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

Kalim, Sahir; Tamez, Hector; Wenger, Julia; Ankers, Elizabeth; Trottier, Caitlin A.; Deferio, Joseph J.; Berg, Anders H.; Karumanchi, S. Ananth; Thadhani, Ravi

doi:10.2215/cjn.04310413

Cited by 42 publications

(38 citation statements)

References 42 publications

(70 reference statements)

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“…The intensity of this reaction is particularly amplified during chronic kidney disease (CKD) because of hyperuremia (25,26). High concentrations of carbamylated plasma proteins constitute a significant risk factor for cardiovascular events and mortality in hemodialysis patients (26,27). Recently, our laboratory has evidenced in a mouse model that tissue proteins, including skin collagen, were more intensely carbamylated during CKD and accumulated in the organism (28).…”

Section: Significancementioning

confidence: 99%

Protein carbamylation is a hallmark of aging

Gorisse

Piètrement

Vuiblet

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

166

125

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Aging is a progressive process determined by genetic and acquired factors. Among the latter are the chemical reactions referred to as nonenzymatic posttranslational modifications (NEPTMs), such as glycoxidation, which are responsible for protein molecular aging. Carbamylation is a more recently described NEPTM that is caused by the nonenzymatic binding of isocyanate derived from urea dissociation or myeloperoxidase-mediated catabolism of thiocyanate to free amino groups of proteins. This modification is considered an adverse reaction, because it induces alterations of protein and cell properties. It has been shown that carbamylated proteins increase in plasma and tissues during chronic kidney disease and are associated with deleterious clinical outcomes, but nothing is known to date about tissue protein carbamylation during aging. To address this issue, we evaluated homocitrulline rate, the most characteristic carbamylation-derived product (CDP), over time in skin of mammalian species with different life expectancies. Our results show that carbamylation occurs throughout the whole lifespan and leads to tissue accumulation of carbamylated proteins. Because of their remarkably long half-life, matrix proteins, like type I collagen and elastin, are preferential targets. Interestingly, the accumulation rate of CDPs is inversely correlated with longevity, suggesting the occurrence of still unidentified protective mechanisms. In addition, homocitrulline accumulates more intensely than carboxymethyl-lysine, one of the major advanced glycation end products, suggesting the prominent role of carbamylation over glycoxidation reactions in age-related tissue alterations. Thus, protein carbamylation may be considered a hallmark of aging in mammalian species that may significantly contribute in the structural and functional tissue damages encountered during aging.

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Section: Significancementioning

confidence: 99%

Protein carbamylation is a hallmark of aging

Gorisse

Piètrement

Vuiblet

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

166

125

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“…• In terms of anaemia of CKD, as mentioned above carbamylation has been linked with altered erythropoietin function [84]; a prospective cohort study of 158 haemodialysis patients found that levels of carbamylated serum albumin predicted resistance to erythropoiesis-stimulating agents and higher mortality risk [96].…”

Section: Sh Amino Acid Protein Lysylmentioning

confidence: 99%

Urea, a true uremic toxin: the empire strikes back

2016

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Blood levels of urea rise with progressive decline in kidney function. Older studies examining acute urea infusion suggested that urea was well-tolerated at levels 8-10× above normal values. More recent in vitro and in vivo work argue the opposite and demonstrate both direct and indirect toxicities of urea, which probably promote the premature aging phenotype that is pervasive in chronic kidney disease (CKD). Elevated urea at concentrations typically encountered in uremic patients induces disintegration of the gut epithelial barrier, leading to translocation of bacterial toxins into the bloodstream and systemic inflammation. Urea induces apoptosis of vascular smooth muscle cells as well as endothelial dysfunction, thus directly promoting cardiovascular disease. Further, urea stimulates oxidative stress and dysfunction in adipocytes, leading to insulin resistance. Finally, there are widespread indirect effects of elevated urea as a result of the carbamylation reaction, where isocyanic acid (a product of urea catabolism) alters the structure and function of proteins in the body. Carbamylation has been linked with renal fibrosis, atherosclerosis and anaemia. In summary, urea is a re-emerging Dark Force in CKD pathophysiology. Trials examining low protein diet to minimize accumulation of urea and other toxins suggest a clinical benefit in terms of slowing progression of CKD.

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“…12 Carbamylation was recently described as a factor inducing resistance to rhEpo treatment. 13 We, therefore, assessed albumin carbamylation as a marker for total carbamylation. As expected, the percentage of carbamylated albumin (c-alb) was higher in patients with CKD than in controls (4.4%; interquartile range, 3.6%-6.1% versus 8%; interquartile range, 6.4%-10.5%; P,0.01).…”

mentioning

confidence: 99%

Increased Synthesis of Liver Erythropoietin with CKD

Seigneux

Lundby

Berchtold

et al. 2016

JASN

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Anemia of CKD seems to be related to impaired production of renal erythropoietin (Epo). The glycosylation pattern of Epo depends on the synthesizing cell and thus, can indicate its origin. We hypothesized that synthesis of Epo from nonkidney cells increases to compensate for insufficient renal Epo production during CKD. We determined plasma Epo levels and Epo glycosylation patterns in 33 patients with CKD before undergoing dialysis and nine patients with CKD undergoing dialysis. We compared these values with values obtained in healthy volunteers and other controls. Although patients with CKD before undergoing dialysis had median (interquartile range) Epo levels higher than those of healthy controls (13.8 IU/L; interquartile range, 10.0-20.7 IU/L versus 8.4 IU/L; interquartile range, 7.6-9.0 IU/L; P,0.01), these patients were moderately anemic (mean6SD; hemoglobin =1186 17 g/L). Detected as the percentage of migrated isoforms (PMI), Epo glycosylation in patients with CKD before undergoing dialysis (PMI=36.1611.7%) differed from that in healthy controls (PMI=9.263.8%; P,0.01) but not from that in umbilical cord plasma (PMI=53.9610.6%; P.0.05), which contains mainly liver-derived Epo. Furthermore, glycosylation modification correlated with eGFR loss. These results suggest that patients with CKD maintain persistent Epo synthesis despite declining renal function, and this maintenance may result in part from increased liver Epo synthesis.

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

Cited by 42 publications

References 42 publications

Protein carbamylation is a hallmark of aging

Protein carbamylation is a hallmark of aging

Urea, a true uremic toxin: the empire strikes back

Increased Synthesis of Liver Erythropoietin with CKD

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