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Stem Cell Transplantation
Asymmetric dimethylarginine serum levels are associated with early mortality after allogeneic stem cell transplantation
Ferrata Storti Foundation
Haematologica 2019 Volume 104(4):827-834
Aleksandar Radujkovic,1 Hao Dai,2 Lambros Kordelas,3 Dietrich Beelen,3 Sivaramakrishna P. Rachakonda,1,2 Carsten Müller-Tidow,1 Rajiv Kumar,2 Peter Dreger1 and Thomas Luft1
1Department of Internal Medicine V, University Hospital Heidelberg; 2Department of Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg and 3Department of Bone Marrow Transplantation, University Hospital Essen, Germany
ABSTRACT
Increasing evidence suggests that endothelial cell distress is associated with mortality after allogeneic stem cell transplantation and acute graft- versus-host disease. Asymmetric dimethylarginine is an endogenous nitric oxide synthase inhibitor that induces endothelial cell dysfunction. We analyzed the impact of pre-transplant serum levels of asymmetric dimethy- larginine on outcome after allogeneic stem cell transplantation. Since acute graft-versus-host disease and its treatment are major contributors to post- transplant mortality, the effect of asymmetric dimethylarginine on outcome measures was also assessed after onset of acute graft-versus-host disease. A total of 938 patients allografted at two centers between 2002 and 2013 were included in the retrospective study. In multivariable models, higher pre- transplant asymmetric dimethylarginine levels were significantly associated with an increased risk of non-relapse mortality (hazard ratio 1.43 per 1-log2 increase, P=0.005) but not with relapse (hazard ratio 1.21, P=0.109) within the first year after transplantation. This translated into worse overall sur- vival (hazard ratio 1.45, P<0.0001) and shorter progression-free survival (hazard ratio 1.30, P=0.002) in the first year after transplantation. Higher pre-transplant asymmetric dimethylarginine levels were also associated with shorter overall survival (hazard ratio 1.46, P=0.001) and progression- free survival (hazard ratio 1.32, P=0.010) and higher non-relapse mortality (hazard ratio 1.36, P=0.042) within 1 year after the onset of acute graft-ver- sus-host disease. Taken together, our data indicate an association between pre-transplant asymmetric dimethylarginine status and early non-relapse mortality in allografted patients, both overall and after the onset of acute graft-versus-host disease. These findings underline the relevance of endothe- lial dysfunction for transplant complications.
Introduction
Non-relapse mortality (NRM) represents a challenge for successful allogeneic stem cell transplantation (SCT). NRM is predominantly driven by graft-versus-host disease (GvHD) as a major complication of allogeneic SCT. There is a body of evi- dence showing that mortality after allogeneic SCT and after acute GvHD is asso- ciated with endothelial cell distress. In previous studies, endothelial markers, such as angiopoietin-2 and nitrates, and, on the genomic level, single nucleotide poly- morphisms (SNP) in the recipients’ thrombomodulin and CD40 ligand genes, were shown to predict overall mortality and GvHD-related mortality already prior to transplantation.1-5
Serum asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthase which competes with arginine and influences the bioavailability of NO.6,7 ADMA may cause endothelial dysfunction and, in patients with a compromised vascular system, elevated ADMA levels can predict cardio- vascular events and mortality.8-10 Recently, two large meta-analyses across different
Correspondence:
THOMAS LUFT
thomas.luft@med.uni-heidelberg.de
Received: July 19, 2018. Accepted: November 23, 2018. Pre-published: December 4, 2018.
doi:10.3324/haematol.2018.202267
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/4/827
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