Asymmetric dimethylarginine serum levels are associated with early mortality after allogeneic stem cell transplantation

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 dimethylarginine 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-log 2 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 survival (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- versus -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 endothelial dysfunction for transplant complications.

Interleukin-18 and outcome after allogeneic stem cell transplantation: A retrospective cohort study

“…As pre-transplant free IL-18 levels were correlated to patient performance status and HCT-CI in the training set, IL-18 may possibly reflect a pro-inflammatory state due to a poorer overall health status in patients with haematologic malignancies as compared to healthy controls. In addition, since IL-18 may be released from dying endothelium [6] , and in one of our previous reports, pre-transplant levels of free IL-18 were positively correlated with serum levels of ADMA [4] , endothelial dysfunction or an impaired endothelial homeostasis in patients due to the previous treatment of the underlying malignancy may also be implicated. The observed positive inter-correlations between IL-18, IL18-BPa, and CXCL9/MIG in patients suggest the involvement of the IFN γpathway.…”

“…In addition, IL-18 can be released from dying endothelium [6] , and de-regulation of the IL-18/IL-18BP pathway itself was also shown to cause endothelial cell dysfunction [16] . In one of our previous reports [4] , pre-transplant levels of free IL-18 were positively correlated with serum levels of asymmetric dimethylarginine (ADMA). ADMA causes endothelial cell dysfunction and is an established risk factor for cardiovascular complications.…”

“…Several studies, including our own, have focused on endothelial markers that correlate with NRM and GVHD-related mortality in order to understand why escalating immunosuppressive therapy is ineffective in a fraction of patients with acute GVHD [1][2][3][4] . Consequently, we put forward the hypothesis of "endothelial vulnerability" in the setting of alloSCT [3] , suggesting that pre-existing endothelial distress can deteriorate outcome after a subsequent severe endothelial challenge such as acute GVHD, without necessarily being associated with a higher incidence of GVHD.…”

Asymmetric dimethylarginine – a prognostic marker for transplant outcome?

“…2,3 In this issue of Haematologica, Radujkovic and colleagues examine a potential role of asymmetric dimethylarginine (ADMA), an endogenous compound derived from endothelial cells, as a pre-transplant marker for post-transplant complications. 4 For this purpose, they studied data from 938 patients transplanted at two German centers who had serum samples collected within 4 weeks before transplantation and that were available for determination of ADMA levels. The results of their analysis indicate that higher levels of ADMA before HCT were associated with an increased risk of non-relapse mortality within the first year after transplantation.…”