TRR 219 – Mechanisms of Cardiovascular Complications in Chronic Kidney Disease


Summary of the research program of the Collaborative Research Center

Patients with chronic kidney disease (CKD) exhibit a massively increased risk for cardiovascular (CV) events: 50% of patients with CKD stage 4-5 suffer from cardiovascular disease (CVD), and CV mortality accounts for ~40-50% of all deaths in patients with CKD, compared with 26% in controls with normal kidney function. In addition to the high risk for fatal atherosclerosis-related complications cardiac deaths also result from heart failure and arrhythmias. In more than 70 studies, correction for CV risk factors did not neutralize the impact of CKD on CV risk. The underlying pathophysiological processes of CVD in CKD patients obviously differ from the CVD processes in the general population. This underlines the importance of non-traditional, CKD-specific CV risk factors and accentuates that CKD itself is an independent risk factor for CV events. This may explain at least in part why traditional strategies to improve CV outcome have largely failed in the context of CKD. This also emphasizes the need to identify pathological mechanisms adversely affecting the CV system in CKD, with the aim to reduce the increased CV mortality in CKD patients through novel therapeutic strategies.

Alterations in the circulation as well as in the myocardium crucially contribute to the increased CV risk in patients suffering from CKD, identifying these alterations as the main critical components for their high CVD risk. However, the molecular mechanisms as well as the mediators involved are largely unexplored. Therefore, the aim of this Transregional Collaborative Research Center TRR219 is to analyze in experimental and clinical studies the multi-factorial aspects of CKD-related CV morbidity and mortality caused by:

(a) the circulation. Here, we will focus on i) the pathological remodeling of the vessel wall and involved mediators and vascular cells, which results in inflammation, endothelial dysfunction, formation of vascular lesions and calcification; and on ii) components of the blood such as dyslipidemia, thrombogenicity, increased mineral load and uremic toxins, all contributing to CV damage;

(b) the myocardium, comprising pathological myocardial remodeling associated with deranged myocardial metabolism, altered oxidative stress, micro-angiopathy, autonomous neuropathy, and impaired cardiac function.

In addition to examining pathological mechanisms affecting the CV system in CKD at the basic science level, we will also study the translational aspects by analyzing novel interventions and diagnostic tests in the context of CKD-related CV pathology. Furthermore, we will search for novel factors contributing to CVD in the context of CKD, to trigger the subsequent development of novel diagnostic and/or predictive tests.