1. ¹Department of Medicine, Renal Section, Toensberg County Hospital, Toensberg, Norway
2. ²Clinical Institute of Medical and Chemical Laboratory Diagnostics, Graz, Austria
3. ³Department of Preventive Medicine and Centre of Clinical Research, Oslo University Hospital Ullevaal, Oslo, Norway
4. ⁴Synlab for Medizinisches Versorgungzentrum für Labordiagnostik Heidelberg, Heidelberg, Germany
5. ⁵Clinical Institute of Medical and Chemical Laboratory Diagnosis, Medical University of Graz, Graz, Austria
6. ⁶Department of Medical Science, Renal Unit, University Hospital, Uppsala, Sweden
7. ⁷Department of Medicine and Therapeutics, Western Infirmary Hospital, Glasgow, United Kingdom
8. ⁸Department of Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway

Correspondence: Sadollah Abedini, Department of Medicine, Renal Section, Toensberg County Hospital, Pb 2168, 3103 Toensberg, Norway. E-mail: sadollah.abedini@gmail.com

⁹These authors contributed equally to this work

Received 10 May 2009; Revised 12 July 2009; Accepted 11 August 2009; Published online 21 October 2009.

Abstract

Increased plasma levels of asymmetric dimethylarginine (ADMA) are associated with endothelial dysfunction and predict the progression to dialysis and death in patients with chronic kidney disease. The effects of these increased ADMA levels in renal transplant recipients, however, are unknown. We used the data from ALERT, a randomized, double-blind, placebo-controlled study of the effect of fluvastatin on cardiovascular and renal outcomes in 2102 renal transplant recipients with stable graft function on enrollment. Patients who were initially randomized to fluvastatin or placebo in the 5- to 6-year trial were offered open-label fluvastatin in a 2-year extension of the original study. After adjustment for baseline values for established factors in this post hoc analysis, ADMA was found to be a significant risk factor for graft failure or doubling of serum creatinine (hazard ratio 2.78), major cardiac events (hazard ratio 2.61), cerebrovascular events (hazard ratio 6.63), and all-cause mortality (hazard ratio 4.87). In this trial extension, the number of end points increased with increasing quartiles of plasma ADMA levels. All end points were significantly increased in the fourth compared to the first quartile. Our study shows that elevated plasma levels of ADMA are associated with increased morbidity, mortality, and the deterioration of graft function in renal transplant recipients.