Protein Carbamylation in Chronic Kidney Disease and Dialysis

Long, Joshua D.; Parada, Xavier Vela; Kalim, Sahir

doi:10.1016/bs.acc.2018.07.002

Cited by 19 publications

(28 citation statements)

References 146 publications

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“…A negative correlation of ASF to several measured uremic toxins, including total levels of pCS, pCG and IxS, indicates an effect of these uremic toxins, per se, on the ability of albumin to bind these uremic toxins. This is in line with multiple studies over recent years showing a link between CKD and PTMs through increased levels of uremic toxins, in particular urea [44][45][46]. The decrease of ASF with the progression of CKD is accompanied by a decrease in the degree of protein binding of IxS and IAA and could be translated to higher toxicity of these uremic toxins due to the increased free circulating fraction [2].…”

Section: Discussionsupporting

confidence: 89%

Gut Microbiota and Their Derived Metabolites, a Search for Potential Targets to Limit Accumulation of Protein-Bound Uremic Toxins in Chronic Kidney Disease

Steenbeke

Gryp

Biesen

et al. 2021

Toxins

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Chronic kidney disease (CKD) is characterized by gut dysbiosis with a decrease in short-chain fatty acid (SCFA)-producing bacteria. Levels of protein-bound uremic toxins (PBUTs) and post-translational modifications (PTMs) of albumin increase with CKD, both risk factors for cardiovascular morbidity and mortality. The relationship between fecal metabolites and plasma concentrations of PBUTs in different stages of CKD (n = 103) was explored. Estimated GFR tends to correlate with fecal butyric acid (BA) concentrations (rs = 0.212; p = 0.032), which, in its turn, correlates with the abundance of SCFA-producing bacteria. Specific SCFAs correlate with concentrations of PBUT precursors in feces. Fecal levels of p-cresol correlate with its derived plasma UTs (p-cresyl sulfate: rs = 0.342, p < 0.001; p-cresyl glucuronide: rs = 0.268, p = 0.006), whereas an association was found between fecal and plasma levels of indole acetic acid (rs = 0.306; p = 0.002). Finally, the albumin symmetry factor correlates positively with eGFR (rs = 0.274; p = 0.005). The decreased abundance of SCFA-producing gut bacteria in parallel with the fecal concentration of BA and indole could compromise the intestinal barrier function in CKD. It is currently not known if this contributes to increased plasma levels of PBUTs, potentially playing a role in the PTMs of albumin. Further evaluation of SCFA-producing bacteria and SCFAs as potential targets to restore both gut dysbiosis and uremia is needed.

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Section: Discussionsupporting

confidence: 89%

Gut Microbiota and Their Derived Metabolites, a Search for Potential Targets to Limit Accumulation of Protein-Bound Uremic Toxins in Chronic Kidney Disease

Steenbeke

Gryp

Biesen

et al. 2021

Toxins

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“…Carbamylation is a post-translational modification involving the addition of isocyanate, usually derived from urea, to protein-bound amino-acid residues, causing alterations in the structure and function of the affected proteins. Increased carbamylation has been observed in aging humans ( Gorisse et al, 2016 ), and as a result of chronic kidney disease ( Long et al, 2018 ) as well as in AD with cerebrovascular disease ( Gallart-Palau et al, 2017 ). It has been shown that tau, which is aggregated in AD and also to a lesser degree in PDD, can be carbamylated, resulting in increased amyloid formation and tau accumulation ( Guru KrishnaKumar et al, 2018 ).…”

Section: Resultsmentioning

confidence: 99%

Severe and Regionally Widespread Increases in Tissue Urea in the Human Brain Represent a Novel Finding of Pathogenic Potential in Parkinson’s Disease Dementia

Scholefield

Church

et al. 2021

Front. Mol. Neurosci.

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Widespread elevations in brain urea have, in recent years, been reported in certain types of age-related dementia, notably Alzheimer’s disease (AD) and Huntington’s disease (HD). Urea increases in these diseases are substantive, and approximate in magnitude to levels present in uraemic encephalopathy. In AD and HD, elevated urea levels are widespread, and not only in regions heavily affected by neurodegeneration. However, measurements of brain urea have not hitherto been reported in Parkinson’s disease dementia (PDD), a condition which shares neuropathological and symptomatic overlap with both AD and HD. Here we report measurements of tissue urea from nine neuropathologically confirmed regions of the brain in PDD and post-mortem delay (PMD)-matched controls, in regions including the cerebellum, motor cortex (MCX), sensory cortex, hippocampus (HP), substantia nigra (SN), middle temporal gyrus (MTG), medulla oblongata (MED), cingulate gyrus, and pons, by applying ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Urea concentrations were found to be substantively elevated in all nine regions, with average increases of 3–4-fold. Urea concentrations were remarkably consistent across regions in both cases and controls, with no clear distinction between regions heavily affected or less severely affected by neuronal loss in PDD. These urea elevations mirror those found in uraemic encephalopathy, where equivalent levels are generally considered to be pathogenic, and those previously reported in AD and HD. Increased urea is a widespread metabolic perturbation in brain metabolism common to PDD, AD, and HD, at levels equal to those seen in uremic encephalopathy. This presents a novel pathogenic mechanism in PDD, which is shared with two other neurodegenerative diseases.

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“…Chronic inflammation is one of the pivotal conditions contributing to the pathogenesis in HD patients. There are numerous factors inducing systemic chronic inflammation in HD patients, such as oxidative stress [32], uremic toxin, carbamylation for protein [33] or leukocyte activation by some dialyzers [34]. Highlysensitive biomarker for inflammation, hs-CRP, could predict all-cause and cardiovascular death in HD patients [35] as well as in non-HD patients [36].…”

Section: Discussionmentioning

confidence: 99%

The predictive role of serum calprotectin on mortality in hemodialysis patients with high phosphoremia

et al. 2020

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Background: The inflammatory mediator calprotectin (CPT, myeloid-related protein 8/14) is known as an endogenous ligand contributing to pathophysiology in inflammatory diseases. Serum CPT reportedly became a potential biomarker in these conditions, though there is no report predicting the prognosis in hemodialysis patients. The aim of this study is to investigate the predictive role of serum CPT on mortality in hemodialysis patients. Methods: We conducted a multicenter, observational cohort study of 388 Japanese subjects undergoing hemodialysis. Serum CPT were measured using an ELISA. The potential associations between serum CPT and clinical variables were cross-sectionally examined. Multivariate Cox regression was used to estimate the association between serum CPT, high-sensitivity C reactive protein (hs-CRP), white blood cell (WBC) count and mortality. Median follow-up was 6.6 years. Results: The median CPT level was 6108 ng/ml (median in healthy subjects, 2800) at baseline. Serum CPT positively correlated with WBC count (ρ = 0.54, P < 0.001) and hs-CRP values (ρ = 0.35, P < 0.001). In multivariate analysis, hs-CRP was an independent predictor of all-cause mortality after adjusting confounding factors (middle vs. low: hazard ratio [HR] 2.09, 95% confidence interval [CI] 1.23-3.66; high vs. low: 2.47, 1.40-4.47). In the analysis by stratum of phosphate levels, elevated CPT levels were significantly associated with all-cause mortality in the highest tertile (18.1; 3.15-345.9) among the high-phosphate group, but not among the low-phosphate group. Conclusions: Serum CPT would become a potential predictive marker on mortality in hemodialysis patients with high-phosphate levels.

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Protein Carbamylation in Chronic Kidney Disease and Dialysis

Cited by 19 publications

References 146 publications

Gut Microbiota and Their Derived Metabolites, a Search for Potential Targets to Limit Accumulation of Protein-Bound Uremic Toxins in Chronic Kidney Disease

Gut Microbiota and Their Derived Metabolites, a Search for Potential Targets to Limit Accumulation of Protein-Bound Uremic Toxins in Chronic Kidney Disease

Severe and Regionally Widespread Increases in Tissue Urea in the Human Brain Represent a Novel Finding of Pathogenic Potential in Parkinson’s Disease Dementia

The predictive role of serum calprotectin on mortality in hemodialysis patients with high phosphoremia

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