Symmetric Dimethylarginine as a Proinflammatory Agent in Chronic Kidney Disease

Abstract

SummaryBackground & objectives Chronic kidney disease (CKD) is characterized by chronic inflammation, considered a nontraditional risk factor for cardiovascular disease, the major cause of death in CKD. Symmetric dimethylarginine (SDMA) was recently demonstrated to induce reactive oxygen species in monocytes. The present study further investigates the inflammatory character of SDMA compared with its structural counterpart asymmetric dimethylarginine (ADMA). Design, setting, participants, & measurementsIn vitro, the effect of SDMA on intracellular monocytic expression of IL-6 and TNF-␣ was studied followed by an evaluation of nuclear factor (NF)-B activation. Additionally, an association of SDMA with inflammatory parameters in consecutive stages of CKD was evaluated in vivo.Results Monocytes incubated with SDMA showed increased IL-6 and TNF-␣ expression and a rise in active NF-B. N-acetylcysteine abrogated both these effects. No significant effects were observed with ADMA. In vivo, 142 patients (67 Ϯ 12 years) at different stages of CKD showed an inverse association between serum SDMA and ADMA and renal function. Correlations between SDMA and IL-6, TNF-␣, and albumin were more significant than for ADMA, while multiple regression analysis only retained TNF-␣ at a high significance for SDMA (P Ͻ 0.0001). In receiver operating characteristic analysis for inflammation, defined as an IL-6 level above 2.97 pg/ml (median), the discriminative power of SDMA (area under the curve [AUC]: 0.69 Ϯ 0.05) directly followed that of C-reactive protein (AUC: 0.82 Ϯ 0.04) and albumin (AUC: 0.72 Ϯ 0.05; for all, P Ͻ 0.0001) and preceded that of ADMA (P ϭ 0.002). ConclusionsThe present study shows that SDMA is involved in the inflammatory process of CKD, activating NF-B and resulting in enhanced expression of IL-6 and TNF-␣, which is corroborated by the clinical data pointing to an in vivo association of SDMA with inflammatory markers in CKD at different stages.

Does cardiac resynchronization therapy restore peripheral circulatory homeostasis?

“…This is most unlikely to be a ‘false positive’ given first, the P  = 0.013 value. SDMA, unlike ADMA, is only a very weak inhibitor of NO synthase, but it is a substantial mediator of inflammatory change 29. This could not be explained by improved renal function, an important consideration because SDMA is excreted (mainly) unchanged in the urine 30.…”

Daño arterial asociado a la enfermedad renal crónica: evaluación mediante técnicas de laboratorio no invasivo en pacientes hemodializados

“…Las mujeres tienen un incremento en la concentración de éste producto mucho más tardío que los hombres y por tanto, éste sería otro factor que podría explicar la disfunción endotelial más severa y precoz en el sexo masculino. La DMAA en enfermedad renal crónica se encuentra en concentraciones altas y recientemente Schepers et al Han descrito un rol porinfl amatorio en ERC, activando NF-κB, lo que lleva al aumento de la expresión de IL-6 y TNF alfa 35 . Todo lo anterior podría contribuir a exacerbar las diferencias de género planteadas.…”

Uremia Retention Molecules and Clinical Outcomes

“…Taken together, these findings corroborate to the current concept that SDMA is not an inert compound. Actually, it has been demonstrated that SDMA has pro-oxidant and pro-inflammatory effects, and inhibits nitric oxide production [10,11] . Finally, a recent meta-analysis found that higher levels of ADMA and SDMA were associated with increased risk of all-cause mortality (RR 1.52, 95% CI 1.37-1.68; RR 1.31, 95% CI 1.18-1.46; respectively) and CVD (RR 1.33, 95% CI 1.22-1.45; RR 1.36, 95% CI 1.10-1.68; respectively) [12] .…”