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ADMA and post-transplant mortality
part, a characteristic of the recipient’s endothelial cell sys- tem, increased risk of mortality, both overall and after the onset of acute GvHD, may be determined (and predicted) already prior to transplantation. However, it should be noted, that, although most markers of “endothelial vulner- ability” are likely to predict outcome after a severe chal- lenge, particularly after acute GvHD, they do not seem to be associated with a higher incidence of acute GvHD. In line with this, in the present study, pre-transplant ADMA was not a biomarker of acute GvHD risk but was associat- ed with early NRM, both overall and following acute GvHD, which translated into shorter survival outcomes.
With regards to the endothelial system, higher ADMA levels correlated positively with endothelium-related serum factors, such as sCD141, free IL-18, and nitrates. Thrombomodulin is a surface receptor protein released/shed from the endothelium in an extracellular sol- uble form (sCD141) during cell distress and elevated serum levels are frequently indicative of inflammatory cell dam- age.24 IL-18 is a pleiotropic, pro-inflammatory cytokine associated with coronary heart disease25 and de-regulation of the IL-18/IL-18BP pathway26 was shown to cause endothelial cell dysfunction. Interestingly, pre-transplant nitrate levels, which are markers of in vivo NO production, also correlated positively with ADMA, which is a NO syn- thase inhibitor. This seemingly contradictory finding is in line with some but not all observations made in other clin- ical settings.27,28
In this context, it should be noted, that higher pre-trans- plant nitrates levels were also associated with a higher inci- dence of NRM in a previous study.4 In pro-inflammatory conditions, large amounts of NO are produced by iNOS in numerous cell types.29 In the cardiovascular system, upreg- ulation of iNOS may contribute to endothelial dysfunc- tion.30
In the present study, however, INOS SNP did not influ- ence the effect of ADMA on mortality. Certainly, interac- tions of ADMA with other NO synthase family members cannot be excluded, and there is also evidence that NO syn- thase-independent mechanisms may contribute to the detrimental biological effects associated with increases in ADMA.31,32 Consequently, in the setting of allogeneic SCT, elevated levels of both ADMA and nitrate prior to condi- tioning and immunosuppressive therapy are likely to reflect compromised endothelial homeostasis in the recipient which, particularly in the context of a severe challenge, such as acute GvHD, may result in an impaired outcome. However, since GvHD is an immune-triggered process, an influence of the donor’s ADMA or nitrate levels on the intensity of the subsequent allogeneic immune response in the recipient cannot definitely be ruled out.
The median pre-transplant ADMA level in our series was 0.73 mM which is in accordance with literature data that suggest normal serum ADMA levels are in the range of 0.25-0.92 mM when measured by an enzyme-linked immunosorbent assay.33 Importantly, since ADMA is direct-
Figure 1. Higher pre-transplant asymmetric dimethylarginine levels are associated with non-relapse mortality and worse overall and progression-free survival in the first year after transplantation and after acute graft-versus-host disease. Meta-analyses of the multivariable effect of pre-transplant asymmetric dimethylarginine (ADMA) levels as a continuous variable (per 1-log2 increase) for overall survival (OS), progression-free survival (PFS), and non-relapse mortality (NRM) in the first year after transplantation and after acute graft-versus-host disease (GvHD), and relapse in the first year after allografting. CI: confidence interval; HR: hazard ratio; IPD: individual patient data.
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