title: Asymmetric dimethylarginine in homocystinuria due to cystathionine beta-synthase deficiency: relevance of renal function.
abstract: OBJECTIVE
  Vascular disease is associated with increased plasma asymmetric dimethylarginine (ADMA) and homocysteine, and both are increased in renal failure. In cystathionine beta-synthase deficiency (CBS) there is severe hyperhomocysteinaemia, precocious vascular disease, and endothelial dysfunction. We investigated whether ADMA levels are elevated in CBS patients with and without renal impairment, and whether lowering plasma homocysteine also lowers ADMA.
  
  
  METHODS
  We measured plasma homocysteine, arginine, asymmetric and symmetric dimethylarginines, nitrate + nitrite, creatinine and cystatin C in 23 CBS-deficient patients and 24 age-matched controls.
  
  
  RESULTS
  In the patients, nitrate + nitrite and the ratio L: -arginine/ADMA were markedly reduced (21.6 +/- 6.1 vs 57.7 +/- 7.5 micromol/L and 132.9 +/- 24.7 vs 181.9 +/- 56.1, respectively, p < 0.001 for both), reflecting endothelial dysfunction. Plasma ADMA for the group was moderately increased (0.55 +/- 0.08 vs 0.49 +/- 0.07 micromol/L, p = 0.018), but this was due to significantly higher levels than controls in only those 7 of the 23 patients who had elevated cystatin C levels (0.59 +/- 0.08 vs 0.49 +/- 0.07 mg/L, p = 0.007). Posttreatment total homocysteine in patients varied widely (15-285, median 92 micromol/L), but was not correlated with ADMA or other measured variables. In three newly-diagnosed patients, marked reduction of total homocysteine during treatment produced minimal changes in ADMA.
  
  
  CONCLUSIONS
  ADMA levels were significantly increased only in the CBS-deficient patients with elevated cystatin C levels, and not in those with normal renal function. The reported relationship between hyperhomocysteinaemia and ADMA may not be direct, but could be secondary to reduced renal function.
authors.affiliation: University of New South Wales, Sydney, Australia. d.wilken@unsw.edu.au
authors.forename: David E L
authors.initials: DE
authors.lastname: Wilcken
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Ah Siew
authors.initials: AS
authors.lastname: Sim
authors.forename: Kathryn
authors.initials: K
authors.lastname: Green
authors.forename: Bridget
authors.initials: B
authors.lastname: Wilcken
mesh_terms: D000328:Adult; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D003404:Creatinine / Q000097:blood; D003541:Cystathionine beta-Synthase / Q000172:deficiency*; D055316:Cystatin C; D015891:Cystatins / Q000097:blood; D005260:Female; D006710:Homocysteine / Q000097:blood; D006712:Homocystinuria / Q000209:etiology / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D011736:Pyridoxine / Q000494:pharmacology; D051437:Renal Insufficiency / Q000097:blood / Q000378:metabolism
chemical_list: C525030:CST3 protein, human; D055316:Cystatin C; D015891:Cystatins; D009566:Nitrates; D009573:Nitrites; D006710:Homocysteine; C018524:N,N-dimethylarginine; D001120:Arginine; D003404:Creatinine; D003541:Cystathionine beta-Synthase; D011736:Pyridoxine