Asymmetric Dimethylarginine (ADMA) in Pediatric Renal Diseases: From Pathophysiological Phenomenon to Clinical Biomarker and Beyond

Abstract

Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide (NO) synthase inhibitor, inhibits NO synthesis and contributes to the pathogenesis of many human diseases. In adults, ADMA has been identified as a biomarker for chronic kidney disease (CKD) progression and cardiovascular risk. However, little attention is given to translating the adult experience into the pediatric clinical setting. In the current review, we summarize circulating and urinary ADMA reported thus far in clinical studies relating to kidney disease in children and adolescents, as well as systematize the knowledge on pathophysiological role of ADMA in the kidneys. The aim of this review is also to show the various analytical methods for measuring ADMA and the issues tht need to be addressed before transforming to clinical practice in pediatric medicine. The last task is to suggest that ADMA may not only be suitable as a diagnostic or prognostic biomarker, but also a promising therapeutic strategy to treat pediatric kidney disease in the future.

Keywords: asymmetric dimethylarginine; biomarker; children; dimethylamine; dimethylarginine dimethylaminohydrolase; kidney disease; nitric oxide; pediatric nephrology; protein arginine methyl transferase.

Figure 2

Person correlation and linear regression analyses between plasma ADMA level and (A) plasma creatinine level and (B) estimated glomerular filtration rate (eGFR) in 216 CKD stage 1–4 children and adolescents. This figure was constructed with data reported in part elsewhere [63,64,72,73].

Figure 1

Simplified schema of synthesis, transport, and elimination of ADMA in the kidney. The enzymes in protein arginine methyltransferases (PRMTs) family methylate protein-bound L-Arginine residues (purple cycle) to generate protein-bound ADMA (red circle) and SDMA (yellow circle). Upon proteolysis, free ADMA is released and moved out of the cells via cationic amino acid transporter (CAT). In the kidneys, ADMA can be removed via urinary excretion or enzymatic degradation. Dimethylarginine dimethylaminohydrolase-1 (DDAH-1) and -2 (DDAH-2) can catalyze ADMA to generate L-Citrulline and dimethylamine (DMA). In addition, ADMA can be metabolized by alanine-glyoxylate aminotransferase 2 (AGXT2). In the kidney, ADMA can inhibit nitric oxide (NO) synthase to inhibit NO production.