Protein Carbamylation in Kidney Disease: Pathogenesis and Clinical Implications

Kalim, Sahir; Karumanchi, S. Ananth; Thadhani, Ravi; Berg, Anders H.

doi:10.1053/j.ajkd.2014.04.034

Cited by 105 publications

(117 citation statements)

References 120 publications

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“…78,79 As kidney function declines, accumulating urea spontaneously dissociates to form cyanate, which reacts irreversibly with proteins and free amino groups in a reaction known as carbamylation ( Figure 4). Impaired acetylcholine-induced vasorelaxation has been observed in mice with urea levels comparable to those in uremic patients, suggesting that protein carbamylation may lead to uremiarelated endothelial dysfunction.…”

Section: Protein Carbamylationmentioning

confidence: 99%

Epidemiology and Mechanisms of Uremia-Related Cardiovascular Disease

2016

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Abstract-Patients with chronic kidney disease and end-stage renal disease are at 5-to 10-fold higher risk for developing cardiovascular disease (CVD) than age-matched controls. Clinically, CVD in this population manifests as coronary artery disease, arrhythmias, stroke, or congestive heart failure. Beyond the traditional risk factors (eg, diabetes mellitus and hypertension), uremia-specific factors that arise from accumulating toxins also contribute to the pathogenesis of CVD.In this review, we summarize the literature on the epidemiology of both traditional and uremia-related CVD and focus on postulated mechanisms of the latter. P. Jousset, MD, 1 describing common causes of death among patients with Bright disease C hronic kidney disease (CKD) is an increasingly urgent public health concern that is projected to grow worldwide at a rate of 8% annually, with the fastest growth expected in developing nations.2,3 It has long been known that patients with kidney failure are predisposed to cardiovascular disease (CVD) that manifests clinically in various forms, including coronary artery disease, atrial or ventricular arrhythmias, myocardial infarction, stroke, or congestive heart failure. Over the last 30 years, it has become clear that the risk of CVD increases early in the course of progressive kidney disease and that the epidemiology, pathophysiology, prevention, and treatment of CVD and CKD are closely related and interdependent. 4 In this review, we initially describe the epidemiology of CVD among people with CKD, noting the limitations of available research. We then discuss common risk factors for CVD (traditional and nontraditional) and key shared aspects of its pathophysiology with CKD. Next we describe emerging diagnostic tools and novel therapies that may help to delay or prevent end-stage renal disease (ESRD) and to curtail the escalating burden of cardiorenal disease. In the final section, we discuss the health services and health policy challenges that CKD and its inextricably linked CVD morbidities pose worldwide, particularly for low-and middle-income countries (LMICs). Phenotypes and Epidemiology of CVD in Patients With CKDPatients with CKD and some forms of CVD share a number of risk factors and underlying pathophysiological mechanisms that, by virtue of their similarities, offer opportunities to improve their management. The epidemiology of 4 of the commonest clinical phenotypes of CVD associated with CKD is discussed below. Coronary Artery DiseaseCoronary artery disease (CAD) is a leading cause of death among people with advanced CKD. Clinical syndromes compatible with CAD (including angina and myocardial infarction) are exceedingly common in patients with nondialysis-dependent CKD, and the incidence of myocardial

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Section: Protein Carbamylationmentioning

confidence: 99%

Epidemiology and Mechanisms of Uremia-Related Cardiovascular Disease

2016

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“…Carbamylation involves the irreversible modifications of primary amines and reversible modifications of thiols, hydroxyls, phenols and imidazole groups [78,79] via addition of a 'carbamoyl' moiety (2CONH 2 ) to a functional group [80]. Under physiologic conditions, urea slowly dissociates into cyanate and its tautomer isocyanate.…”

Section: Indirect Toxicity: Protein Carbamylation In Ckdmentioning

confidence: 99%

“…Under physiologic conditions, urea slowly dissociates into cyanate and its tautomer isocyanate. Cyanate is non-reactive but is rapidly converted to isocyanic acid which is a reactive electrophile with high affinity for nucleophilic groups such as primary amines (Figure 2) [80]. Isocyanic acid has a physiologic concentration approximately 45 nmol/l in humans that can reach 140 nmol/l in patients with advanced CKD [81].…”

Section: Indirect Toxicity: Protein Carbamylation In Ckdmentioning

confidence: 99%

Urea, a true uremic toxin: the empire strikes back

Lau

Vaziri

2016

Clinical Science

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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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“…This process occurs in healthy individuals with aging, but is increased in certain disease states. Alterations to protein stru cture may result in functional changes, which can be pathogenetic [99] . Carbamylation is one form of post translational protein modification specifically associated with CKD and uremia.…”

Section: Post-translational Protein Modificationmentioning

confidence: 99%

“…Cyanate, a dissociation product of urea, binds to proteins and free amino acids, resulting in abnormal cellular responses that may contribute to inflammation and atherosclerosis. As carbamylation results from a direct product of uremia it may serve as a quantitative biomarker of timeaveraged urea concentrations in addition to its potential use in risk assessment [99] . One of the most widely studied and publicised forms of posttranslational protein modification is glycation.…”

Section: Post-translational Protein Modificationmentioning

confidence: 99%

Aging and uremia: Is there cellular and molecular crossover?

White

Yaqoob

Harwood

2015

WJN

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immune systems. However, whilst much has been documented about the shared physical characteristics of aging and uremia, the molecular and cellular similarities between the two have received less attention. In order to bridge this perceived gap we have reviewed published research concerning the common molecular processes seen in aging subjects and CKD patients, with specific attention to altered proteostasis, mitochondrial dysfunction, post-translational protein modification, and senescence and telomere attrition. We have also sought to illustrate how the cell death and survival pathways apoptosis, necroptosis and autophagy are closely interrelated, and how an understanding of these overlapping pathways is helpful in order to appreciate the shared molecular basis behind the pathophysiology of aging and uremia. This analysis revealed many common molecular characteristics and showed similar patterns of cellular dysfunction. We conclude that the accelerated aging seen in patients with CKD is underpinned at the molecular level, and that a greater understanding of these molecular processes might eventually lead to new much needed therapeutic strategies of benefit to patients with renal disease. AbstractMany observers have noted that the morphological changes that occur in chronic kidney disease (CKD) patients resemble those seen in the geriatric population, with strikingly similar morbidity and mortality profiles and rates of frailty in the two groups, and shared characteristics at a pathophysiological level especially in respect to the changes seen in their vascular and REVIEW

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Protein Carbamylation in Kidney Disease: Pathogenesis and Clinical Implications

Cited by 105 publications

References 120 publications

Epidemiology and Mechanisms of Uremia-Related Cardiovascular Disease

Epidemiology and Mechanisms of Uremia-Related Cardiovascular Disease

Urea, a true uremic toxin: the empire strikes back

Aging and uremia: Is there cellular and molecular crossover?

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