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ADMA and post-transplant mortality
ABC
Figure 3. Relationship between quartiles of pre-transplant asymmetric dimethylarginine serum concentration and serum concentration of nitrates, free inter- leukin-18, and soluble thrombomodulin (sCD141). Trend analysis showed that pre-transplant concentrations of (A) nitrates (n=375, (B) soluble thrombomodulin (n=776) and (C) free interleukin-18 (n=746) were positively correlated with quartiles of pre-transplant ADMA concentration (Jonckheere trend test, P=0.010, P<0.0001 and P<0.0001, respectively). ADMA, asymmetric dimethylarginine; IL-18: free interleukin-18; Q1-4, quartiles 1-4 of the ADMA distribution; sCD141: sol- uble thrombomodulin.
ly involved in endothelial dysfunction, it may be a thera- peutic target. However, a specific ADMA-lowering agent is not yet available.34 Supplementation of L-citrulline may be employed to boost intracellular arginine levels and to reduce ADMA production. In a few clinical studies, supple- mental L-citrulline in multi-gram doses was well tolerated and was shown to exert various effects suggestive of car- diovascular protection; it could, therefore, be studied in high-risk patients with elevated ADMA.35,36 Given the con- tinuous relation between ADMA serum levels and survival outcomes in our study, treatment of patients irrespective of the individual’s pre-transplant ADMA status may be favored and such a clinical study should ideally be placebo- controlled. However, given the necessity of oral L-citrulline ingestion in multi-gram doses (3-10 g/day) and possible drug interactions,36 the first interventional study in the set- ting of allogeneic SCT setting may rather enroll patients with markedly elevated pre-transplant ADMA serum con- centrations, who are at high risk of early mortality accord- ing to our retrospective analysis. Based on literature data and our results, in a possible clinical trial setting, ADMA levels ≥1 mM could be used to define such a high-risk pop- ulation of patients.
Besides its retrospective nature, some limitations of our study need to be addressed. ADMA was measured at a sin- gle time point and thus no information on the serum kinet- ics of ADMA levels in the post-transplant period can be provided. Furthermore, with regard to the known associa- tion of ADMA with cardiovascular pathologies, one could ask whether the NRM events in our study were related to cardiovascular disease. However, it should be noted that in the absence of disease recurrence, the exact cause of death in allografted patients, particularly in the early post-trans- plant period, is often difficult to determine and for the pur- poses of categorization, infection, GvHD and (general) organ failure are generally used. In a recently published large registry study,37 the main causes of NRM were (in descending order): infection, GvHD and respiratory disease, all of which may be linked to endothelial distress. The fre-
quency of (isolated) cardiovascular events after transplanta- tion is rather low with a cumulative incidence of 6% after 15 years.38 However, it should be taken into account that endothelial factors play a crucial role in many important complications of allogeneic SCT, such as transplant-associ- ated microangiopathy, veno-occlusive disease, and refracto- ry GvHD.1,39,40 Finally, like most clinical research on ADMA, our data are observational, describe a relationship and do not allow for interpretation of causality. Our results need to be validated, ideally in a prospective interventional study. As already pointed out above, investigating the effects of L- citrulline treatment in high-risk patients undergoing allo- geneic SCT may be a feasible approach.
In summary, this retrospective study shows an associa- tion between ADMA levels and outcome after allogeneic SCT. Higher ADMA levels were a risk factor for early mortality in allografted patients, both overall and after the onset of acute GvHD, and were correlated with other bio- markers of endothelial vulnerability. Further studies on the role of the endothelium and markers associated with endothelial distress in the setting of allogeneic SCT are warranted.
Acknowledgments
The authors would like to thank Michael Hess and Alexandra Hof for their excellent technical assistance and construction of the tissue bank, Maria Gawlik for assistance in the collection of clinical data, and Thorsten Brenner and Stefan Hofer (Department of Anesthesiology, University of Heidelberg) for helpful discussions. We also wish to acknowledge the excellent help of Axel Benner (Department of Biostatistics, German Cancer Research Center) regarding the statistical analyses.
Funding
This work was supported by grants from the Helmholtz- Alliance on Immunotherapy of Cancer, B.L.U.T. e.V. (Weingarten, Germany) and the Wilhelm-Sander-Stiftung (grant n. 2008.068.1). HD was sponsored by the China Scholarship Council.
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