Asymmetric and symmetric dimethylarginines: metabolism and role in severe sepsis

Introduction

Asymmetric dimethylarginines (ADMA) and symmetric dimethylarginines (SDMA) are markers of protein breakdown; both compete with arginine for cellular transport and are excreted in urine. In addition, ADMA is a nonselective inhibitor of NO synthase, and is also metabolized by dimethylarginine-dimethylaminohydrolase (DDAH), a specific hydrolase whose activity in stress is controversial [1]. While the ADMA increase is associated with adverse events in many critical conditions, little attention has been focused on the role of SDMA [2].

Methods

In three Italian university ICUs we measured plasma ADMA, SDMA, their ratio (a marker of ADMA catabolism, a rough indicator of DDAH activity), arginine, IL-6, TNFα, and C-reactive protein (CRP) level at days 1, 3, 6, 9, 12 and at discharge in 72 consecutive patients with severe sepsis/septic shock.

Results

Basal glycaemia, creatinine, IL-6, TNFα, CRP, ADMA and SDMA were higher than normal; arginine was normal. ADMA was related to total Sequential Organ Failure Assessment and arginine, inversely related to IL-6 and CRP; SDMA was related to Simplified Acute Physiology Score II score, daily, worst-day, total Sequential Organ Failure Assessment score, blood urea, creatinine, and arginine. The ADMA/SDMA ratio was inversely related to IL-6. In 58 patients discharged alive, creatinine, IL-6 and CRP decreased over time, ADMA increased, SDMA remained stable, and the ADMA/SDMA ratio increased. In 14 patients who died in the ICU, creatinine, IL-6, TNFα, CRP, and ADMA did not vary, SDMA significantly increased, and ADMA/SDMA ratio variation was not significant. In both groups the last ICU day confirms data trends. SDMA but not ADMA was associated with ICU mortality.

Conclusion

In severe sepsis SDMA is a more robust predictor of organ failure/mortality than ADMA. Stress reaction seems to activate ADMA catabolism, while in survivors, when inflammation subsides, the catabolism seems to be reduced.