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The Projects

 

 

Hematopoietic Stemcell transplantation

Emerging data suggest a critical role for bone marrow angiogenesis in hematologic malignancies. We measured Ang-2 in sera from 20 healthy controls and 90 patients with high-risk acute myeloid leukemia or myelodysplastic syndrome before conditioning for HSCT. Using regression tree analysis, we recursively identified bone marrow blasts and Ang-2 as being the best predictors for disease free survival. Because few predictors for DFS exist in the setting of allo-HSCT, Ang-2 may be used as a readily available powerful biomarker to pre-estimate DFS and may open new perspectives for risk-adapted treatment of high-risk myeloid malignancies. Because few predictors for DFS exist in the setting of allo-HSCT, Ang-2 may be used as a readily available powerful biomarker to pre-estimate DFS and may open new perspectives for risk-adapted treatment of high-risk myeloid malignancies (Kümpers P. and Koenecke C. et al. Blood 2008) . We are currently trying to validate these exciting findings in a larger cohort including good, and standard risk AML patients.

 

 

ANCA associated vasculitis & Systemic Lupus Erythematosus

We could demonstrate a marked imbalance of the angiopoietin–Tie system in favor of Ang-2 in patients with endothelial diseases, such as ANCA-associated vasculitis (AAV) and SLE. Ang-2 levels correlated well with clinical and laboratory markers of disease activity. Our data suggest that Ang-2 might be a mediator for endothelial cell detachment, which is considered the histologic hallmark in AAV (Kümpers P, Hellpap J. et al. NDT 2009) In SLE, Ang-2 was the strongest predictor for disease activity using regression tree analysis (Kümpers P. et al. Ann Rheum Dis).

 

 

ESRD, Hemodialysis, and Atherosclerosis

Endothelial activation has recently emerged as a key mechanism in atherosclerosis. The risk and prevalence of vascular inflammation is increasingly higher in patients with essential hypertension, reduced renal function, or ESRD requiring hemodialysis. We could show that elevated Ang-2 concentrations correlate with the overall atherosclerotic burden in patients on chronic hemodialysis (David S., Kümpers P. et. al 2008 Am J Kidney Dis submitted). Furthermore, Ang-2 levels correlate closely with endothelial soluble adhesion molecules such as ICAM-1 and VCAM-1 in a large cohort of hypertensive patients (David S et al. manuscript in preparation). Administration of Ang-1 has recently been shown to reduce end-organ damage in a hypertensive rat model. Based on these data, the Ang-Tie2 axis might be a rational new drug target in atherosclerosis.

 

 

Critical Care & Critical Care Nephrology

Various pilot studies have indicated that Ang-2 driven shutdown of protective Ang-1/Tie2 signalling is operational in critically ill patients. Aside from its function as a mediator, we wanted to identify the value of Ang-2 as a marker for outcome. Indeed, excess Ang-2 levels on admission were identified as the best predictor of inferior outcome in a cohort of medical ICU patients using multivariate analyses (Kümpers P. et al. Crit Care 2008). Preliminary data suggest that Ang-2 is beyond that a valuable marker of survival during the course of critically illness: Ang-2 is an independent predictor of survival at the time of nephrology consultation/start of renal replacement therapy in ICU patients with acute kidney injury (Kümpers P. et al. manuscript in preparation). Taken together, circulating Ang-2 and probably the respective Ang-2/Ang-1 ratio constitute potential new biomarkers to assess endothelial activation and subsequent outcome in critical care and critical care nephrology.