Urea, a true uremic toxin: the empire strikes back

Abstract

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.

The Cardiovascular Burden in End-Stage Renal Disease

“…Older studies suggested the non-toxicity of high blood urea concentration after acute infusion, but now there are evidences of direct and indirect toxicities of chronically high urea levels, inducing alterations of gut epithelial barrier allowing passage of bacterial toxins into the blood causing systemic inflammation and activating protein carbamylation reaction where isocyanic acid (from urea catabolism) alters the structure and function of proteins in the body. Carbamylation is linked with renal fibrosis, atherosclerosis, and anemia, thereby increasing the CV risk in ESRD patients [21,22] . Intensification of hemodialysis therapy in renal replacement therapy patients, promotion of low-protein diets in CKD patients, could help maintain low levels of plasma urea and reduce carbamylate protein concentration by reducing the CV risk [23] .…”

Preserved cardiac function by vinculin enhances glucose oxidation and extends health- and life-span

“…Conversely, abundance decreased for urea [Fig. S4(b)], a known marker of aging which can cause cardiovascular disease, 35,36 and for branched-chain (valine, leucine, and isoleucine) and other amino acids (threonine, phenylalanine, tyrosine, and tryptophan) in VincHE flies [Fig. S4(c)].…”

Serum Glutaredoxin Activity as a Marker of Oxidative Stress in Chronic Kidney Disease: A Pilot Study

“…Importantly, CKD affects red blood cell and platelets that are activated and produce reactive oxygen species, which in turn activates intracellular redox enzymes, for example, superoxide dismutase, catalase, glutathione peroxidase, transferases, and glutathione reductase [6], showing and increased redox imbalance in platelets and red blood cells of CKD patients [5,6,[18][19][20][21]. Markers of protein and lipid peroxidation, for example, malondialdehyde (MDA/TBARS), advanced glycation end products including pentosidine [7,8], advanced oxidation protein products [1,5] are also altered in CKD; however, to date, there are no redox markers that are readily used in the point-of-care testing.…”