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Editorials
Asymmetric dimethylarginine – a prognostic marker for transplant outcome?
Janghee Woo1,2 and H. Joachim Deeg1,2
1Fred Hutchinson Cancer Research Center and 2University of Washington School of Medicine, Seattle, WA, USA E-mail: H. JOACHIM DEEG - jdeeg@fredhutch.org
doi:10.3324/haematol.2018.212191
Results of allogeneic hematopoietic cell transplanta- tion (HCT) have improved progressively over the
1
past two decades. However, disease relapse, graft-
versus-host disease (GvHD), and various other causes of non-relapse mortality continue to be hurdles to greater suc- cess. These challenges have been tackled from various angles, both clinically and in the laboratory. One focus of research has been on the role of endothelial cells in the pathophysiology and manifestations of GvHD, sinusoidal obstruction syndrome, diffuse alveolar hemorrhage, and transplant-associated microangiopathy. There is a substan- tial body of literature on the effects of pro-inflammatory cytokines, derived from endothelial cells or other cellular compartments, on the interactions between donor-derived cells and host tissues and organs.2,3
In this issue of Haematologica, Radujkovic and colleagues examine a potential role of asymmetric dimethylarginine (ADMA), an endogenous compound derived from endothe- lial cells, as a pre-transplant marker for post-transplant com- plications.4 For this purpose, they studied data from 938 patients transplanted at two German centers who had serum samples collected within 4 weeks before transplan- tation and that were available for determination of ADMA levels. The results of their analysis indicate that higher lev- els of ADMA before HCT were associated with an increased risk of non-relapse mortality within the first year after transplantation. There was no association with relapse or GvHD. However, overall survival and progression-free survival during the first year after transplantation were neg- atively affected by higher pre-HCT levels of ADMA. Higher AMDA levels were also associated with shortened overall survival, shortened progression-free survival, and a higher incidence of non-relapse mortality within 1 year after the onset of acute GvHD. As ADMA is an endogenous molecule, the authors conclude that their findings under- score the importance of endothelial cell function for post- transplant outcome.
ADMA occurs naturally as a metabolic byproduct of pro- tein modification processes in human cells, as first described by Vallance et al. in 1992.5 One important func- tion is its interference with L-arginine – via nitric oxide (NO) synthase6 – in the production of NO, a molecule well- known to be involved in endothelial function. The presence of elevated ADMA levels has, therefore, broad implica- tions, including interference with vasodilation, facilitation of atherogenesis, insulin resistance, the development of autoimmune disorders, and rejection of kidney allografts, among others.7-10 It should not, therefore, be surprising that ADMA plays a significant role in disorders such as cardio- vascular disease, diabetes mellitus, certain forms of renal disease, and in erectile dysfunction.6 ADMA levels increase substantially in response to native or oxidized low density lipoprotein cholesterol, thereby further inhibiting NO pro- duction. Studies in animal models have indicated that
ADMA increases at a time when vascular disease may not be clinically evident.
These data suggest that ADMA, originating from endothelial cells, may also directly affect endothelial func- tion, which is relevant to transplant outcomes as reported by the authors. Reduced NO levels will alter tissue perfu- sion, resulting in organ dysfunction and, conceivably, greater susceptibility of lungs, intestinal tract, liver or kid- neys to the effects of HCT conditioning regimens and the cytokines released as a consequence of donor/host interac- tions.2 As ADMA has also been suggested to be a potential biomarker for insulin resistance,10 it might be involved in altered blood glucose regulation, a problem for many patients after HCT. Furthermore, NO is a potent inhibitor of platelet aggregation and adhesion, as well as leukocyte adhesion, and thereby reduces the risk of thrombotic events. Thus, reduction of NO production in the presence of elevated levels of ADMA might facilitate the formation of microthrombi and contribute to microvascular dysfunc- tion.11 The reference of the authors to post-transplant microangiopathy is, therefore, relevant, and it is unfortu- nate that no data on specific causes of death, in particular no histological data, were available.
Clearly, this paper raises many questions. As the authors note, they present an observational study, which does not allow any cause-and-effect relationship to be determined, and they remain undecided in their discussion. For exam- ple, it is puzzling that nitrate levels were elevated along with ADMA prior to transplantation, as were, incidentally, thrombomodulin levels, which were also associated with increased non-relapse mortality in a previous report.3 Since ADMA levels were analyzed in pre-HCT samples, a logical assumption would be that pre-HCT events, such as expo- sure to chemotherapy or infectious agents or, possibly, genetic factors, were responsible for raised levels of ADMA. There are data showing that a polymorphism in dimethy- larginine dimethylaminohydrolase 2 (DDAH2), the enzyme that promotes ADMA metabolism, is associated with elevated ADMA levels,12 and it is tempting to specu- late that this polymorphism might affect post-HCT non- relapse mortality. Limited studies on polymorphism of the NO synthase gene by the authors failed to show a correla- tion with outcome, and such a polymorphism (or mutation) would not by itself explain elevated ADMA levels.
It is of interest to see that the authors provide outcome data, not only relative to the day of HCT, but also relative to the onset of GvHD, considering the possibility that the development of GvHD might have affected the subsequent course in an ADMA-dependent way. However, there was no significant impact of ADMA levels on post-GvHD out- come, relapse, overall survival, or progression-free survival, and the results were not different from those given in rela- tion to the transplant date. What might one have expected?
The authors had reported previously that patients with
haematologica | 2019; 104(4)