Cardiorenal interaction : therapeutic perspectives

Backgrounds Chronic renal failure is a world wide health problem which will progress to dialysis or transplantation. It is important to prevent this further progression of renal failure. Patient with renal failure have an increased risk to experience a cardiovascular event and when they will undergo such an event, renal function will decrease even more. Therefore, a vicious circle arises between the heart and the kidneys. The Renin-Angiotensin-Aldosteron-System (RAAS) is probably an important mechanism in this vicious circle. Out of large clinical trials became clear that Angiotensin Converting Enzyme inhibitors (ACEi) are effective in the prevention of further progression of renal and cardiac damage. Unfortunately, there is a large inter-individual variation in therapy response to ACEi, therefore not every patient is optimally treated. Because every millimetre mercury blood pressure reduction and every milligram reduction of urine protein leakage will increase life expectancy, optimization of ACEi therapy is of utmost importance. Cardio-renal interaction In chapter 1 and 2 we investigate if RAAS intervention is effective in prevention of further cardiac and renal damage in a rat model for cardio-renal interaction. Chapter 1 focuses on mild damage, while in chapter 2 a model with more severe cardiac and renal damage is used. In chapter 3 we investigated if cardiac remodelling due to renal function loss is associated with cardiac telomeric shortening, as a measure of aging. Telomeres form the end of chromosomes and prevent the loss of genetic information. Optimization of the ACEi-therapy response In chapter 1, 4 and 5 is ACEi therapy compared with intervention in other vasoactive peptide systems in different rat models for renal and cardiac failure. The effects of a Vasopressin 1a antagonist on proteinuria are investigated in early and late intervention. The effects of an ACE/Neutral Endopeptidase (NEP) inhibitor and an endotheline converting enzyme (ECE)/NEP inhibitor or cardiac and renal damage are investigated in a late intervention protocol. In chapter 6, the mechanism behind ACEi therapy resistance is investigated. To optimize therapy response in the rat with a blunted therapy response caused by a high sodium diet, the effects of specific targeting of an ACEi to the kidneys is investigated. Implications From chapter 1 and 2 came clear that RAAS activation is a very important contributor in the maintenance of the cardio-renal interaction and that intervention with an ACEi has beneficial effects on both the heart and the kidneys. This confirms the advice to prescribe ACEi to patients after a myocardial infarction or with heart failure to prevent further decrease of their renal function and to break through the previously mentioned vicious circle. In chapter 3 is shown that cardiac as well as renal function loss leads to telomeric shortening in the heart. Out of chapter 1 and 4 can be concluded that ACEi therapy is the first choice in late intervention therapy protocols and that more research is needed to explore the additive effects of ACE/NEPi and ECE/NEPi to ACEi in early intervention protocols. In chapter 5 is shown that a vasopressin 1a antagonist is effective in the prevention of renal damage in an early intervention protocol. From chapter 6 became clear that the therapy response of ACEi is probably dependent on a combination of pharmaco-dynamic and kinetic variation. In chapter 7 is shown that blunted therapy response caused by a high sodium diet can be optimized by delivering the ACEi in high concentrations in the kidney by means of drug targeting.