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In effect, he had shown that we are made of the same materials as the rest of Nature, and are therefore a part of the world around us. Urea is produced commercially by several steps, which begin with the direct reaction of ammonia with carbon dioxide in a high pressure, high temperature reactor.
It is a very important starting material in a number of chemical syntheses, and is used on an industrial scale for the manufacture of fertilisers, pharmaceuticals and resins. For example, urea is one of the precursors to the various barbiturates , which are widely used as sedatives and sleeping pills. Urea is also used in the production of urethanes , which are then polymerised to form polyurethane foams.
Another important application is in the manufacture of resins and polymers. Urea can react with formaldehyde to make the urea-formaldehyde resins, which are highly important in moulded plastics. Another product is, melamine , which is formed by the dehydration of urea, and is used primarily in the production of melamine-formaldehyde resins which have much greater hardness and stain resistance than urea-formaldehyde resins.
In our review paper, we discussed more recent evidence pointing to urea as a potent toxin that affects several organ systems Fig. Blood urea increase in chronic kidney disease and promotes several disease pathways including intestinal inflammation, atherosclerosis, vascular calcification, anemia, kidney fibrosis and insulin resistance. There are several limitations of the clinical trials done in dialysis patients such as the HEMO and FHN trials that reported no benefit with more rigorous urea clearance.
One major point is that dialysis end stage kidney failure patients have been exposure to elevated urea conditions for many years, and the systemic damage may be too far advanced at that point for urea lowering to exert any benefit. Secondly, the hemodialysis treatment itself can activate inflammation and obscure benefits of urea reduction. Finally, blood urea levels can be affected by a variety of factors aside from kidney function, including dietary protein intake, dehydration and internal bleeding.
The most convincing evidence that lowering of urea levels is advantageous comes from the practice of adhering to a low protein diet to slow progressive loss of kidney function. Low protein diet was first promoted by the Italian nephrologists Giovannetti and Maggiore in the s as a way to limit production of urea and other nitrogenous wastes. Since then, several studies have shown that a carefully monitored low protein diet with avoidance of malnutrition can be protective for kidney function and delay progression to end stage kidney failure.
Urea exerts both direct and indirect toxic effects on several organs in the body. A high urea level causes changes in the gut bacterial population microbiome such that A there is increased production of bacterial toxins such as indoxyl sulfate and p-cresyl sulfate; and B inflammation in the intestinal wall leads to break down of intercellular tight junctions. The net result is that bacterial toxins move across into the bloodstream and induces systemic inflammation which is linked with progression of kidney failure and cardiovascular death.
This failure could be explained if uremic toxicity is actually a summation effect of multiple toxins, each at individual subtoxic levels in the patient. Other solutes could be used as surrogates to measure clearance, but urea happens to be available in high concentrations, is easily measured by all clinical laboratories, and is easily dialyzed, so changes in concentration are sensitive indicators of clearance. Measurements of creatinine clearance are confounded by the disequilibrium that occurs across red cells within the dialyzer and in the patient.
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