Sympathetic hyperactivity in patients with chronic kidney disease

Sympathetic hyperactivity in patients with chronic kidney disease Chronic kidney disease (CKD) is often characterized by the presence of sympathetic hyperactivity. This contributes to the pathogenesis of renal hypertension. It is also associated with cardiovascular (CV) morbidity and mortality independently of its effect on blood pressure (BP). These data suggest that reducing sympathetic hyperactivity might be beneficial. In the present thesis we studied sympathetic nerve activity in CKD patients, the pathophysiological aspects and its clinical outcome. In our research we registered muscle sympathetic nerve activity (MSNA) to assess sympathetic activity. MSNA is a reproducible direct online registration of post-synaptic nerve activity to resistance vessels and there is a direct correlation between MSNA and systemic vascular resistance. It has long been recognized that sympathetic activity increases with age and is feedback-regulated by baroreflex control and volume status. To unravel the mechanisms affecting the sympathetic nervous system we studied a large group of CKD patients and healthy controls in different volume states. On average MSNA was higher in normovolemic patients than in controls and was shifted parallel in both groups after changing the volume status. Furthermore after nephrectomy for kidney donation in healthy subjects the creatinine clearance was decreased by 25% by unchanged BP and MSNA. These results suggest that in hypertensive CKD patients MSNA is inappropriately high for the volume status and that the renal injury and not the reduction of nephrons in itself influences sympathetic activity. Previous studies have demonstrated that treatment with angiotensin converting enzyme inhibitor (ACEi) and angiotensin II receptor blocker (ARB) decreased MSNA without normalization in CKD patients. We investigated the effect of treatment with the ARB eprosartan and the combined therapy with eprosartan and moxonidine (central inhibitor) in hypertensive CKD patients. Eprosartan reduced BP and MSNA comparably to other ACE and ARB, also without reaching normalization of MSNA and BP. When we added moxonidine to eprosartan, the therapy normalized BP and MSNA to levels comparable to healthy controls. The question was raised how often MSNA is increased in hypertensive patients with CKD. We studied a large data set of MSNA in CKD patients and healthy controls. More than 80% of the hypertensive patients had a MSNA higher than the mean in healthy controls. Chronic ACEi or ARB therapy reduced the sympathetic activity but did not normalize it. The fact that these treatments both decreased the activities of the renin angiotensin system and the MSNA, suggests a cause and effect relationship between these two systems or a common origin. Until now there are barely any data on the long term effect of sympathetic hyperactivity on CV outcome in CKD patients. We investigated the relationship between MSNA and clinical outcome in CKD patients by following CV morbidity and mortality in CKD patients who were on standard treatment with an ACEi or ARB for a median of 78 months. Despite of the positive effect of ACEi and ARB on BP and MSNA, the sympathetic hyperactivity predicted poor clinical outcome. In conclusion, this thesis presents; 1. the first long term research of the effects in sympathetic nerve activity in CKD patients 2. a breakthrough in controlling sympathetic activity pharmacologically 3. relevant information on the pathophysiology of sympathetic hyperactivity and hypertension in CKD patients.