Cardiovascular outcome in asymptomatic hemodialysis patients submitted to aggressive medical therapy: results of a four-year follow-up.

AIM: Cardiovascular disease is a leading cause of morbidity and mortality in end-stage renal disease (ESRD) patients on maintenance hemodialysis (HD). Neither traditional nor emerging risk factors for cardiovascular disease can explain completely this excess of morbidity and mortality and the role and timing of primary prevention strategies in this population has not been clarified. The aim of this study was to assess if an aggressive pharmacological preventive treatment may reduce the myocardial ischemic burden and then improve the cardiovascular outcome In ESRD patients. METHODS: Forty-three asymptomatic ESRD patients on maintenance HD were evaluated. Asymptomatic patients with neither history nor clinical evidence of cardiovascular disease were considered. A total of 31 ESRD patients were enrolled into the study and were submitted to Tc-99m SESTAMIBI myocardial gated- single-photon emission computed tomography (SPECT) stress test. All patients then received an aggressive medical regimen with statins, antiplatelet drugs, ACE inhibitors (ACE-I) and/or Angiotensin II Receptor Blockers (ARB) and other hypotensive, glucose-lowering medications, sevelamer, calcium carbonate and calcitriol if required. RESULTS: A significant reduction of coronary functional reserve was found in more than 50% of otherwise asymptomatic HD patients and may often be reverted by prolonged aggressive medical therapy. After a four-year follow-up under aggressive medical therapy no significant difference was observed neither in the incidence of conventional and emerging cardiovascular risk factors nor in cardiovascular outcome of patients with or without silent myocardial ischemia (SMI). CONCLUSION: As cardiovascular disease (CVD) is by far the first cause of death in ESRD, an aggressive medical management may be highly advisable for the primary prevention of major adverse cardiac events in all HD patients despite the stress test evidence of inducible myocardial ischemia .

The usefulness of the prognostic inflammatory and nutritional index (PINI) in a haemodialysis population.

BACKGROUND AND AIM: Protein-Energy Wasting and inflammation are the principal risk factors of haemodialysis complications. We evaluated the reliability of a simple and non expensive test, the Prognostic Inflammatory and Nutritional Index (PINI), for regular screening of maintenance haemodialysis (MHD) patients in order to detect early onset of inflammation and malnutrition. METHODS AND RESULTS: 121 adult patients on maintenance dialysis were followed up for 32 months and screened every 6 months for PINI, calculated as alpha1-Acid Glycoprotein (alpha1-AG)xC-Reactive Protein (CRP)/AlbuminxTransthyretin. PINI score < or =1 was considered normal. Patients were stratified according to their PINI score: 86 patients (71.66%) had a normal score, whereas 35 (28.33%) had PINI > or = 1. The latter also had higher CRP levels, despite no clinical evidence of inflammation at the time of enrolment. Survival in patients with normal PINI was similar to patients with normal CRP, while in patients with abnormal PINI it was significantly lower than in patients with low serum albumin (p<0.05) or elevated CRP (p<0.05). After follow-up, all surviving MHD patients with PINI > or = 1 had at least one cardiovascular event vs 2.5% of patients with PINI > or = 1. CONCLUSION: The assessment of PINI can reliably identify MHD patients at higher risk of mortality and morbidity even in the absence of overt Malnutrition-Inflammation Complex Syndrome (MICS). This simple test appears to be more sensitive and specific of the single components, and not expensive, so that it could be routinely used to identify patients with sub-clinical inflammation and/or malnutrition.

Cardiac calcifications in hemodialysis patients assessed with spiral computed tomography.

AIM: Cardiac disease is a major cause of mortality in uremic patients. The aim of this paper was to evaluate cardiac calcium content in uremic patients with multislice computed tomography (MSCT). METHODS: The study has been carried out on 120 uremic and 28 nonuremic patients affected by cardiovascular disease. Serum calcium, phosphorus, calcium-phosphate product, intact PTH were assayed. Several lipidic and nutritional parameters were measured. Calcification values obtained with the MSCT were reported in terms of Agatson scores. RESULTS: We found that the average score values in cohort on uremic was 10 times higher than in nonuremic patients (score values 3.389 vs 328). Cardiac calcification score was found to be correlated significantly to age (P=0.006), HD age (P=0.010), serum calcium (P=0.006), iPTH (P=0.004). Multiregression analysis (MRA) with the cardiac score as dependent variable selected the following variables (R(2) 0.612): age (P=0.002), HD age (P=0.010), serum cholesterol (P<0.000), triglycerides (P=0.001) and inversely HDL cholesterol (P=0.001) and non-HDL cholesterol (P=0.001) as predictive variables for cardiac score. By comparing patients with scores lower and higher than 400, the group with score <400 showed a significantly lower age (P=0.0001), HD vintage (P=0.01) and a significantly higher serum cholesterol (P=0.009), HDL cholesterol (P=0.05) and non-HDL cholesterol (P=0.05). CONCLUSIONS: The MSCT could help in identifying and stratifying high-risk patients to implement preventive strategies. The control of mineral metabolism and of lipid levels is important in prevention of arterial calcification in uremic patients.

Vitamin E suppresses 5-lipoxygenase-mediated oxidative stress in peripheral blood mononuclear cells of hemodialysis patients regardless of administration route.

A number of pathological conditions caused by oxidative stress have been reported in uremic patients undergoing maintenance hemodialysis (HD). Enhanced lipid peroxidation was previously observed in peripheral blood mononuclear cells (PBMCs) of HD patients. Upregulation of 5-lipoxygenase (5-Lox) activity and protein content with enhanced production of leukotriene B(4) (LTB(4)) and membrane lipoperoxides was also shown in PBMCs of HD patients. Administration of free vitamin E specifically inhibited 5-Lox activity without affecting gene expression at the protein level. To assess whether oral or intramuscular (IM) administration of vitamin E may suppress 5-Lox in HD patients, PBMCs from 16 subjects on maintenance HD therapy for at least 6 months were investigated before and after a short course of IM or oral administration of vitamin E (8 patients per group). PBMCs from 13 healthy controls were also evaluated and assumed as the reference standard. Vitamin E significantly reduced lipid peroxidation, LTB(4) content, and 5-Lox activity in PBMCs, whereas 5-Lox gene expression at the protein level was not affected. There were no significant differences in these parameters between patients treated with IM or oral vitamin E. PBMCs of HD patients showed enhanced membrane lipid peroxidation and release of LTB(4), both linked to upregulation of 5-LOX: 5-Lox activity and related oxidative stress were significantly (although not completely) suppressed by vitamin E regardless of the administration route.

Vitamin E supplementation and oxidative status of peripheral blood mononuclear cells and lymphocyte subsets in hemodialysis patients.

Increased oxidative damage to cell membrane constituents causes profound changes in the membrane cytoarchitecture and modifications of the membrane physiological properties, e.g., the ability to respond to hormonal stimuli. In uremic patients receiving intermittent hemodialysis, a metabolic block of the phosphate pentose shunt has been described. This leads to insufficient detoxication of the hydroxyl radicals formed within the cells and therefore to increased oxidative damage to the polyunsaturated fatty acid constituents of the cell membranes. Vitamin E is known to reduce this oxidative damage and its harmful effects. We studied vitamin E (alpha-tocopherol acetate) administration in 10 chronically uremic patients receiving intermittent hemodialysis for positive effects on cell membrane-receptor response. The patients were studied before and after treatment for the extent of oxidative damage in peripheral mononuclear cells and for response to monoclonal antibodies to specific markers of T-lymphocyte subsets. After vitamin E treatment, oxidative damage decreased, and the membranes of peripheral mononuclear cells contained greater amounts of some unsaturated fatty acids. This is in agreement with a modification of the membrane phenotype markers of T-lymphocyte subsets and seems to confirm in vivo that changes in membrane structure first induced by increased oxidative damage due to the blockage of the phosphate pentose shunt can be reduced by the antioxidant action of vitamin E, which significantly influences the expression of membrane determinants.

Effects of alpha-tocopherol administration on red blood cell membrane lipid peroxidation in hemodialysis patients.

The result of vitamin E treatment in 19 uremic patients in chronic hemodialysis is evaluated. In particular, the levels of erythrocyte malonyldialdehyde (MDA) and vitamin E were determined, and the fatty acid composition of red blood cell (RBC) membrane before and after treatment with parenterally administered vitamin E. A decrease of RBC MDA levels, an increase of RBC vitamin E concentrations, and a decreased saturated fatty acid to unsaturated fatty acid ratio were found after treatment with vitamin E. There was a statistically significant increase of the packed RBC volume.

Red blood cell lipid peroxidation in predialysis chronic renal failure.

In hemodialysis patients the pentose-phosphate shunt activity is deficient. As a consequence, the lipid peroxidation of the erythrocyte membranes is increased as shown by the increase in malonyldialdehyde concentrations and is accompanied by a decrease of the level of vitamin E in RBC. In the present study we have found that increased lipid peroxidation of the erythrocyte membranes is present also in chronic renal failure patients in the predialysis state, provided that the serum creatinine levels are higher than 5 mg/dl.

Vitamin E supplementation in hemodialysis patients: effects on peripheral blood mononuclear cells lipid peroxidation and immune response.

Lipid peroxidation and vitamin E levels in peripheral blood mononuclear cells (PBMC) were studied in 10 patients on maintenance hemodialysis. Significant increases of PBMC malonyldialdehyde (MDA) were detected, together with low vitamin E levels. After a fifteen-day-course of parenteral vitamin E supplementation, PBMC MDA reverted to normal values, while PBMC vitamin E levels remained lower than controls. In a parallel study an immunological monitoring was performed in the same patients before and after vitamin E supplementation. NK activity and PHA blastogenesis were not influenced by treatment, while a reduction of the number of OKT8+ lymphocytes were observed after vitamin E therapy. It is tempting to speculate that peroxidative damage of PBMC cell membranes in hemodialysis patients could, by impairing their functionality, influence immune responses and expression of functionally relevant membrane determinants.

Administration of GSH has no influence on the RBC membrane: oxidative damage to patients on hemodialysis.

In patients on hemodialysis, a metabolic block of the pentose phosphate shunt has been described that impairs the reduction of oxidized glutathione. The block results in lack of detoxication of the free hydroxyl radicals produced inside the red blood cell (RBC) and causes oxidative damage to the polyunsaturated fatty acids of the RBC membrane that results in formation of aldehydes. Malonyldialdehyde has been used as an index of the oxidative damage. In a study group of 13 patients on hemodialysis, the authors have tested whether administering reduced glutathione (GSH) at 1200 mg/day for 1 month could minimize oxidative damage to the RBC membranes and improve the hematologic parameters. Treatment with GSH was followed by significant improvement of hematocrit (P = 0.008), hemoglobin (P = 0.03), and RBC count (P = 0.0037); however, oxidative damage to the membranes was increased (P = 0.0004), which suggests that improvement of the hematologic parameters is not related to reduction of the oxidative damage. This is because oxidized glutathione, formed in the oxidative process, cannot be reduced back to GSH because of alteration of the pentose phosphate shunt.

Plasmapheresis versus plasma perfusion in acute Guillain-Barré syndrome.

Guillain-Barré Syndrome (GBS) is an acute post infectious or disimmune illness that affects nerve roots and peripheral nerves. Multicenter studies have clearly shown that plasma exchange (PE) provides valuable amelioration of GBS. It was recently suggested that plasma perfusion (PP) on phenylalanine columns displays the same therapeutic effects of PE in neuroimmunologic disorders, without the infectious risks linked with plasma replacement. In this study, the authors compared the efficacy of PE versus that of PP in two groups of patients suffering from GBS by investigating the clinical outcomes and the electrophysiologic and cerebrospinal fluid findings. Of 22 patients suffering from GBS, 16 underwent seven sessions of PE in a mean time of 15 days (Group A). Six patients, showing the same clinical pattern, underwent three sessions of PP in a mean time of 10 days (Group B). Data reported in Group A show that PE: 1) stops the progressive worsening of the disease, 2) prevents the development of acute respiratory failure, 3) allows an early and significant clinical improvement with change in disability grade, and 4) improves motor conduction velocities and motor action potentials when recorded 45 days after the end of treatment. Data in Group B show that PP allows a slower and later improvement in disability grade, and electrophysiologic data recorded at the end of treatment was worse after 45 days. Finally, it may be concluded that PE has beneficial effects on GBS in terms of time of recovery, complication rate, and relapses. Plasma perfusion did not show the same results.

Correction of uremic acid-base imbalance in biofiltration: standardization of the amount of bicarbonate infused.

Beneficial effects of biofiltration on acid-base balance have been described, especially in patients showing poor tolerance to standard hemodialysis. This study was designed to standardize the amounts of bicarbonate to be infused for optimal control of the acid-base balance, without the adverse reactions of symptomatic metabolic alkalosis. In three adult patients (body weight greater than 55 kg) a 300 mEq. bicarbonate infusion achieved normal pre- and post-dialysis plasma levels of bicarbonate and normal pre- dialysis pH. Conversely, in three adolescent patients (body weight less than 40 kg) pre- dialysis plasma bicarbonate levels and pre- dialysis pH could not be adequately corrected in spite of increasingly high doses of bicarbonate infused up to a maximum of 240 mEq per treatment. Larger amounts brought on symptoms of metabolic alkalosis.

Clinical evaluation of biofiltration in uremic patients undergoing chronic hemodialysis.

The clinical efficiency of biofiltration (BF) was evaluated in six hemodialysis patients with poor clinical tolerance for standard hemodialysis. Three were adults (mean age 34 years, mean body weight 67 kg) and three adolescents (mean age 17 years, mean body weight 38 kg). Mean maintenance hemodialysis time was 90.5 months (range 49-132). BF treatments lasted three hours in all cases, for a total of nine hours weekly, with AN69 S membranes and infusion of 3 liters of HCO3 solution (100 mEq/l for the adults, 80 mEq/l for the adolescents). We recorded intra- and inter-dialytic symptoms daily, hematological values and acid-base status monthly. Multimodality evoked potentials were recorded after 3 and 9 months. Biochemical values reached a steady state 9 months from the beginning of the study, metabolic acidosis was corrected more efficiently in both groups at the end of dialysis, but only in the adult patients, were pre-dialysis plasma bicarbonates within normal limits. A clear drop in the number of episodes of intradialytic hypotension was noticed in both groups, but the adolescent patients' tolerance for dialysis did not improve. In conclusion our data show that in adult patients with poor tolerance BF offers a dependable alternative to standard hemodialysis, and the length of treatment can be reduced.

Lack of oxidative damage in serum polyunsaturated fatty acids before and after dialysis in chronic uremic patients.

We described previously that in the erythrocytes and mononuclear blood cells from uremic patients on chronic hemodialysis, the membrane concentrations of malonyldialdehyde (MDA), resulting from peroxidation of polyunsaturated fatty acids (PUFA) in the membrane itself increased, and the concentrations of vitamin E (VIT E), the major antioxidizing agent, were lower. In the present study we analysed whether similar oxidative damage is seen in the serum from hemodialysis patients and whether the serum fatty acid pattern is affected. No evidence was found of oxidative damage in the serum during hemodialysis, serum concentrations of MDA and VIT E remaining constant before and after dialysis. No change was observed in serum pattern of PUFA, particularly linoleic acid. We therefore assume that the oxidative damage described in uremic patients is mainly intracellular.

Evaluation of acid-base balance and pO2 with acetate dialysis in non-uremic patients.

The aim of our work was to evaluate the immediate effects of acetate-dialysis in patients with normal renal and respiratory function. For this purpose pH, pO2, pCO2 and HCO3- were monitored in arterial blood before dialysis, after 60, 120, 180 mns and at the end of each treatment in two groups of patients on chronic hemodialysis, a first group of schizophrenic patients and a second group of uremic patients. In the first group of patients the predialytic values were in the normal range. After hemodialysis HCO3- and pCO2 significantly decreased, both these changes were associated with a stable pH. The pO2 significantly decreased after 60 mns of dialysis. At the end of dialysis the pO2 increased without significant variation compared to predialytic values. In conclusion in non-uremic hemodialysis patients metabolic acidosis due to the loss of bicarbonate through the membrane is compensated by respiratory alkalosis. This respiratory alkalosis is not due to hypoventilation secondary to respiratory centre inhibition, but is mainly due to the pCO2 loss through the dialysis membranes.

25-hydroxycholecalciferol in the treatment of renal osteodystrophy in haemodialysed patients.

The effects of 25-OHD3 on renal osteodystrophy have been studied in 6 patients on maintenance haemodialysis. Administration of 25-OHD3, 50 microgram/day, did not improve biochemical data and intestinal absorption of calcium. With a dose of 100 microgram/day in all patients an increase in blood calcium levels eventually reaching hypercalcemic values was observed. In two cases a fall in alkaline phosphatase toward normal values was noted. In the same cases the treatment-induced hyperphosphatemia, uncontrolled by AI(OH)3 supplementation and similarly high iPTH levels were observed. In two cases repeated bone biopsy following 8 months treatment and not show substantial improvement of bone lesions. In one case addition of 1,25-(OH)2D3 to the treatment with 25-OHD3 led to a more rapid improvement in biochemical parameters and iPTH serum levels. Doses of 25-OHD3 capable to correct blood calcium levels and intestinal absorption of calcium, may have minimal benefit on the osteitis fibrosa component of the bone lesion.

Present status of hemoperfusion/hemodialysis in Italy.

The use of charcoal hemoperfusion in the treatment of chronic renal failure has been proposed and applied by several authors. The availability of coating membranes of increased biocompatibility currently allows a safer and wider use of this purifying technique. It has been recently demonstrated that long-term treatment with combined hemodialysis/hemoperfusion yields an improvement of certain dialysis-resistant uremic signs in patients on regular dialysis treatment, while in selected patients it affords a marked reduction (up to one-third) in the overall time of treatment per week. The tolerance of long-term treatment is good. In line with these findings, a multicenter study has been carried out in Italy with two main aims: (1) to see whether long-term treatment with charcoal hemoperfusion is really safe and substantially free from side effects; (2) to verify in a larger and more varied population of patients whether such long-term treatment actually improves certain uremic signs persisting despite adequate dialysis treatment. A third phase of the multicentric study (reducing the weekly time of treatment) is currently being worked on. Five nephrology and dialysis departments took part in the study: in Bologna, Rome, Chieti, Ancona, and Lecce.