Plasma protein carbamylation and decreased acidic drug protein binding in uremia

Erill, S.; Calvo, Rosario; Carlos, R.

doi:10.1038/clpt.1980.87

Cited by 65 publications

(30 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our study corroborates prior observations, in which carbamylation is associated with deleterious effects in various disease states (7,9,12,16,17,(25)(26)(27)(28). Although carbamylated EPO loses its erythropoietic properties both in vitro and in vivo (10,11), the timeframe for this process is unclear, and EPO dosing at every dialysis session provides uncarbamylated EPO routinely.…”

Section: Discussionsupporting

confidence: 79%

Carbamylation of Serum Albumin and Erythropoietin Resistance in End Stage Kidney Disease

Kalim

Tamez

Wenger

et al. 2013

Clinical Journal of the American Society of Nephrology

View full text Add to dashboard Cite

SummaryBackground and objectives The mechanisms underlying erythropoietin resistance are not fully understood. Carbamylation is a post-translational protein modification that can alter the function of proteins, such as erythropoietin. The hypothesis of this study is that carbamylation burden is independently associated with erythropoietin resistance.Design, setting, participants, & measurements In a nonconcurrent prospective cohort study of incident hemodialysis patients in the United States, carbamylated albumin, a surrogate of overall carbamylation burden, in 158 individuals at day 90 of dialysis initiation and erythropoietin resistance index (defined as average weekly erythropoietin dose [U] per kg body weight per hemoglobin [g/dl]) over the subsequent 90 days were measured. Linear regression was used to describe the relationship between carbamylated albumin and erythropoietin resistance index. Logistic regression characterized the relationship between erythropoietin resistance index, 1-year mortality, and carbamylation.Results The median percent carbamylated albumin was 0.77% (interquartile range=0.58%-0.93%). Median erythropoietin resistance index was 18.7 units/kg per gram per deciliter (interquartile range=8.1-35.6 units/kg per gram per deciliter). Multivariable adjusted analysis showed that the highest quartile of carbamylated albumin was associated with a 72% higher erythropoietin resistance index compared with the lowest carbamylation quartile (P=0.01). Increasing erythropoietin resistance index was associated with a higher risk of death (odds ratio per unit increase in log-erythropoietin resistance index, 1.69; 95% confidence interval, 1.06 to 2.70). However, the association between erythropoietin resistance index and mortality was no longer statistically significant when carbamylation was included in the analysis (odds ratio, 1.44; 95% confidence interval, 0.87 to 2.37), with carbamylation showing the dominant association with death (odds ratio for high versus low carbamylation quartile, 4.53; 95% confidence interval, 1.20 to 17.10).Conclusion Carbamylation was associated with higher erythropoietin resistance index in incident dialysis patients and a better predictor of mortality than erythropoietin resistance index.

show abstract

Section: Discussionsupporting

confidence: 79%

Carbamylation of Serum Albumin and Erythropoietin Resistance in End Stage Kidney Disease

Kalim

Tamez

Wenger

et al. 2013

Clinical Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…On the other hand, in vitro carbamylation of normal plasma with potas sium cyanate produces a decrease in the binding of salicylate without changes in the binding of quinidine. This is similar to what is observed in uremia [14,16], and can be achieved with degrees of carbamylation in the range of those detected in uremia [8]. Salicylate binds to two different sites on the albumin molecule [5,13] and its decreased binding in uremic plasma can be partially corrected by treatment of plasma with char coal [8].…”

Section: Introductionsupporting

confidence: 64%

“…Carbamylation of plasma proteins has been detected in uremia, correlating with the impairment of acidic drug binding seen in this condition [8]. On the other hand, in vitro carbamylation of normal plasma with potas sium cyanate produces a decrease in the binding of salicylate without changes in the binding of quinidine.…”

Section: Introductionmentioning

confidence: 92%

Effects of Carbamylation of Plasma Proteins and Competitive Displacers on Drug Binding in Uremia

Calvo¹,

Carlos²,

Erill³

1982

Pharmacology

View full text Add to dashboard Cite

The effects of in vitro carbamylation of plasma with potassium cyanate on the binding of sulfisoxazole and diazepam have been investigated. Incubation of plasma with potassium cyanate produced varying degrees of carbamylation of plasma proteins which were associated with a decrease in the binding of sulfisoxazole (100 mg/l), a drug bound to site I on the human albumin. Scatchard plots showed that this decreased binding resulted from a decrease in affinity without changes in the number of binding sites. Similar changes were detected in uremia. Carbamylation of plasma proteins did not affect the binding of diazepam (3 mg/l), a drug bound to site II. The plasma protein binding of sulfisoxazole and diazepam was decreased in samples from uremic patients. Charcoal treatment did not modify the binding of sulfisoxazole to normal or carbamylated plasma while it reduced, but did not normalize, the binding defect in uremic plasma. On the other hand, charcoal treatment brought the binding of diazepam in uremic plasma to normal values. It seems that only drug binding site I is carbamylated in uremia, while competitive displacers bind to sites I and II.

show abstract

“…Cyanate subsequently reacts irreversibly with the N-terminal groups of amino acids, peptides and many proteins by a process known as carbamylation (2)(3)(4). Accordingly, the potential role of cyanate and carbamylation has to date been investigated only in the context of uremia (2,(5)(6)(7). Proteins isolated from patients with chronic renal failure and end-stage renal disease have been shown to be easily carbamylated due to the urea-derived high concentrations of cyanate.…”

Section: Introductionmentioning

confidence: 99%

Cyanate attenuates insulin secretion in cultured pancreatic β cells

2012

Mol Med Report

View full text Add to dashboard Cite

Abstract. The vast majority of long-term complications in transplanted patients are associated with cardiovascular disease. Previously, an alternative and dominant mechanism for cyanate formation in atherosclerotic lesions has been discovered. This study was designed to determine the effect of cyanate on insulin secretion in cultured pancreatic β cells (INS-1 cells). The cytotoxicity of cyanate was determined by 3-(4,5-Desethyithiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Insulin secretion was measured by ELISA in cyanatetreated INS-1 cells. Reactive oxygen species (ROS) generation was also determined by measuring the fluorescent oxidized product of 2,7-dichlorefluorescein in cyanate-treated INS-1 cells. FACS analysis was carried out to determine the effect of cyanate on the apoptosis of INS-1 cells. Firstly, we found that cyanate, within concentration ranges in which no cytotoxic effect was observed (0.01, 0.1 and 1.0 mM), decreased insulin secretion dose-dependently in both non-glucose-stimulated and glucose-stimulated INS-1 cells. Cyanate at a 1.0 mM concentration inhibited insulin secretion by more than 50% in non-glucose-stimulated cells and glucose (5 and 10 mM)-stimulated cells. Cyanate, however, did not affect ROS generation. Furthermore, no pro-or anti-apoptotic effect was observed in cyanate-treated INS-1 cells. The results in this study suggest the possible inhibitory effect of cyanate on insulin secretion in INS-1 pancreatic β cells. The inhibitory effect was not mediated either by ROS generation or by apoptosis. Further studies to determine the underlying mechanisms will be of benefit.

show abstract

Plasma protein carbamylation and decreased acidic drug protein binding in uremia

Cited by 65 publications

References 5 publications

Carbamylation of Serum Albumin and Erythropoietin Resistance in End Stage Kidney Disease

Carbamylation of Serum Albumin and Erythropoietin Resistance in End Stage Kidney Disease

Effects of Carbamylation of Plasma Proteins and Competitive Displacers on Drug Binding in Uremia

Cyanate attenuates insulin secretion in cultured pancreatic β cells

Contact Info

Product

Resources

About