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Soluble CD154 Is a Unique Predictor of Nonfatal and Fatal Atherothrombotic Events in Patients Who Have End-Stage Renal Disease and Are on Hemodialysis

Berthold Hocher^*, Lutz Liefeldt, Thomas Quaschning, Philipp Kalk^*,, Reinhard Ziebig^||, Michael Godes^*,, Katharina Relle^*,, Gernot Asmus^¶ and Johannes-Peter Stasch^**

^* Center for Cardiovascular Research/Department of Pharmacology, Department of Nephrology, and ^|| Institute of Clinical Chemistry, Charité–Universitaetsmedizin Berlin, Institute of Vegetative Physiology, Charité, Campus Mitte, and ^¶ Kuratorium für Heimdialyse, Dialysezentrum Sonnenallee, Berlin, Department of Nephrology, University of Freiburg, Freiburg, and ^** Cardiovascular Research, Bayer HealthCare AG, Wuppertal, Germany

Address correspondence to: Prof. Berthold Hocher, Center for Cardiovascular Research/Institute of Pharmacology, Charité–Universitätsmedizin Berlin, Hessische Strasse 3-4, 10115 Berlin, Germany. Phone: +49-30-450-514238; Fax: +49-30-450-514938; E-mail: berthold.hocher{at}charite.de Website: http://www.ccr.charite.de/site/html/de/ag_hocher.html

Received for publication July 2, 2006. Accepted for publication January 5, 2007.

Cardiovascular mortality is remarkably high in patients who are on hemodialysis. Soluble CD154 (sCD154), a protein that belongs to the TNF receptor superfamily, has been implicated in the pathogenesis of atheromatous plaque destabilization and thrombotic events. The predictive value of sCD154 as a marker for clinical outcome in patients with ESRD was investigated. A total of 232 patients were prospectively followed for 52 mo. At study entry, clinical characteristics were documented and plasma concentrations of sCD154 and those of conventional risk predictors were analyzed. The time and cause of any hospitalization and death were documented during the entire follow-up. Survival rates were compared by Kaplan-Meier and Cox regression analyses. A total of 122 patients died, 64 of cardiovascular disease, including 20 cases of fatal atherothrombotic diseases (myocardial infarction, stroke, mesenteric ischemia). All 20 cases of fatal atherothrombotic events had high sCD154 plasma levels (cutoff >6.42 ng/ml) at study entry. The total number of fatal and nonfatal atherothrombotic events was 66. Only five atherothrombotic nonfatal events occurred in patients with sCD154 <6.42 ng/ml, whereas 61 fatal and nonfatal events were seen in patients with sCD154 6.42 ng/ml (P < 0.005). This was confirmed by Kaplan-Meier curves for fatal atherothrombotic events (P = 0.0214) and the combined end point fatal and nonfatal atherothrombotic events (P = 0.0039). Cox regression analysis revealed that high sCD154 is an independent predictor (relative risk 6.80; 95% confidence interval 1.64 to 28.26; P = 0.008) for the combined end point death or hospitalization as a result of atherothrombotic events. Death or hospitalizations as a result of any other reason (arrhythmia, heart failure, infectious diseases, and cancer) were not linked to sCD154 plasma concentrations. In conclusion, sCD154 predicts nonfatal and fatal atherothrombotic events (myocardial infarction, stroke, mesenteric ischemia) but not death and hospitalization as a result of any other reason in stable patients who have ESRD and are on hemodialysis.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673