Mineral and electrolyte metabolism最新文献

It is possible to potentiate the response to epoietin by co-administering other agents. In some instances, this response is seen when there is a deficiency of a certain substance. In other cases, administration of an adjuvant such as intravenous iron, vitamin D, L-carnitine, or androgens can enhance the response to epoietin when given as a surfeit. With most of these agents, with perhaps the exception of intravenous iron, further research is required to determine the exact role they may play in clinical practice. As long as the cost of epoietin therapy remains fairly high, the challenge will continue as to the best way of optimizing its effect, and we can look forward to new developments in this expanding area of research.

In uremia, accelerated muscle protein degradation results from activation of the ATP-ubiquitin proteasome proteolytic pathway. Like uremia, other conditions (e.g., acidosis and diabetes) activate this pathway in rat muscles and are associated with excess glucocorticoids (GC) and impaired insulin action. To define the stimuli responsible for muscle wasting in IDDM, the roles of glucocorticoids, insulinopenia and acidosis in streptozotocin (STZ) - induced diabetes were studied. Proteolysis in isolated epitrochlearis muscles from acutely (3d) diabetic rats was 52% higher than pair-fed, sham-injected rats; this increase was eliminated by an inhibitor of the proteasome or by blocking ATP synthesis. In muscles of STZ-diabetic rats, the levels of ubiquitin-conjugated proteins and mRNAs encoding ubiquitin, the ubiquitin-carrier protein, E2(14k) and the C3, C5 and C9 proteasome subunits were increased. Transcription of ubiquitin and C3 proteasome subunit genes in muscle was also increased by IDDM. Oral NaHCO(3) eliminated acidemia but did not prevent accelerated muscle proteolysis. Corticosterone excretion was higher in IDDM rats and adrenalectomy (ADX) prevented these catabolic responses; physiologic doses of glucorcoticoids restored the excessive protein catabolism in ADX-STZ rats. Giving IDDM rats replacement insulin also normalized protein degradation in muscles. In conclusion, reduced insulin together with physiologic levels of glucocorticoids activate the ubiquitin-proteasome pathway by a mechanism that includes enhancing ubiquitin conjugation and proteolysis by the proteasome. The balance between these stimuli could regulate muscle proteolysis in uremia.

Vitamin D therapy is widely used for the treatment of secondary hyperparathyroidism associated with chronic renal failure. However, administration of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] or its precursor 1alpha(OH)D(3), especially in combination with calcium-based phosphate binders, often produces hypercalcemia. Several vitamin D analogs have been developed that retain the direct suppressive action of 1,25(OH)(2)D(3) on the parathyroid glands but have less calcemic activity. These analogs offer a safer and more effective means of controlling secondary hyperparathyroidism. 22-Oxa-1,25(OH)(2)D(3) (22-oxacalcitriol or OCT), 19-nor-1, 25(OH)(2)D(2) (19-norD(2)) and 1alpha(OH)D(2) have been tested in animal models of uremia and in clinical trials. Intravenous 19-norD(2) and oral 1alpha(OH)D(2) have been approved for use in the United States; OCT is currently under review. The mechanisms by which these analogs exert their selective actions on the parathyroid glands are under investigation. The low calcemic activity of OCT has been attributed to its rapid clearance which prevents sustained effects on intestinal calcium absorption and bone resorption, but still allows a prolonged suppression of PTH gene expression. The selectivity of 19-norD(2) and 1alpha(OH)D(2) is achieved by a distinct mechanism(s). Knowledge of how these compounds exert their selective actions on the parathyroid glands may allow the design of more effective analogs in the future.

Renal failure patients require vitamin replacement therapy that addresses the specialized needs of renal failure. Four factors including restricted diet, uremic toxins, drug-nutrient interactions, and in ESRD, the dialysis process, affect the normal absorption, retention and activity of necessary micronutrients which support all aspects of carbohydrate, protein, lipid and nucleic acid metabolism. Studies have shown that the typical renal failure diet is low in B vitamins, that uremic factors affect folate and pyridoxine activities and that many B vitamins are lost on dialysis at a rate greater than are lost with normal urinary excretion. In addition, retention of vitamin A or inappropriately high supplementation of vitamin C may cause toxicities which exacerbate existing pathologies. Further, emerging research suggests some vitamins such as folic acid and pyridoxine, if provided in higher than normal amounts, may have an impact on reducing the risk of some aspects of renal cardiovascular disease. It is therefore important to supplement some vitamins, and use restraint in the supplementation of others. It is clear that renal failure patients, including predialysis, ESRD and transplant patients need specialized supplementation that meets the requirements of disease and its management.

Metabolic changes in peritoneal dialysis (PD) patients are an important aspect concerning long-term outcome. Liver plays the main role in regulating metabolism. The effects of peritoneal dialysis fluids (PDF) on liver cell function are scarcely investigated. Therefore, we investigated the effects of PDF, different in some components, on liver cell metabolism in vitro. Metabolic activity (MTT), cell integrity (LDH release), proliferation (BrdU incorporation) and synthesis of albumin and transferrin are measured by incubating HepG2 cells for 3 h and 24 h with six different PDFs: (a) lactate-buffered, pH5.5: PDF I (1.5% gluc.); PDF II (4.5% gluc. ); (b) bicarbonate-buffered, pH7.4: PDF III (1.5% gluc.), PDF IV (4. 5% gluc.); (c) amino acid-based solutions, pH 7.4: PDF V (low AA level) and PDF VI (high AA level). Metabolic activity of bicarbonate-treated cells is greatly enhanced in comparison to lactate-buffered PDFs. These findings are confirmed by proliferation data. Synthesis of albumin and transferrin is significantly enhanced by amino acid-based solutions. Our data demonstrate, that lactate-buffered PDF impair liver cells much stronger than bicarbonate-buffered PDF. pH is the parameter which contributes to cytotoxicity and impaired metabolism to a major extent. In contrast to glucose-containing solutions, amino acid-based PDF stimulate protein synthesis in liver cells.

Nitric oxide (NO), a gaseous free radical derived from L-arginine, is a potent modulator of vascular tone and platelet functions. A number of recent studies, both in the experimental model of renal mass reduction (RMR) in rats and in uremic patients, have raised the hypothesis that abnormalities of NO synthetic pathway could have a key role in mediating the complex hemodynamic and hemostatic disorders associated to the progression of renal disease. Thus, kidneys from rats with RMR produce less NO than normal rats and NO generation negatively correlates with markers of renal damage. The abnormality is due to a strong defect of inducible NO synthase (iNOS) content in the kidney. Recent in vitro and in vivo data have raised the possibility that excessive renal synthesis of the potent vasoconstrictor and promitogenic peptide endothelin-1 (ET-1) is a major determinant for progressive iNOS loss in the kidney of RMR rats. In contrast, uremia is associated with excessive systemic NO release, both in experimental model and in human beings. In the systemic circulation of uremic rats, as well as uremic patients, NO is formed in excessive amounts. Possible cause of the increased NO levels is higher release from systemic vessels due to the augmented expression of both iNOS and endothelial NOS. A putative cause for excessive NO production in uremia can be guanidinosuccinate, an uremic toxin that accumulates in the circulation of uremic patients and upregulates NO synthesis from cultured endothelial cells. Upregulation of systemic NO synthesis might be a defense mechanism against hypertension of uremia. On the other hand, more NO available to circulating cells may sustain the bleeding tendency, a well-known complication of uremia.

Decreased muscle mass in patients with chronic renal failure (CRF) can be caused by mechanisms that activate the ubiquitin-proteasome proteolytic system. This system accelerates the degradation of muscle protein. Concurrent with muscle protein breakdown, there is an increase in transcription of genes encoding components of this pathway, including ubiquitin and subunits of the proteasome. Potential activating signals include metabolic acidosis which stimulates proteolysis in CRF patients and in muscle of rats with CRF by a mechanism involving glucocorticoids. In CRF patients, there is insulin resistance and high circulating levels of tumor necrosis factor and other cytokines. As the ubiquitin-proteasome proteolytic system is activated in acute diabetes and in catabolic conditions associated with high levels of circulating cytokines, these factors could also activate this pathway. Consequently, we examined whether the transcription factor activated by certain cytokines, NF-kappaB, is involved in the transcriptional regulation of subunits of the 26S proteasome complex. The results suggest that cytokines may be involved in the regulation of muscle protein degradation in uremia.

Circumstantial evidence from clinical and pathologic correlations in patients with glomerular diseases and proteinuria suggest that glomerular protein ultrafiltration contributes to tubulointerstitial injury. A series of studies was performed to examine the hypothesis that in rats with adriamycin-induced nephropathy or with diabetic nephropathy (but not in normal rats) high molecular wt. growth factors are ultrafiltered into tubular fluid and act on tubular cells through apical membrane receptors. Analysis of proximal tubular fluid that was collected by nephron micropuncture indicates ultrafiltration of IGF-I, TGF-beta and HGF. Respective receptors are also expressed in apical membranes in some parts of the nephron as examined by immunohistochemistry. In vitro cell culture experiments using proximal tubular fluid obtained from rats with experimental glomerular diseases indicate that ultrafiltered IGF-I may contribute to increased distal tubular Na-absorption. Indirect evidence also suggests that this growth factor may increase the secretion of collagen types I and IV in proximal tubular cells. TGF-beta and HGF cause increased expression and basolateral secretion of MCP-1 in proximal tubular and collecting duct cells. There may be other biologic effects on tubules that are caused by apical exposure to ultrafiltered growth factors. These studies suggest that the glomerular ultrafiltration of bioactive proteins causes or contributes to tubulo-interstitial pathology in glomerular proteinuria.

Malnutrition is a known risk factor for survival in renal failure patients. Of concern, a significant degree of malnutrition may develop in the predialysis period due to dietary restrictions and uremia. To further define this issue, we evaluated 25 predialysis patients using serum chemistries, body mass index (BMI), fat free mass (FFM), body cell mass (BCM), and protein appearance rate (PAR) as surrogates of nutritional status and compared their results to those obtained in established hemodialysis patients and recipients of living donor renal allografts during a nine-month observation period. Pre- dialysis patients had significantly (p<0.0001) higher body weight (28%), body mass index (26%), body cell mass (17%) and fat free mass (15%) than hemodialysis and transplant patients. Intracellular water content was similar in all groups. As many patients do not start dialysis until clearance values fall below 10 ml/min, it is possible that greater tissue mass losses occur in the weeks preceding initiation of dialytic therapy. Why renal transplant recipients fail to increase tissue mass may relate to the catabolic effects of immunosuppression. We conclude that the early stages of pre-end stage renal disease are associated with relatively good preservation of body cell mass.