The Saga of Two Centuries of Urea: Nontoxic Toxin or Vice Versa?

In the early 1700s, a substance ultimately identified as urea was reported for the first time in urine. About a century later, in 1828, synthesis of this organic compound was achieved, thus giving rise to modern organic chemistry. In parallel, physicians showed that urine comes from the kidneys and contains large amounts of urea, which is produced outside of the kidneys, establishing the humoral approach of renal physiology. Urea was the first uremic retention solute to be identified and it has been used as a marker of renal disease ever since. However, progress in the knowledge of urea metabolism has shown that it is susceptible to many extrarenal variations and, therefore, it cannot be a reliable marker of renal function. It reflects protein intake in the stable patient and has been used to assess nutrition and dialysis efficacy in renal patients. Although it has been studied for almost 200 years, its toxicity has been largely debated. An indirect toxicity occurring through carbamylation of lysine residues is now well established and some evidence from recent work also supports direct toxicity of urea, offering additional rationale for interventional prevention of uremic complications.