Mineral and electrolyte metabolism最新文献

The angiotensin II receptor 1 antagonist losartan (L) inhibited the advanced glycated end-products (AGEs) induced expression of transforming growth factor beta(1) in in vitro experiments performed on renal tubuloepithelial cells. To test the pathophysiological importance of these findings, the possible link between serum AGEs levels and angiotensin system was investigated in the model of normotensive subtotally nephrectomized rats(4/6-NX). Concentration of AGEs in serum of placebo administered 4/6-NX rats (n = 7, 1.09+/-0.09 U/l) increased slightly in comparison with sham-operated healthy controls (CTRL, n = 8, 0.94+/-0.10 U/l, p<0.02) as measured by competitive ELISA. Treatment of 4/6-NX rats with L over 12 weeks ameliorated the rise in serum AGEs concentration (1.00+/-0.12 U/l, n = 15 <0.005) almost to the level observed for CTRL. This effect was further corroborated by the observation, that the impaired renal excretion of AGEs in 4/6-NX-placebo rats (0.07+/-0.02 U/micromol creatinine) was significantly restored by L (0.09+/-0.02 U/micromol creatinine, <0.009) and resembled that of the CTRL (0.10+/-0.03 U/micromol creatinine). Administration of L to 4/6-NX rats significantly improved renal function as evaluated by a smaller rise in serum creatinine and urea concentration. In spite of the improvement in renal function, there were no differences in concentrations of transforming growth factor beta(1) in serum and in urine among the two groups. These effects were independent of blood pressure. Our data give first evidence, that long-term treatment with angiotensin II receptor 1 antagonist may exert salutary effects on AGEs levels in the rat remnant kidney model, probably due to improved renal function.

Homocysteine, a sulfur amino acid, is an important methionine derivative, which has been implicated in the pathogenesis of atherothrombosis. Although only observational, epidemiological studies are available at present, the evidence of an association between hyperhomocysteinemia and increased cardiovascular risk is quite strong and this is confirmed also in a population of chronic renal failure patients. From a biochemical standpoint at least three mechanisms have been summoned so far in order to explain homocysteine toxicity including: oxidation, hypomethylation, and acylation. Proteins are believed to play a crucial role as homocysteine molecular targets. Interference with the functions of several of such macromolecules has been so far described being mediated by any of the above mechanisms. Vitamins may positively influence homocysteine metabolism, thus facilitating the metabolic clearance of this compound. Therefore they are presently considered as potential means for reducing plasma levels of this amino acid and preventing vascular occlusions in hyperhomocysteinemic patients. These compounds, with special regard to folate, are eligible for interventional clinical trials, from which the definitive answer on the role of homocysteine in atherothrombosis is expected.

Low protein diets have been used for a long time in the conservative management of chronic renal failure as they have a beneficial effect in preventing the appearance of symptoms. However, with the exception of the beneficial effect on hyperphosphatemia of the very low protein diets supplemented with ketoacids, they have no proven effects on the other aspects of the uremic syndrome. Moreover, the weight of the evidence suggests that the effect of these diets on preservation of GFR, if any, in patients with nondiabetic renal disease is small and of little clinical relevance. There is very little evidence in the literature of its role in patients with diabetes. The nutritional safety of these diets is still suspect. Patients with chronic renal failure have low energy intakes, which is further reduced when these diets are prescribed. Metabolic studies predict that these patients would be in negative nitrogen balance and in fact, even nutritionally sound, nondiabetic patients enrolled in the Modification of Diet in Renal Disease Study developed subclinical signs of malnutrition. It is possible that the nutritional decline may have been more pronounced on longer duration of follow-up. Finally, these diets are difficult to follow, leading to issues of compliance and exert a great toll on the time of the dietitians. Hence, we conclude that low protein diets are not necessary in chronic renal failure.

The activated form of vitamin D(3), 1alpha,25(OH)(2)D(3), not only plays a central role in bone and calcium metabolism but has also potent antiproliferative and prodifferentiating effects. Moreover, the combined presence of 25(OH)D(3)-1alpha-hydroxylase as well as the vitamin D receptor in several tissues introduced the idea of a paracrine role for 1alpha,25(OH)(2)D(3). By introducing chemical modifications into the flexible parent molecule 1alpha,25(OH)(2)D(3), a whole generation of vitamin D analogs was created. Due to a clear dissociation of the antiproliferative and prodifferentiating effects from calcemic effects, these analogs can be used not only for the treatment of bone disorders but also for non-classical applications.

Urinary excretion of vitamin B(6), oxalic acid and vitamin C was investigated in 15 healthy subjects during maximal water diuresis and in the group of 12 patients in polyuric stage of chronic renal failure without dialysis treatment receiving a diet containing high sodium chloride (15g/day). Urinary excretions of the same parameters were investigated in another group of 15 patients in polyuric stage of chronic renal failure without dialysis treatment after i.v. administration of 20 mg furosemide. Urinary excretion of vitamin B(6), oxalic acid and vitamin C significantly increased during maximal water diuresis while during high intake of sodium chloride the urinary excretions of these substances were not affected. The results suggest that urinary excretion of vitamin B(6), oxalic acid and vitamin C depends on the urinary excretion of water. Intravenous administration of 20 mg furosemide led to an increase of urinary excretion of vitamin B(6), oxalic acid and vitamin C in patients with chronic renal failure. The increased urinary excretion of vitamin B(6) and vitamin C is a new negative side effect of furosemide and increased urinary excretion of oxalic acid is a new positive side effect in patients with chronic renal failure.

Metabolic acidosis has been shown to act as a causative factor in muscle protein breakdown and negative nitrogen balance, as well as in decreased albumin synthesis. Albumin and other acute phase proteins (APP) are mainly synthesized in the liver following induction by interleukins, hormones and other mediators. Acute phase proteins have been shown to be predictors of cardiovascular mortality in the general population and in patients with end stage renal disease (ESRD). Clinical investigation gives evidence that albumin is reduced by acidosis in ESRD patients. The aim of our study was to investigate the role of the liver in acidosis, i.e. the influence of acidosis on metabolic activity and secretion of APP by liver cells (HepG2). Cells were cultured in a medium containing different amounts of bicarbonate. Metabolic activity was significantly diminished when the bicarbonate concentration of the extracellular medium was reduced (86.13+/-1.90% (pH 7.0) vs. 99. 53+/-90% (pH 7.4); p<0.01). While cellular release of negative APP was significantly decreased (albumin: 4.6+/-0.41 (pH 7.0) vs. 7.54+/-0.62 (pH 7.4) [ng/microg protein], p<0.001, transferrin: (0. 78+/-0.08 (pH 7.0) vs. 1.07+/-0.07 (pH 7.4) [ng/microg protein], p<0. 05), no significant influence of acidosis (pH 7.0) on the positive APP, alpha(1)-acid glycoprotein (AGP) (1.69+/-0.25) (pH 7.0) vs. 1.62+/-0.23 (pH 7.4) [ng/microg protein]), could be shown. Our data indicate that acidosis results in inhibition of liver cell metabolic activity and in reduced secretion of the negative acute phase proteins albumin and transferrin. In contrast, secretion of the positive acute phase protein AGP seems to be unchanged at pH 7.0 as compared to pH 7.4. We conclude that negative and positive APP in liver cells (HepG2) appear to be differently regulated by acidosis.

Hypoalbuminemia and reduction in lean body mass are potentially a reflection of malnutrition and portend a poor prognosis in patients with end stage renal disease (ESRD). The classic understanding of this relationship has been that ESRD patients receive insufficient dialysis, reduce dietary intake and become malnourished. Inflammation also causes many of the same changes in serum protein composition and in body morphometry as malnutrition does even with adequate calorie and protein intake. It has recently been recognized that this, the acute phase response, occurs with frequency in ESRD patients and that both the physical attributes of malnutrition and reduction in the serum concentration of albumin, transferrin, prealbumin and apolipoprotein A-I all may lack a nutritional base. The serum concentration of the acute phase proteins, C reactive protein (CRP) and serum amyloid A (SAA), as well as the cytokines orchestrating the acute phase response, predict albumin concentration as well as a number of clinically important outcomes: specifically, erythropoietin resistance rejection of renal transplant and survival. ESRD per se does not cause the acute phase response, and indeed may blunt the response to infection. Activation of the acute phase response may be a consequence of the interaction of mononuclear cells with dialysis membranes, especially cuprophane, with endotoxin in dialysate, or represents either clinically evident or obscure infection. Evaluation of the acute phase response by measurement of CRP is advisable in the evaluation of hypoalbuminemia or other stigmata of malnutrition in dialysis patients.

Malnutrition is common in chronic hemodialysis (CHD) patients and is strongly related to increased morbidity and mortality. Among the various approaches to treat malnutrition in this patient population, intradialytic parenteral nutrition (IDPN) is the treatment of choice for a small but important percentage of malnourished CHD patients. However, the new revised policies relating to IDPN reimbursement by Medicare in the US have made it very difficult to qualify patients for this potentially useful therapy. This restrictive policy was adopted mainly because there are no clear data that support IDPN use or efficacy. Studies to date in the literature do not provide clear documentation of the benefits of IDPN or their cost-effectiveness. The purpose of this review is to critically evaluate studies relating to the use of IDPN as a potential therapy to treat malnutrition in CHD patients and to discuss potential trials to prove its cost-effectiveness.

Metabolic acidosis and glucocorticoids act in concert to stimulate branched-chain amino acid (BCAA) oxidation in adrenalectomized rats. In muscles of normal rats, metabolic acidosis increases the maximal activity of the rate-limiting enzyme, branched-chain alpha-ketoacid dehydrogenase (BCKAD) and a genetic response to catabolic conditions like uremia is implicated by concurrently higher levels of BCKAD subunit mRNA. To determine if acidification or glucocorticoids increase transcription of BCKAD subunit genes, transfection studies were performed with BCKAD promoter-luciferase reporter minigenes in LLC-PK(1) cells which do not express gluco-corticoid receptors or LLC-PK(1) cells which express a rat glucocorticoid receptor gene (LLC-PK(1)-GR101). Acidification significantly increased luciferase activity in LLC-PK(1) cells and LLC-PK(1)-GR101 cells transfected with reporter plasmids containing 7.0 kb of E2 subunit or 0.8 kb of E1alpha subunit promoter region, respectively. Glucocorticoids in the form of dexamethasone induced transcription of these minigenes but only in LLC-PK(1)-GR101 cells. Using promoter deletion analysis, independent transactivation response elements to acidification or glucocorticoids were localized in the E2 promoter. In summary, catabolic responses to low extracellular pH and glucocorticoids include enhanced expression of genes encoding BCKAD subunits.

All peritoneal dialysis (PD) solutions are designed to remove toxins and water, normalize the blood electrolyte profile, and provide alkali to help maintain acid-base balance. Different formulations, however, may have different effects upon nutrition status. Solutions with 40, as opposed to 35, mEq/l of sodium lactate have been found to promote weight and muscle mass gain and reduce hospitalization in malnourished PD patients. Glucose is varied to produce solutions with different ultrafiltration potential. The glucose absorbed from the PD solution has a protein-sparing effect. The high glucose concentrations necessary for sustained ultrafiltration over a long dialysis dwell, however, often produce appetite suppression and metabolic abnormalities. Solutions formulated with glucose polymers, instead of hypertonic glucose, may provide sustained ultrafiltration over long dwells with lower carbohydrate absorption and perhaps fewer metabolic effects. Amino acids can also be substituted for glucose at relatively low concentrations. A number of studies have shown that amino acids absorbed from the dialysis solution can provide nutritional benefit to malnourished PD patients.