Asymmetric dimethylarginine and symmetric dimethylarginine: axis of evil or useful alliance?

Almost 40 years ago, in 1970, Kakimoto and Akazawa were the first to isolate and describe N-N, N-G- and N-G,N'-G-dimethyl-arginine from human urine. Today, these substances are known as asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). In their detailed and meticulous publication, Kakimoto and Akazawa speculated about these two compounds: "They may have functional importance in proteins in which they are formed. If they are excreted into the urine as metabolites of body proteins, amounts of these substances in human urine may reflect methylation rate of body proteins and their turnover rates and determination of these substances might be important for the study of various pathological states." The following decades proved them to be right. ADMA, the most potent endogenous nitric oxide synthase (NOS) inhibitor was first found to be elevated in hemodialysis patients. It has been shown to correlate with traditional and nontraditional cardiovascular risk factors. ADMA is also a strong predictor of cardiovascular events and death in both patients with chronic kidney disease (CKD, stage 2-5) and in the general population. Moreover, ADMA predicts the progression of CKD. SDMA, the structural isomer of ADMA, has been shown to be an excellent marker of renal function in human and animal studies. There is emerging evidence that SDMA might also be involved in inflammation and atherosclerosis although it is only thought to be a (weak) indirect inhibitor of NOS. There is burgeoning evidence that these two substances may indeed damage normal physiological functions, or interfere with physiological defense mechanisms in CKD, play a role in the progression of renal disease, induce uremic symptoms, and may even contribute to dialysis-related complications. Hence these compounds are considered uremic toxins. This review summarizes our current concept how these two compounds might play a crucial part in the pathophysiology of uremia, either alone or in their combination. We also allude to the potential physiological role these substances might have.