- 15.8 to 18.6 +/- 11.7 ng/ml and from 533.2 +/- 200.0 to 249.5 +/- 136.2 pg/ml, respectively. The frequency of harmful elevations of serum calcium levels was not significantly increased in comparison with that in the previous period of the study, because serum calcium levels were strictly monitored with frequent checks. In conclusion, we could safely obtain an effect similar to the intravenous administration of the vitamin through the intermittent administration of a high oral dose 1,25(OH)2vitamin D3 in the treatment of refractory 2nd HPT in patients on HD therapy.     

Association of cardiac valve calcification and inflammation in patients on hemodialysis

BACKGROUND/AIMS: This study investigates the possible relationship between inflammation and cardiac valve calcification (VC) in patients on hemodialysis (HD), and identifies risk factors for VC in this patient group. METHODS: Seventy-nine patients on HD (mean age, 52.2 +/- 13.6 years; mean HD duration, 46.8 +/- 34.3 months) were assessed echocardiographically for the presence of VC. Systolic and diastolic blood pressure (BP) values were determined. The blood parameters studied in each case were hemoglobin, blood urea nitrogen, creatinine, calcium, phosphate, calcium-phosphorous (Ca x P) product, albumin, alkaline phosphatase, intact parathyroid hormone, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglyceride, lipoprotein(a), fibrinogen, and C-reactive protein (CRP). The number of patients receiving vitamin D and calcium-containing phosphate binder was determined from records, and presence of diabetes mellitus was noted. RESULTS: Cardiac VC was detected in 36 patients (46%). Five of these patients (6%) had mitral VC, 11 (14%) had aortic VC, and 20 (25%) had calcification of both valves. The patients with VC were significantly older than those without VC (60 +/- 11 vs. 43 +/- 15 years, respectively; P=.001). Compared with the group without VC, the group with calcification had significantly higher systolic (145.1 +/- 14.7 vs. 124.3 +/- 20.7 mmHg, P=.001) and diastolic BP (91.3 +/- 10.3 vs. 75.09 +/- 14.9 mmHg, P=.001); significantly higher phosphate (5.1 +/- 1.4 vs. 4.5 +/- 1.4 mg/dL, P=0.04), CaxP product (48.6 +/- 16.2 vs. 39.8 +/- 11.8, P=.01), lipoprotein(a) [28 (15, 45) vs. 16 (5,42) mg/dL, P=.04], fibrinogen (4.2 +/- 1.2 vs. 3.5-0.9, P=.005), and CRP levels [9 (4, 19) vs. 5 (3, 11) mg/L, P=.05]; and significantly longer HD duration [49 (27, 99) vs. 26 (17, 52) month, P=.01). Apart from age, duration of HD, systolic and diastolic BP, and Ca x P product, VC was associated with CRP (odds ratio, 1.151; P=.007) and fibrinogen (odds ratio, 1.119; P=.005). CONCLUSIONS: The results confirm well-known risk factors for cardiac VC in HD patients, such as older age, longer HD duration, elevated BP, and high Ca x P product. In addition, they suggest that elevated levels of CRP and fibrinogen were associated with VC in the HD population.     

A randomized, double-blind, placebo-controlled trial of supplementary vitamins E, C and their combination for treatment of haemodialysis cramps.

BACKGROUND: Muscle cramps that improve after carnitine or vitamin E therapies are common in haemodialysis (HD) patients. Because vitamin C participates in carnitine biosynthesis, and its levels are reduced in uraemia, subclinical vitamin C depletion may contribute to HD cramps. Our aim was to determine the effects of vitamins C, E and their combination on the frequency and intensity of HD cramps. METHODS: In this placebo-controlled, double-blind study, 60 HD-patients were randomized into four therapeutic groups. Each group (n=15) received six identical capsules daily for 8 weeks, containing one of the following: vitamin E (400 mg), vitamin C (250 mg), their combination, or placebo. RESULTS: The frequency and intensity of HD cramps decreased significantly in all three vitamin groups compared with the placebo group at the end of the trial, and compared with the pre-treatment values. At the end of the trial, vitamins E, C, their combination, and placebo produced cramp reductions of 54, 61, 97 and 7%, respectively. The percentage cramp reduction had no significant correlation with age, sex, aetiology of end-stage renal disease, serum electrolytes or HD duration, but showed a positive correlation (r=0.33, P=0.01) with the type of therapy. No vitamin-related adverse effects were encountered during the trial. CONCLUSION: Short-term treatment with the combination of vitamins E and C is safe and effective in reducing HD cramps; however, its safety for prolonged therapy has yet to be evaluated in HD patients.     

Circulating levels of ICAM-1, VCAM-1, and MCP-1 are increased in haemodialysis patients: association with inflammation, dyslipidaemia, and vascular events.

BACKGROUND: Increased levels of circulating adhesion molecules and chemokines have been reported in haemodialysis (HD) patients but the influence of the HD membranes on their secretion, as well as their pathophysiological implications, remains largely unknown. METHODS: Circulating levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and monocyte chemoattractant protein-1 (MCP-1) were measured by immunosorbent assay (ELISA) in 81 HD patients (45 male, mean age 57+/-13 years) and 35 normal subjects. All patients had been stabilized on renal replacement therapy for >3 months and were free of active infection. Thirty-three patients (40.7%) were routinely dialysed with modified cellulose membranes and 48 patients (59.3%) were dialysed with polysulfone membranes. Blood samples were taken directly from the arteriovenous fistula immediately before and at the end of a routine HD session. RESULTS: Pre-dialysis levels were significantly elevated in HD patients compared with controls (ICAM-1 515+/-177 vs 238+/-664 ng/ml, P<0.0001; VCAM-1 2107+/-648 vs 1012+/-115 ng/ml, P<0.0001; MCP-1 427+/-148 vs 125+/-42 pg/ml, P<0.0001). The HD session resulted in a significant increase in the levels of all three molecules measured (515+/-177 vs 679+/-187 ng/ml, P<0.0001; 2107+/-648 vs 2662+/-800 ng/ml, P<0.0001; 427+/-148 vs 567+/-153 pg/ml, P<0.0001, respectively). There was no difference in pre- or post-dialysis levels of the above molecules between patients routinely dialysed with either modified cellulose or polysulfone membranes. MCP-1 levels had a positive correlation with ICAM-1 levels (r=0.41, P<0.0005). VCAM-1 levels had a negative correlation with HDL levels (r=-0.30, P<0.01) and were significantly elevated in patients with HDL <35 mg/dl compared with patients with HDL > or = 35 mg/dl (2300+/-606 vs 1890+/-633 ng/ml, P<0.005). Log-transformed exact C-reactive protein (CRP) values were significantly correlated with ICAM-1 and VCAM-1 levels (r=0.41, P<0.005 and r=0.43, P<0.005, respectively). In addition, compared with patients with normal CRP values, patients with elevated CRP had significantly increased levels of ICAM-1 (466+/-166 vs 580+/-172 ng/ml, P<0.005). Patients with cardiovascular, cerebrovascular, or peripheral vascular diseases had significantly increased serum CRP and ICAM-1 levels compared with patients with no evidence of vascular disease (19.2+/-12.9 vs 7.9+/-11.8 mg/l, P<0.001 and 608+/-189 vs 474+/-155 ng/ml, P<0.005 respectively). CONCLUSIONS: Serum levels of ICAM-1, VCAM-1, and MCP-1 are increased in HD patients and probably result from either inadequate clearance or enhanced synthesis and release. HD session resulted in a significant increase of the above molecule levels but the exact mechanism(s) responsible for these alterations are yet to be fully elucidated. Increased levels of adhesion molecules are associated with inflammation, dyslipidaemia, and cardiovascular events. However, the potential link between these processes and its clinical significance warrants further investigation.     

Efficacy of methylcobalamin on lowering total homocysteine plasma concentrations in haemodialysis patients receiving high-dose folic acid supplementation.

BACKGROUND: Hyperhomocysteinaemia, which is considered to be induced by impairment of the remethylation pathway in patients with chronic renal failure (CRF), cannot be cured solely by folic acid therapy. In the present study, we investigated the additional benefit of administration of methylcobalamin, which is a co-enzyme in the remethylation pathway, on lowering total homocysteine (tHcy) plasma concentrations in haemodialysis (HD) patients receiving high-dose folic acid supplementation. METHODS: In order to assess the efficacy on lowering plasma tHcy levels (fasting concentration), 21 HD patients, were randomly assigned and provided folic acid supplementation: 15 mg/day orally (group I, n=7); methylcobalamin 500 mg intravenously after each HD, in addition to folic acid (group II, n=7); or vitamin B(6) (B(6)), 60 mg/day orally, in addition to folic acid and methylcobalamin (group III, n=7). All patients were treated for 3 weeks. A methionine-loading test was conducted before and after supplementation. The following measurements were also made before and after supplementation for each group: serum folic acid, B(6), and vitamin B(12) (B(12)) concentrations (including measurement of proportion of methylcobalamin fraction). Twelve HD patients receiving methylcobalamin alone served as the HD control group and seven healthy volunteers served as the normal control group for this study. RESULTS: In our randomized HD patients the proportions of methylcobalamin fraction (48.3+/-7.5%) and plasma vitamin B(6) concentration (2.9+/-1.1 ng/ml) were significantly lower than in the normal controls (methylcobalamin 58.7+/-2.2%, P<0.01; B(6) 20.1+/-10.8 ng/ml, P<0.01), while folic acid and vitamin B(12) were not significantly different from the normal controls. Mean percentage reduction in fasting tHcy was 17.3+/-8.4% in group I, 57.4+/-13.3% in group II, 59.9+/-5.6% in group III, and 18.7+/-7.5% in HD controls. The power of the test to detect a reduction of tHcy level was 99.6% in group II and 99.9% in group III when type I error level was set at 0.05. Groups II and III had normal results for the methionine-loading test after treatment. Treatment resulted in normalization of fasting tHcy levels (<12 ng/ml) in all 14 patients treated by the combined administration of methylcobalamin and supplementation of folic acid regardless of whether there was supplementation of vitamin B(6). CONCLUSION: The benefit of methylcobalamin administration on lowering plasma tHcy levels in HD patients was remarkable. Our study suggested that both supplementations of high-dose folic acid and methylcobalamin are required for the remethylation pathway to regain its normal activity. This method could be a therapeutic strategy to combat the risk associated with atherosclerosis and cardiovascular disease in patients with chronic renal failure.     

Direct effect of the correction of acidosis on plasma parathyroid hormone concentrations, calcium and phosphate in hemodialysis patients: a prospective study

BACKGROUND: Metabolic acidosis contributes to renal osteodystrophy and together with hyperphosphatemia, hypocalcemia and altered vitamin D metabolism may result in increased levels of intact parathyroid hormone (iPTH) and metastatic calcifications. However, the impact of the correction of metabolic acidosis on iPTH levels and calcium-phosphate metabolism is still controversial. STUDY DESIGN: The effects of the correction of metabolic acidosis on serum concentrations of iPTH, calcium (Ca), phosphate (PO(4)) and alkaline phosphatase were prospectively studied. Twelve uremic patients on maintenance hemodialysis (HD) for 49 months (median; range 6-243 months) with serum bicarbonate levels < or =20 mmol/l were studied before and after 3 months of oral sodium bicarbonate supplementation. Predialysis serum bicarbonate, arterial pH, ionized calcium, plasma sodium, plasma potassium, serum creatinine, hemoglobin, K(t)/V, postdialysis body weight, predialysis systolic and diastolic blood pressure were also evaluated before and after correction. RESULTS: Serum bicarbonate levels and arterial pH increased respectively from 19.3 +/- 0.6 to 24.4 +/- 1.2 mmol/l (p < 0.0001) and 7.34 +/- 0.03 to 7.40 +/- 0.02 (p < 0.001). iPTH levels decreased significantly from 399 +/- 475 to 305 +/- 353 pg/ml (p = 0.026). No changes in total serum Ca, plasma PO(4), serum akaline phosphatase, K(t)/V, serum creatinine, hemoglobin, body weight, predialysis systolic and diastolic blood pressures were observed. iCa decreased significantly. CONCLUSIONS: Our study demonstrates that the correction of metabolic acidosis in chronic HD patients reduces iPTH concentrations in HD patients with secondary hyperparathyroidism possibly by a direct effect on iPTH secretion.     

The prognostic role of brain natriuretic peptides in hemodialysis patients

BACKGROUND: Although plasma concentrations of brain natriuretic peptides (BNP) increase in hemodialysis (HD) patients as well as patients with cardiovascular diseases (CD), the clinical significance of BNP in HD patients has yet to be elucidated. In this study, we investigated the pathophysiological significance of BNP in HD patients. METHODS: Plasma BNP concentrations were measured in 164 HD patients after HD and 14 healthy volunteers. In 12 patients without CD, BNP was also measured before HD. Multiple regression analysis was performed to determine the important factors causing increased plasma BNP concentrations. Cardiac mortality was monitored for 36 months after baseline analysis, and the prognostic role of BNP was examined by Cox proportional hazards regression analysis. RESULTS: Plasma BNP concentrations of HD patients without CD decreased significantly during HD session (124.5 +/- 90.7 vs. 91.4 +/- 67.6 pg/ml, mean +/- SD, p = 0.004), but were still significantly higher than those of the healthy subjects (9.7 +/- 9.2 pg/ml, p = 0.0002). Plasma BNP concentrations of patients with CD were significantly higher than of those without CD (579.6 +/- 564.3 vs. 204.0 +/- 241.5 pg/ml, p < 0.0001). Plasma BNP concentrations were also significantly higher in diabetes mellitus (DM) patients than in non-DM patients (514.1 +/- 585.4 vs. 296.0 +/- 347.0 pg/ml, p = 0.0031). Multiple regression analysis showed that left ventricular mass index (LVMI), CD and DM were independent factors for the elevated BNP (R(2) = 0.303, p < 0.0001). During a 36-month follow-up period, cardiac death occurred in 13 patients. Kaplan-Meier survival estimates of patients from varying plasma BNP quartiles (<200, 200-450, 450-700 and >700 pg/ml) differed between the four groups (p < 0.0001). The group with the highest BNP level (>700 pg/ml) had the lowest survival. When compared with patients with BNP <200, the hazard ratios for cardiac death of patients with BNP of 200-450, 450-700 and >700 pg/ml were 2.3 [95% confidence interval (CI) 0.14-36.7], 18.7 (1.9-183.4) and 51.9 (6.5-416.3), respectively. The univariate Cox proportional hazards model showed that BNP, left ventricular ejection fraction, LVMI, age, DM, serum albumin and C-reactive protein (CRP) were significantly associated with the risk of cardiac mortality. By stepwise multivariate Cox proportional hazards analysis, only BNP, LVMI and CRP remained powerful independent predictors of cardiac death. The relative risk ratios were 1.002 (95% CI 1.001-1.002) for BNP, 2.192 (1.532-3.135) for CRP and 1.027 (1.013-1.042) for LVMI. CONCLUSION: High plasma BNP concentrations in HD patients were associated with volume overload, left ventricular hypertrophy, CD and DM. Plasma BNP concentration may be a useful parameter for assessing the risk of cardiac death in HD patients by providing prognostic information independently of other variables previously reported.