title: Plasma ADMA associates with all-cause mortality in renal transplant recipients.
abstract: Asymmetric dimethylarginine (ADMA) is a key endogenous inhibitor of endothelial NO synthase that affects endothelial function, blood pressure and vascular remodeling. Increased plasma levels of ADMA are associated with worse outcome from cardiovascular disease. Due to endothelial dysfunction before and after kidney transplantation, renal transplant recipients (RTR) are at high risk for the alleged deleterious effects of ADMA. We investigated the associations of ADMA levels with all-cause mortality and graft failure in RTR. Plasma ADMA levels were determined in 686 stable outpatient RTR (57 % male, 53 ± 13 years), with a functioning graft for ≥1 year. Determinants of ADMA were evaluated with multivariate linear regression models. Associations between ADMA and mortality were assessed using multivariable Cox regression analyses. The strongest associations with plasma ADMA in the multivariable analyses were male gender, donor age, parathyroid hormone, NT-pro-BNP and use of calcium supplements. During a median follow-up of 3.1 [2.7-3.9] years, 79 (12 %) patients died and 45 (7 %) patients developed graft failure. ADMA was associated with increased all-cause mortality [HR 1.52 (95 % CI 1.26-1.83] per SD increase, P < 0.001], whereby associations remained upon adjustment for confounders. ADMA was associated with graft failure [HR 1.41 (1.08-1.83) per SD increase, P = 0.01]; however, upon addition of eGFR significance was lost. High levels of plasma ADMA are associated with increased mortality in RTR. Our findings connect disturbed NO metabolism with patient survival after kidney transplantation.
authors.affiliation: Department of Pathology and Medical Biology, University Medical Center Groningen and University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.
authors.forename: Anne-Roos S
authors.initials: AR
authors.lastname: Frenay
authors.forename: Else
authors.initials: E
authors.lastname: van den Berg
authors.forename: Martin H
authors.initials: MH
authors.lastname: de Borst
authors.forename: Bibiana
authors.initials: B
authors.lastname: Beckmann
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Tsikas
authors.forename: Martin
authors.initials: M
authors.lastname: Feelisch
authors.forename: Gerjan
authors.initials: G
authors.lastname: Navis
authors.forename: Stephan J L
authors.initials: SJ
authors.lastname: Bakker
authors.forename: Harry
authors.initials: H
authors.lastname: van Goor
mesh_terms: D000328:Adult; D000368:Aged; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D018572:Disease-Free Survival; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000097:blood* / Q000401:mortality*; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D015996:Survival Rate
chemical_list: C018524:N,N-dimethylarginine; D001120:Arginine