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PubMed1989

1,25(OH)2 vitamin D3 inhibits parathyroid cell proliferation in experimental uremia.

Parathyroid cell proliferation and parathyroid hyperplasia are features of renal secondary hyperparathyroidism. Since parathyroids have recently been recognized as an important target for 1,25(OH)2D3, the effects of administration of variable doses of 1,25(OH)2D3 on ex vivo radiothymidine incorporation in the parathyroid glands, on parathyroid cell mitoses, on parathyroid weight, morphometric indices and on parathyroid protein/DNA ratio were examined in rats with uremia (subtotal nephrectomy; NX) or with calcium deficiency. 3H-thymidine incorporation (3 hr; 37 degrees C; PBS with 10 mmol glucose) was elevated in NX animals, that is, 204 +/- 51 dpm/micrograms DNA versus 96 +/- 28 in controls. In vivo pretreatment with 1,25(OH)2D3, either by intermittent i.p. injection or by osmotic minipump, dose-dependently decreased 3H-thymidine incorporation and parathyroid cell mitoses without affecting morphometric indices of parathyroid cells. Prophylactic administration (i.p.) of 1,25(OH)2D3, starting on the day of nephrectomy, prevented parathyroid hyperplasia (NX + 1,25(OH)2D3 0.84 micrograms tissue/g body wt vs. 1.25 micrograms in untreated NX and 0.54 in ad libitum fed controls), but 10 days of treatment beginning on the 21st day of uremia did not reverse existing hyperplasia (NX + 1,25(OH)2D3 1.5 micrograms/g body wt vs. 1.37 micrograms in untreated NX and 0.56 micrograms in ad libitum fed controls). The inhibitory effect was specific for 1,25(OH)2D3 and not imitated by Dexamethason. However, the effect was not specific for parathyroid hyperplasia of uremia, since similar inhibition of 3H-thymidine incorporation by 1,25(OH)2D3 was also observed in rats on low calcium diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Efficacy of 19-Nor-1,25-(OH)2D2 in the prevention and treatment of hyperparathyroid bone disease in experimental uremia.

BACKGROUND: The control of parathyroid hyperplasia and high circulating parathyroid hormone (PTH) levels is crucial in preventing secondary hyperparathyroidism (SH) in renal failure. Parathyroid gland enlargement and elevated levels of PTH are major contributors to increase bone resorption, a feature of renal osteodystrophy. METHODS: These studies assessed the efficacy of the 1,25(OH)2D3 analog, 19-Nor-1,25(OH)2D2 (19-Nor), in the prevention (protocol I) and treatment (protocol II) of SH and renal osteodystrophy in uremic rats. In protocol I, normal and uremic rats were fed a high phosphorus diet for 2 months; uremic rats were administered intraperitoneal injections of either vehicle or 19-Nor (200 ng three times a week). In protocol II, normal and uremic rats were fed a high phosphorus diet for 4 months; 2 months after the onset of uremia, rats were administered either intraperitoneal vehicle or 19-Nor (200 ng three times a week). Serum PTH and bone histology were used to assess the degree of SH. RESULTS: 19-Nor was effective in preventing (protocol I) and suppressing (protocol II) the significant SH induced by uremia and further enhanced by a high phosphorus diet. In protocol I, bone histology in uremic controls showed a threefold increase in the cancellous bone mass compared to normal rats. This expansion in unmineralized bone was accompanied by 5-, 1.5-, and 7-fold increases in eroded surface, mineralization lag time (MLT), and bone formation rate (BFR/BS), respectively. Moreover, cortical bone porosity in untreated uremic rats increased 267-fold compared to normal animals. 19-Nor ameliorated these changes in cancellous and cortical bone. In protocol II, the reported indices worsened even further. In contrast, 2 months of 19-Nor treatment improved bone histology by reducing cortical bone porosity, woven bone formation, MLT, and BFR/BS. CONCLUSION: In an experimental model of chronic renal failure (CRF), 19-Nor prevents SH and ameliorates the histomorphometric changes induced by uremia and high phosphorus diet. In addition, 19-Nor suppresses serum PTH and improves bone histology in uremic rats with established severe SH. Further studies in patients with CRF are necessary to define the clinical applicability of 19-Nor on bone histology in humans.

Animals↗
PubMed2003

Endothelial permeability in uremia.

The risk of cardiovascular disease is significantly higher in patients with long-term uremia than in otherwise healthy adults. In addition, the risk is greater than what would be predicted from classic vascular risk factors. This is true even before patients proceed to dialysis. Although the reasons for this accelerated vascular disease are unknown, transendothelial transport of lipids and other macromolecules in both large vessels and the microcirculation has been implicated in the generation of cardiovascular disease. Furthermore, endothelial cell dysfunction is widely accepted as a cardinal feature of both modest and dialysis-dependent uremia, and is regarded as a critical step in the initiation of this aggressive pathology. This overview considers the severity of the clinical problem, the nature of the vascular endothelium, microvascular permeability (and the measurement thereof) as a functional property of the endothelium, and the in vitro and in vivo evidence for endothelial dysfunction in uremia.

Capillary Permeability↗
PubMed2001

Increased Fas antigen in uremia accelerates adhesion of mononuclear cells to endothelial and sinovial cells via stimulated hyaluronan production.

We examined influences of increased soluble Fas (sFas) and hyaluronan in uremia on apoptosis and peripheral blood mononuclear cell (MNC) adhesiveness. Synovocytes, human umbilical cord endothelial cells (HUVEC), human coronary artery smooth muscle cells (CASMC), and MNC were prepared in this study. In cultures of synovocytes, HUVEC, and CASMC, sFas or high molecular hyaluronan was added to media at medium change. After 1 day, Fas-positive cells were calculated by fluorescence-activated cell sorting. Uremic level of sFas enhanced Fas-positive cells in all cell lines (P < 0.01) not in CASMC. On the contrary, hyaluronan inhibited Fas expression in all cell lines (P < 0.05). In culture with uremic serum, Fas were induced in all cell lines. At this time, the hyaluronan levels of the supernatant were measured and hyaluronan production was estimated. In contrast to the results using sFas supplement, hyaluronan production was increased in culture with sFas and uremic sera. MNC adhesiveness was increased in synovocytes and HUVEC lines by adding hyaluronan or sFas. Higher adherent cell numbers were recognized when both sFas and hyaluronan were added to the media. A most remarkable increase in cell numbers was observed in uremic MNC suspension as compared with that of MNC from healthy subjects. In conclusion, these results indicate that increased sFas in uremia stimulates apoptosis and hyaluronan production. Both sFas and hyaluronan are responsible for accelerated MNC adhesiveness in uremia.

Adhesiveness↗
PubMed2004

Vascular biology in uremia: insights into novel mechanisms of vascular injury.

Cardiovascular disease is the leading cause of death in patients with end-stage renal disease. Although the prevalence of traditional atherosclerotic risk factors is increased in patients with chronic kidney disease, these traditional risk factors alone do not seem to account for the increased cardiovascular mortality. It has been proposed that additional risk factors may play a role in vascular injury. Among nontraditional risk factors, chronic inflammation, oxidative stress, and vascular calcification have been implicated in the accelerated athersclerosis of chronic kidney disease. Uremia is a proinflammatory state. Elevated levels of the proinflammatory cytokine interleukin-6 and suppressed levels of the anti-inflammatory cytokine interleukin-10 are present in chronic kidney disease and have been implicated in accelerated atherosclerosis. Uremia also results in increased oxidative stress. Asymmetric dimethyl arginine and myeloperoxidase may be critical mediators of the endothelial damage that results from oxidative stress. Finally, the uremic milieu seems to promote vascular calcification. The abundance of proinflammatory cytokines, the possible deficiency in calcification inhibitory proteins and the high phosphorus that are often present in uremia contribute to vascular calcification. Smooth muscle cells in calcifying lesions undergo phenotypic changes and molecular reprogramming that are reminiscent of endochondral bone formation during embryogenesis.

Calcinosis↗
PubMed2007

Vascular sources of oxidative stress: implications for uremia-related cardiovascular disease.

Chronic oxidative stress that characterizes uremia has potentially devastating effects on the vasculature and has been advocated in the pathogenesis of accelerated atherosclerosis in this disease. Recent advances have been made in our understanding of the molecular mechanisms that regulate expression and activity of key enzymes of vascular oxidative stress (eg, nicotinamide adenine dinucleotide phosphate [NAD{P}H] oxidase) and that dissect their interactions with signalling pathways of inflammation. The finding that NAD(P)H oxidase is upregulated in experimental uremia has important consequences from a physiologic and a therapeutic standpoint. In addition, identification of novel proteins involved in systemic oxidative stress has shed some new light on the pathogenesis of vascular disease. p66(shc) is a cytoplasmic protein that is expressed in a wide range of cell types. Initially believed to be involved in signalling pathways that regulate cell growth and oxidative stress, it has now been shown to play a pivotal role in promoting endothelial dysfunction and atherosclerosis. Although a specific role in uremia-related vascular disease has not yet been shown, available data in humans suggest involvement of p66(shc) in clinical conditions associated with increased oxidative stress.

Adaptor Proteins, Signal Transducing↗
PubMed1992

Relief of pruritus and decreases in plasma histamine concentrations during erythropoietin therapy in patients with uremia.

BACKGROUND: The pathophysiologic aspects of pruritus in patients with chronic renal insufficiency are poorly understood, and there is no universally effective treatment. The improvement of pruritus in several patients receiving erythropoietin therapy raised the possibility that erythropoietin affects uremic pruritus directly. METHODS: We undertook a 10-week placebo-controlled, double-blind, crossover study in a group of patients receiving hemodialysis who had severe pruritus, to investigate the effects of recombinant human erythropoietin on their pruritus and plasma histamine levels. Twenty patients with uremia, of whom 10 had severe pruritus and 10 did not, received erythropoietin (36 units per kilogram of body weight three times weekly) and placebo in random order, each for five weeks. The severity of pruritus was scored weekly, and plasma histamine levels were measured at the beginning and end of each five-week period. RESULTS: Eight of the 10 patients with pruritus had marked reductions in their pruritus scores during erythropoietin therapy. The mean (+/- SE) pruritus score decreased from 25 +/- 3 to 6 +/- 1 in these patients. The pruritus returned within one week after the discontinuation of therapy. The improvement was not related to the change in hemoglobin level. These eight patients were successfully treated again with low doses of erythropoietin (18 units per kilogram three times weekly), and the effect has persisted for six months. The patients with pruritus had elevated plasma histamine concentrations (20.7 +/- 2.7 nmol per liter), as compared with the patients without pruritus (4.2 +/- 0.6 nmol per liter; P less than 0.001) and normal subjects (2.1 +/- 0.2 nmol per liter; P less than 0.001). Therapy with erythropoietin induced a decrease in plasma histamine concentrations in both groups of patients with uremia, and recurrences of pruritus after the discontinuation of erythropoietin were accompanied by increases in plasma histamine concentrations. CONCLUSIONS: Erythropoietin therapy lowers plasma histamine concentrations in patients with uremia and can result in marked improvement of pruritus.

Double-Blind Method↗
PubMed2002

Thrombopoietin inside the pulmonary vessels in patients with and without pulmonary hypertension.

There is substantial evidence that platelet production and release take place in the lungs. Thrombopoietin (Tpo) stimulation can cause platelet release in the pulmonary vasculature. On the other hand, myelofibrosis can occur in Tpo-overexpressing transgenic mice models, and there is unexplained pulmonary hypertension in chronic myeloproliferative disorders including primary myelofibrosis. In this study, we aimed to assess local Tpo concentrations inside the pulmonary artery and associated vessels in humans. We measured Tpo concentrations in plasma samples taken concurrently from the right ventricle, the pulmonary artery, and the left ventricle during cardiac catheterization in patients with and without pulmonary hypertension. The study group comprised 10 patients with normal pulmonary arterial pressure (Group A, male/female 4/6, mean age 48 +/- 19) and 14 patients with pulmonary hypertension (Group B, male/female 9/5, mean age 57 +/- 16). The Tpo levels inside the right ventricle, the pulmonary artery and the left ventricle were 33.3 +/- 15.6, 47.2 +/- 33.9, and 34.4 +/- 18.6 pg/ml, respectively, in Group A; and 85.0 +/- 39.8, 128.4 +/- 50.4, and 81.5 +/- 35.5 pg/ml, respectively, in Group B. Levels of the Tpo were significantly higher in all three localizations in Group B compared to Group A. Moreover, the Tpo concentration inside the pulmonary artery is significantly higher than the Tpo concentrations in the right and left ventricles in Group B patients. There were positive correlations between the Tpo levels and pulmonary artery systolic pressure over the whole patient group. In conclusion, there could be an association between pulmonary hypertension and Tpo level. Moreover, lung vasculature holding the major regulatory thrombopoietic hormone, Tpo, may be an important place for megakaryocytopoiesis.

Adult↗
PubMed2003

Acute uremia produced in rats by nephrotoxic chemicals is alleviated by protein deficient diet.

Rats injected with mercuric chloride develop an acute renal tubular necrosis with uremia, which is frequently lethal. Pretreatment for 3 or 7 days with a protein-free diet reduces the mortality, the clinical signs (tremor), and the severity of renal tubular necrosis, and ameliorates the uremic chemical findings in the serum. Similar results followed injection of a nephrotoxic amino acid, D-serine, after pretreatment with a protein-free diet. Indirect evidence suggests that induction of metallothionein may be involved, at least in the experiments with mercury. Acute uremia produced by nephrotoxic chemicals may be useful for further studies of the role of nutrition in uremia, while avoiding the surgical procedures and prolonged observations required for the "remnant kidney" models.

Acute Disease↗
PubMed1980

Amino acid metabolism in uremia: insights gained from normal and diabetic man.

The physiology of the interorgan exchange of amino acids in healthy subjects and in insulin-dependent diabetics is reviewed and compared with changes observed in patients with chronic renal failure. In contrast to the diabetic, who has elevated fasting branched-chain amino acid levels and diminished muscle uptake of branched-chain amino acid following protein feeding, fasting levels of leucine, isoleucine, and valine are decreased in uremia. Furthermore, the decline in branched-chain amino acids following insulin in normal and intracellular levels of leucine and isoleucine have been reported to be normal. With respect to alanine metabolism, the diabetic state is characterized by diminished fasting alanine levels which are due to a 2-fold increase in splanchnic alanine extraction. Accordingly, gluconeogenesis can potentially account for over 30 to 40% of hepatic glucose production compared to 15 to 20% in normal man. In uremia, fasting alanine levels are normal and hepatic alanine uptake is not increased. Similarly, basal hepatic glucose production, as well as suppression of glucose production following insulin, are normal in uremic subjects. Thus, although uremia is characterized by abnormalities in the metabolism of many individual amino acids, it does not appear to share the same disturbances in alanine and branched-chain amino acid metabolism that are associated with insulin deficiency.

Amino Acids↗
PubMed1975

Prurigo nodularis and uremia.

Patients with uremia frequently have generalized pruritus that is usually related to a disturbance of calcium and phosphorus metabolism. This report describes three patients with uremia who had prurigo nodularis due to localized scratching and rubbing. The diagnosis of uremia in one case was made when the patient was hospitalized for evaluation of skin lesions.

Adult↗
PubMed1997

Digitoxinlike and digoxinlike immunoreactivitis in sera of patients with uremia and liver disease as measured by fluorescence polarization immunoassays: poor correlation between digitoxinlike and digoxinlike immunoreactivities.

Digoxinlike immunoreactive substances (DLIS) cross-react with antidigoxin antibodies and falsely elevante total digoxin levels. Cross-reactivity of DLIS with various immunoassays for digoxin has been extensively studied in the past. The digitoxin molecule differs from digoxin by having one extra hydroxyl group in the aglycone ring. Therefore, DLIS may also falsely elevate total digitoxin concentrations. However, in the past, limited studies have shown the presence of digitoxinlike immunoreactive substances (DTLIS) in cord blood and sera of neonates. We compared DLIS and DTLIS concentrations in sera of patients with uremia, liver disease, and hypoalbuminemia. We found measurable DLIS concentrations in 11 of 45 patients by the fluorescence polarization immunoassay (FPIA) for digoxin (range, 0.20-0.89 ng/ml digoxin equivalent). These patients did not receive any digoxin or digitoxin. Using the FPIA, we also found elevated DTLIS concentrations in 10 of these 45 patients (range, 2.88-21.24 ng/ml digitoxin equivalent). Given the narrow therapeutic range of digitoxin (15-30 ng/ml), this cross-reactivity is significant. Elevated concentrations of DTLIS in sera falsely elevated the measured concentrations of digitoxin (positive interference) when known amounts of digitoxin were added to such sera. Interestingly, we found a poor correlation between DLIS and DTLIS concentrations in sera of patients with liver disease and uremia (r = 0.58), with some patients having no measurable DLIS activity but measurable DTLIS activity and vice versa. Digoxin showed only 4-8% cross-reactivity against digitoxin antibody with a wide range of concentration. Some proposed DLIS compounds (nonesterified fatty acids, cholic acid, lysophospholipid, and DHEA-sulfate) did not show any cross-reactivity with the digitoxin assay at a concentrations much higher than the physiologic range. We conclude that DTLIS activity is present in patients with liver disease and uremia, and the correlation between DLIS activity and DTLIS activity is poor. Moreover, some proposed DLIS do not explain the DTLIS activity detected in serum.

Digitoxin↗
PubMed1982

Is uremia immunosuppressive in renal transplantation?

We have quantitated the impact of post-transplantation uremia on the antiallograft immune response by transplant aspiration cytology. Sixty-four consecutive renal transplants, treated with a similar immunosuppresive regimen, were aspiration biopsied at 2-day intervals during the first 15 days postoperatively. The patients were allocated into three groups on the basis of their serum creatinine level on the 3rd postoperative day: transplants with a delayed onset of function (highly uremic group, serum creatinine level greater than or equal to 600 mumol/liter; 24 cases), transplants with a partially delayed onset of function (partially uremic group, 200 to 600 mumol/liter; 21 cases), and transplants with an immediate onset of function (nonuremic group, less than or equal to 200 mumol/liter; 14 cases). These three groups were comparable in respect to the mean age, sex ratio, number of HLA-ABC mismatches (DR was not typed), number of pretransplant blood transfusions, and underlying diseases. Seventy percent of the transplants in the high uremic group, 60% in the moderately uremic group, and 60% in the nonuremic group underwent an early inflammatory episode during days 0 to 15 post-transplantation. The date of onset of inflammation was not significantly different in the three groups. However, the size and type of inflammation were significantly different: compared with the transplants in nonuremic patients, the total inflammatory response was slightly (P = 0.272) depressed in the transplants of moderately uremic patients and significantly (P = 0.007) depressed in the transplants of highly uremic patients. This depression was attributable to the depression of the blastogenic response: compared with nonuremic patients the blastogenic response was distinctly (P = 0.059) depressed in the moderately uremic group and significantly (P = 0.003) depressed in the highly uremic group. Instead, the frequency of in situ macrophages was the same in the three groups, or moderately elevated in the highly uremic group (P = 0.079). However, the graft survival was only 40% in the highly uremic group compared with 79% in the nonuremic controls and 81% in the moderately uremic patients (P = 0.016). We conclude that post-transplantation uremia partially impairs the antiallograft immune response, but this impairment is so small that other factors, whose nature cannot be explained on the basis of the present results, overrule the effects of uremia on graft survival.

Adult↗
PubMed1992

Differential effects of preexisting uremia and a synchronous kidney graft on pancreas allograft functional survival in rats.

Pancreas transplant results have been better in uremic recipients of a simultaneous kidney than in nonuremic recipients of a pancreas alone. We studied the relative effect of uremia versus a double transplant on functional survival by performing bladder-drained pancreas transplants alone (PTA), kidney transplants alone (KTA), and simultaneous pancreas/kidney (SPK) transplants from Buffalo donors to diabetic Lewis rat recipients that were or were not made uremic 2-3 weeks before by 1 4/5 native nephrectomy. Pancreas graft exocrine function was monitored by urinary amylase (UA). In the PTA and SPK recipients made diabetic by streptozotocin, endocrine function was monitored by measuring nonfasting plasma glucose (PG) levels. Kidney graft function was monitored by plasma creatinine (Cr). Rejection of the endocrine pancreas was defined as an increase of PG to greater than 200 mg/dl; of the exocrine pancreas, as a decline in UA to less than 6000 U/L or to less than 100 U/24 hr; and of the kidney, as an elevation of Cr to greater than 3 mg/dl. The mean functional survival times (MST) of both the endocrine (12.0 +/- 2.1 versus 10.1 +/- 1.1 days, P = 0.036) and exocrine (8.0 +/- 2.1 versus 6.3 +/- 1.3 days, P = 0.016) components of the pancreas grafts were significantly longer in SPK than in PTA recipients. The MST of kidney allografts, however, was not significantly longer in nonuremic SPK than nonuremic KTA recipients (6.7 +/- 1.4 versus 5.7 +/- 0.7 days, P = 0.13). In parallel experiments in recipients immunosuppressed with cyclosporine, the graft survival times were longer, but the relative differences between the PTA, SPK, and KTA groups persisted. Histologically, lymphocyte infiltration began in the two organs almost simultaneously, but the severity of the rejection was more vigorous in the kidney than in the pancreas in doubly grafted rats, and destruction of pancreas grafts progressed more slowly in SPK than in PTA recipients. Preexisting uremia delayed pancreas rejection in both SPK (exocrine 10.6 +/- 2.3, P = 0.032, and endocrine 14.8 +/- 3.4 days, P = 0.065, versus nonuremics) and PTA (exocrine 8.5 +/- 1.7, P = 0.007, and endocrine 12.6 +/- 2.5, P = 0.026, versus nonuremics) nonimmunosuppressed recipients. The MST of kidney grafts was not significantly longer in uremic (8.9 +/- 2.8 days) than in nonuremic (6.7 +/- 1.4 days) SPK recipients (P = 0.081). A synchronous kidney transplant and uremia independently down-modulate the rejection response to a pancreas graft, and a simultaneous pancreas graft has no detrimental effect on the survival of a kidney graft.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2003

Oxidative stress in uremia.

PURPOSE OF REVIEW: Oxidative stress has been described as 'a disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. In uremic patients, an increase in oxidative stress may occur because of the loss of residual renal function, and may be exacerbated by dialysis. This review will focus on the emerging biochemical evidence of an increase in oxidative stress in uremic patients, the relationship with renal replacement therapy, and the potential linkages to acute-phase inflammation, malnutrition, and adverse cardiovascular outcomes in uremic patients. RECENT FINDINGS: Many studies from multiple research laboratories around the world have recently utilized in-vivo biomarkers to describe increased oxidative stress in uremic patients. An emerging literature suggests that there are links between an increase in oxidative stress, endothelial dysfunction, an increase in acute-phase inflammation, and an accelerated risk of cardiovascular complications in dialysis patients. Additional uremia-associated metabolic abnormalities, including hyperhomocysteinemia, intravenous iron exposure, and biocompatibility changes related to dialysis, may contribute to an increase in oxidative stress. Finally, two well-conducted pilot clinical randomized trials have suggested that antioxidant therapy may have efficacy in reducing cardiovascular events in uremic patients. SUMMARY: The implications of the findings of a generalized increase in oxidative stress associated with uremia have led to the suggestion that antioxidative therapy may be efficacious in reducing cardiovascular complications. Pilot studies have suggested potential efficacy for this approach. However, further large-scale randomized clinical trials will be required to establish a compelling, evidence-based approach to the use of antioxidants in patients with uremia.

Humans↗
PubMedDate not supplied

Paraoxonase activity and paraoxonase 1 gene polymorphism in patients with uremia.

Patients on hemodialysis (HD) show an increased risk for developing atherothrombotic events. The oxidative modification of low density lipoproteins (LDL) play an important role in the pathogenesis of atherosclerosis. In patients with uremia (chronic renal failure and HD), the increased oxidative stress induces oxidative modification of LDL. High density lipoproteins (HDL) exhibit a double antiatherogenic role, removing both lipid peroxides from LDL and cholesterol from tissues or vascular wall. Paraoxonase 1 (PON1) is one of three enzymes shown to prevent the formation of oxidized LDL. PON1 activity is modulated by its genetic polymorphism and by non-genetic factors, such as diet, smoking, acute phase reactants, and hormones. PON1 activity has been found to be significantly decreased in uremia. The present study aimed to verify the possibility that this reduced activity could be caused by a different PON1 gene polymorphism between patients on HD and healthy subjects, but this was not the case. The main cause may be identified in the different distribution of HDL subspecies, rather than in the different PON1 allele distribution between healthy subjects and patients with uremia.

Adult↗
PubMed2004

Uremia and insulin resistance: N-carbamoyl-asparagine decreases insulin-sensitive glucose uptake in rat adipocytes.

BACKGROUND: In uremia, urea-derived cyanate reacts with amino groups irreversibly forming carbamoyl amino acids (C-AA) and carbamoyl proteins. Carbamoylated molecules can affect binding and trafficking and alter metabolic pathways. The C-AA role in insulin-sensitive glucose transport has not been explored and may contribute to insulin resistance in uremia. METHODS: Insulin-stimulated glucose uptake by cultured rat adipocytes was measured using both 3-minute and 3-second assays. Adipocytes were incubated for 24 hours in medium containing 0.5 micromol/mL of 15 different C-AA. 125I-insulin binding studies were done. C-asparagine in plasma from 10 uremic patients on continuous ambulatory peritoneal dialysis (CAPD) was measured using high-performance liquid chromatography (HPLC). RESULTS: Insulin-sensitive glucose uptake was reduced 34% by N-carbamoyl-l-asparagine, (N-C-Asn), in a dose-dependent manner with a half-maximally effective concentration of 0.15 micromol/mL. Fourteen other N-carbamoyl-amino acids as well as 0.5 micromol/mL of asparagine did not affect insulin sensitive glucose uptake. N-C-Asn, l-asparagine, and the other N-carbamoyl amino acids (0.5 micromol/mL) had no effect on basal glucose uptake. These data suggest that that N-C-Asn affects the insulin sensitive glucose transporter system. 125I-insulin binding studies demonstrated that N-C-Asn did not alter insulin binding. Glucose uptake measured using a 3-second assay showed that the glucose affinity of the transporter and glucose phosphorylation were not affected. In uremic patients managed by CAPD, the mean free N-C-Asn plasma level was 1.33 micromol/mL. CONCLUSION: These data suggest that N-C-Asn concentration may contribute to the insulin resistance seen in uremia.

Adipocytes↗
PubMed2004

In vitro evidence for immune activating effect of specific AGE structures retained in uremia.

BACKGROUND: Advanced glycation end-products (AGEs) have been identified to be accumulated in blood and tissues of patients with end-stage renal disease (ESRD). AGEs have been shown to modulate immune competent cell activities and in this way they may contribute to the progression of atherosclerosis. All studies in this context have been performed, however, with generated mix of glycation compounds, and not with structures similar to those encountered in uremia. In the present study, the immunologic effect of specific AGE compounds, known to be retained in uremia, has been evaluated. METHODS: Four albumin preparations, modified chemically at lysine or arginine residues, respectively, to contain N-epsilon-carboxymethyllysine (CML albumin), N-epsilon-carboxyethyllysine (CEL albumin), glyoxal-induced imidazolinones (Arg I albumin) or methylglyoxal-induced imidazolinones (Arg II albumin) were applied. Their effect on chemiluminescence production, CD14 expression, and the DNA synthesis of calcitriol-differentiated HL-60 (monocyte/macrophage phenotype) was studied. RESULTS: The phorbol 12-myristate 13-acetate (PMA)-stimulated chemiluminescence production of the calcitriol differentiated HL-60 cells was enhanced in the presence of CEL albumin (44.1 +/- 18.5 vs. 64.7 +/- 28.1 counts 10(3)/30 min) (P < 0.05), Arg I albumin (46.4 +/- 18.8 vs. 66.1 +/- 32.6 counts 10(3)/30 min) (P < 0.05) and CML albumin (41.9 +/- 25.5 vs. 60.9 +/- 5.5 counts 10(3)/30 min) (P= 0.0625) pointing to an increase in free radical production. The latter AGE compounds also significantly increased the calcitriol-induced CD14 expression on HL-60 cells (1675 +/- 796 vs. 2075 +/- 1044; 768 +/- 143 vs. 890 +/- 150; 647 +/- 63 vs. 716 +/- 69 mean fluorescence intensity) (P < 0.05, respectively) pointing to an increase in expression of the lipopolysaccharide (LPS) receptor. Finally, the DNA synthesis of the calcitriol-differentiated HL-60 cells was enhanced in the presence of Arg I albumin [34.5 +/- 4.6 vs. 27.7 +/- 9.7% 5-bromo-2'-deoxyuridine (BrdU)-positive cells] (P < 0.05) resulting in an increased cell proliferation. CONCLUSION: Genuine AGE compounds, as they are encountered in the uremic condition, activate leukocyte response, and hence could play a role in uremia related atherogenesis.

Bromodeoxyuridine↗