Atherosclerosis significantly contributes to the high incidence of cardiovascular complications and death of uremic patients. Whereas some of the mechanisms that are being discussed in the atherogenesis of chronic renal failure are well established, many others remain hypothetical at present. One of the main reasons is that no long-term, well-controlled studies are available in this area which would have systematically tested the importance of factors such as high blood pressure, via the use of antihypertensive drugs, or disturbances of lipoprotein metabolism, via the use of lipid-lowering medications. Current clinical practice as to the use of the latter has been extensively reviewed in a recent meta-analysis by Massy et al. [69]. The majority of studies have been limited to relating hemodynamic or metabolic parameters to parameters of ischemia. Controlled long-term studies are required to reach valid conclusions on the implications of the numerous factors which theoretically may play a role in the atherosclerotic complications of chronic renal failure patients.
Anorexia, nausea and vomiting in patients with severe renal failure may cause or contribute to development of protein-energy malnutrition, which is associated with increased morbidity and mortality. However, the specific mechanisms that cause appetite suppression in uremia are poorly understood. This review summarizes the general mechanisms by which appetite is regulated. Various factors are discussed that may potentially be involved in appetite suppression in chronic renal failure.
Dialysis patients constitute a high-risk group for cardiovascular disease, which accounts for 40% of deaths in these patients. After stratification for age, race and gender, cardiovascular mortality is several orders of magnitude (10–20 times) higher in dialysis patients than in the general population. A clustering of risk factors renders dialysis patients especially susceptible to cardiovascular disease. Their morbidity and mortality can be favorably altered by interventional measures which systematically address and modify each individual risk factor. It is necessary to institute intervention during the course of progressive renal failure, well before the onset of end-stage renal disease and the initiation of dialysis.
In patients with severe heart failure life expectancy is short, the quality of life is affected, and the service costs are very high. Drug therapies remain restricted despite continuous clinical research. Therefore new therapeutic approaches have been attempted to improve the signs and symptoms of the disorder. In our study we followed patients suffering from class-IV cardiac failure concomitant with chronic renal failure. The patients were initially treated by means of hemofiltration, and subsequently they underwent a personalized dialysis program. The survival rate after 2 years was 62.5%. In 7 of the 8 patients the results revealed a drop to a class-III condition. The hospitalization period was limited to a few days. Early dialytic therapy represents a reality for such patients.
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.
Neuropeptide Y (NPY) is a polypeptide containing 36 amino acids. Circulating NPY originates predominantly from the sympatho-adrenomedullary nervous system. It has a vasoconstrictive and mitogenic effect on blood vessels and seems to be involved in blood pressure regulation and angiogenesis. NPY is a potent orexigenic agent and is presumed to play a leading role in the regulation of eating behavior. Stimulation of the NPY-ergic arcuate - paraventricular nucleus (ARC-PVN) pathway by exercise, fasting, energy loss (glucosuria) is followed by increased appetite and food intake and increased parasympathetic activity, but suppression of sympathetic activity and energy expenditure. The end result of this process is an increase of energy stores. Activity of the NPY-ergic ARC-PVN pathway is suppressed by leptin - a polypeptide produced by adipocytes. Although functioning of an NPY-leptin feedback was found in rodents, it seems likely that also in man the NPY-leptin axis is involved in the regulation of food intake and energy expenditure.
The activated form of vitamin D-3, 1 alpha,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-3-1 alpha-hydroxylase as well as the vitamin D receptor in several tissues introduced the idea of a paracrine role for 1 alpha,25(OH)(2)D-3. By introducing chemical modifications into the flexible parent molecule 1 alpha,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. Copyright (C) 2000 S. Karger AG, Basel.
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 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.
Leptin, the recently identified ob gene product, regulates food intake and energy expenditure in animal models. Leptin reaches the brain by a saturable transport mechanism and, via direct effects on the hypothalamus, decreases appetite and increases metabolism. Several recent studies have demonstrated markedly elevated serum leptin levels in patients with chronic renal failure (CRF) and it has been speculated that hyperleptinemia may contribute to uremic anorexia and malnutrition. Several factors may influence serum leptin levels in uremia and apart from decreased glomerular filtration rate also body fat mass and plasma insulin levels are important factors that determine serum leptin levels. The possible influence of chronic inflammation on serum leptin levels in CRF need further studies. Patients treated by peritoneal dialysis seem to have higher leptin levels compared to patients treated by hemodialysis. This could be the effect of a marked increase in body fat mass as a consequence of the continuous carbohydrate load. Leptin receptors have by now been identified in several peripheal organs which suggests that leptin besides having central effects also has a pleiotropic action. Indeed, recent findings indicate that besides regulating appetite leptin may play a role in sympathico-activation, insulin metabolism, renal sodium handing and hematopoiesis.
AIMS:To study the distribution of vitamin D receptor (VDR) gene alleles in hypercalciuric and nonhypercalciuric nephrolithiasis patients, hypothesizing that distinct biochemical parameters would be associated with different VDR genotypes.METHODS:12 hypercalciuric, 15 normocalciuric nephrolithiasis patients, and 150 healthy subjects were recruited. The individual genetic pattern for VDR was evaluated by DNA extraction followed by polymerase chain reaction amplification of the VDR gene and digestion with the restriction enzyme BsmI.RESULTS:In the hypercalciuric group, Bb patients represented 50% (6/12); bb patients 33% (4/12), and BB cases were 16% (2/12). The VDR frequency distribution was not statistically different in hypercalciuric patients and controls (Bb 72%; bb 16%; BB 12%). In the nonhypercalciuric group, the prevalence of the bb genotype (7/15; 47%) was thrice the percentage of control subjects, while the percentage of BB patients was similar to that of the control group (2/15; 13%). Patients with the bb haplotype exhibited a higher daily urinary calcium excretion. Among hypercalciuric patients, after a calcium-restricted diet, bb patients showed a 39% reduction in daily urinary calcium excretion in comparison with a nonsignificant 13% reduction observed in BB subjects (p = 0.004).CONCLUSIONS:The effects of VDR gene polymorphism on calcium metabolism contribute to the understanding of the pathogenesis of urinary calculi.
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.
Gallium nitrate, an approved antitumor drug, has found clinical application in the treatment of cancer-related hypercalcemia and of Paget's disease; the exact mechanism of its action, however, remains unknown. The present study utilized rats in a 7-day exposure to gallium at doses similar to those used clinically. Quantitative histomorphometry and ultrastructural examination of osteoclast fine structure were carried out on specimens from animals with documented hypocalcemia. Gallium exposure produced striking changes in the osteoclast. The number of nuclei/osteoclast increased, and the ruffled borders of the osteoclasts were markedly decreased along the length of the Howship's lacunar cavity. The absence of a decrease in osteoclast number and the types of changes seen in ultrastructure suggest that the mechanism of action of gallium seen here may differ from that of calcitonin, a nontoxic, reversible anti-resorbing agent. Results underscore the difficulty in assessing the toxicity of agents such as gallium on the osteoclast, a mature differentiated cell which does not divide and which does not produce a characteristic extracellular matrix component.
Letters| July 14 1999 Cystic Fibrosis and Metabolic Alkalosis in Children – Revisited Subject Area: Nephrology Robert Kleta; Robert Kleta Universitäts-Kinderklinik, Münster, Deutschland Search for other works by this author on: This Site PubMed Google Scholar Thomas Brune; Thomas Brune Universitäts-Kinderklinik, Münster, Deutschland Search for other works by this author on: This Site PubMed Google Scholar Erik Harms Erik Harms Universitäts-Kinderklinik, Münster, Deutschland Search for other works by this author on: This Site PubMed Google Scholar Mineral and Electrolyte Metabolism (1999) 25 (3): 210. https://doi.org/10.1159/000057447 Article history Published Online: July 14 1999 Content Tools Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Robert Kleta, Thomas Brune, Erik Harms; Cystic Fibrosis and Metabolic Alkalosis in Children – Revisited. Mineral and Electrolyte Metabolism 1 June 1999; 25 (3): 210. https://doi.org/10.1159/000057447 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsMineral and Electrolyte Metabolism Search Advanced Search Article PDF first page preview Close Modal Keywords: Sorry, there are no key words. This content is only available via PDF. 1999Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. You do not currently have access to this content.
Thyroid hormones affect the functions of several organs including the heart and kidney. Using isolated left papillary muscles we have investigated the action of thyroid hormones on the mechanical and electrical properties of the heart. We found that pure hypothyroidism causes a depression in contractile and electrical parameters, but we noticed that superimposed hypoparathyroidism accounts for the marked prolongation in contractile kinetics and action potential duration. At kidney level we have shown that thyroid hormones affect proximal tubular sodium transport and this effect is only partially mediated by the action of thyroid hormones on Na-K-ATPase activity. Using the micropuncture technique, we hypothesized that the early effect of thyroid hormone action is on the potassium permeabilty of proximal tubular cell membrane. This latter effect would explain the increase in isotonic fluid reabsorption through an increase in the driving force for sodium. Finally, hypothyroid patients have a decrease in glomerular filtration rate and renal plasma flow that are completely reversed by thyroxine administration. On the other hand, hyperthyroid subjects exhibit a significant increase in both parameters.
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, E214k 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 NaHCO3 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.
Cardiac hypertrophy, a well-known independent risk factor for cardiovascular death, is a very frequent complication in ESRD patients. Its frequency tends to be even higher in dialyzed patients due to the fact that the current dialytic treatments are unable to keep under a satisfactory control the various responsible factors and particularly the blood pressure, which is largely the most important. Daily hemodialysis, a more frequent schedule consisting of 6-7 sessions/week lasting 2 or more hours, has definitely proved its superiority in controlling blood pressure and in improving anemia, and thus has the requisites for positively influencing cardiac hypertrophy. In fact, a series of studies, both retrospective and prospective, performed during the last years by our group, have confirmed that this new, more frequent and thus more physiological schedule, is able not only to stop the progression of the cardiac hypertrophy in uremic patients but also to revert toward the normality, in a relatively short time. This appears to be essentially a consequence of the excellent blood pressure control, which in turn derives from the easier control of the true dry weight, achievable with this type of dialytic treatment.
