Sympathetic hyperactivity and clinical outcome in chronic kidney disease patients during standard treatment.

BACKGROUND: Sympathetic hyperactivity has been associated with adverse clinical outcome and is common in patients with chronic kidney disease (CKD). Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) have been shown to reduce sympathetic activity in CKD patients. The present study was performed to investigate whether sympathetic hyperactivity was related to clinical outcome in CKD patients treated with ACEi or ARB. METHODS: Muscle sympathetic nerve activity (MSNA) was measured in 66 nondiabetic patients (70% men) with CKD, median age 47 years (range 21-65) and mean estimated glomerular filtration rate (eGFR) 39+/-29 ml/min per 1.73 m2. Patients were followed up for a median 78 months (range 6-123), and subsequent clinical events were recorded. RESULTS: During follow-up, average blood pressure was 131+/-11 mm Hg systolic and 83+/-6 mm Hg diastolic. Twenty-one events (4 deaths and 17 nonfatal cardiovascular events) occurred in 16 patients. MSNA among the group with events was 40+/-18 bursts/min, compared with 30+/-11 bursts/min in those with no events (p=0.009). An increase of MSNA of 10 bursts/min was related to an increased risk of an event (hazard ratio=1.6; 95% confidence interval, 1.0-2.8; p=0.08), independent of GFR and blood pressure. Age attenuated this relation. CONCLUSION: Sympathetic hyperactivity was associated with the composite of all-cause mortality and nonfatal cardiovascular events in CKD patients, despite treatment with ACEi or ARB. Further studies to investigate potential effects of additional sympatholytic therapy in these patients are warrented.

Enhanced Angiotensin II type 1 receptor expression in leukocytes of patients with chronic kidney disease.

Previously, we demonstrated increased Angiotensin II type I receptor expression in leukocytes from patients with untreated, but not in treated, essential hypertension (essential hypertension). We hypothesized that the Angiotensin II AT1 receptor is also increased in leukocytes from patients with chronic kidney disease, however and can still be corrected with combined anti-hypertensive treatment with renin-angiotensin system (RAS) blockers and statins. Blood pressure, cholesterol, renal function oxidative stress parameters, inflammation, and leukocyte Angiotensin II AT1 receptor mRNA expression were measured both on and (6 weeks) off treatment. Data were compared to data of 10 healthy control subjects. Untreated chronic kidney disease patients (n=20) had higher blood pressure, cholesterol and leukocyte Angiotensin II AT1 receptor mRNA expression, but no different ox-LDL, thiobarbituric acid reactive substances, paraoxonase activity or hs-CRP. OxLDL and Lipoprotein(a) were increased in untreated chronic kidney disease. Angiotensin II AT1 receptor expression inversely correlated with renal function (R(2)=0.15, P<0.03) and Lipoprotein(a) but not with the other parameters. Treatment with RAS blockers and statins normalized blood pressure and cholesterol, however it did not correct enhanced leukocyte Angiotensin II AT1 receptor expression. Leukocyte Angiotensin II AT1 receptor expression is inappropriately high in chronic kidney disease, correlates inversely with renal function and does not depend on antihypertensive and lipid-lowering treatment. The uremic environment seems to dominate over previously reported actions of high blood pressure and cholesterol to enhance leukocyte Angiotensin II AT1 receptor expression.

Sympathetic hyperactivity in hypertensive chronic kidney disease patients is reduced during standard treatment.

Standard treatment in chronic kidney disease (CKD) patients includes an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker. CKD is often characterized by sympathetic hyperactivity. This study investigates the prevalence of sympathetic hyperactivity (quantified by assessment of muscle sympathetic nerve activity [MSNA]) in a sizable group of patients with CKD and assessed whether chronic angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker normalizes increased MSNA. In 74 CKD patients (creatinine clearance 54+/-31 mL/min), MSNA, blood pressure, and plasma renin activity were measured in the absence of antihypertensive drugs except for diuretics. In a subgroup of 31 patients, another set of measurements was obtained after > or =6 weeks of enalapril (10 mg PO), losartan (100 mg PO), or eprosartan (600 mg PO). Patients as compared with control subjects (n=82) had higher mean arterial pressure (113+/-13 versus 89+/-7 mm Hg), MSNA (31+/-13 versus 19+/-7 bursts per minute), and log plasma renin activity (2.67+/-036 versus 2.40+/-0.32 fmol/L per second; all P<0.001). During angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker therapy (n=31), mean arterial pressure (115+/-11 to 100+/-9 mm Hg) and MSNA (33+/-11 to 25+/-9 bursts per minute) decreased (both P<0.01) but were still higher than in control subjects (both P<0.01). Multiple regression analysis identified age and plasma renin activity as predictive for MSNA. In conclusion, sympathetic hyperactivity occurs in a substantial proportion of hypertensive CKD patients. Angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker treatment reduces but does not normalize MSNA.

Moxonidine normalizes sympathetic hyperactivity in patients with eprosartan-treated chronic renal failure.

Enalapril and losartan reduce but not normalize sympathetic hyperactivity in patients with hypertensive chronic renal failure (CRF). This study assessed the effect of chronic eprosartan on BP and sympathetic activity, and assessed the effect of moxonidine during chronic eprosartan treatment. In 11 stable patients with CRF (creatinine clearance 47 +/- 10 ml/min), muscle sympathetic nerve activity (MSNA; peroneal nerve), BP, and baroreceptor sensitivity were measured in the absence of antihypertensive drugs (except diuretics) during chronic eprosartan therapy (600 mg for 6 wk) and in 9 patients after moxonidine (0.2 mg for 6 wk) was added. Normovolemia was controlled by diuretics and confirmed by extracellular fluid volume measurements. BP, heart rate, and MSNA were higher in patients than in 22 controls. During eprosartan therapy, mean arterial pressure (111 +/- 9 to 98 +/- 7 mmHg, P < 0.001), heart rate (71 +/- 10 to 65 +/- 8 bpm, P < 0.001), and MSNA (35 +/- 10 to 27 +/- 8 bursts/min, P < 0.001) decreased. After the addition of moxonidine (n = 9), a further reduction of mean arterial pressure to 89 +/- 7 mmHg (P < 0.05) and of MSNA to 20 +/- 10 bursts/min (P < 0.05) occurred. Sympathetic activity in patients with CRF can be normalized, and angiotensin II-independent sympathetic hyperactivity contributes to the pathogenesis of renal hypertension. Sympathetic hyperactivity is associated with poor cardiovascular outcomes, implying that reduction might be beneficial to the patients. The addition of moxonidine to angiotensin II antagonist treatment might be appropriate.

Sympathetic hyperactivity in chronic kidney disease: pathogenesis, clinical relevance, and treatment.

Cardiovascular morbidity and mortality importantly influence live expectancy of patients with chronic renal disease (CKD). Traditional risk factors are usually present, but several other factors have recently been identified. There is now evidence that CKD is often characterized by an activated sympathetic nervous system. This may contribute to the pathogenesis of renal hypertension, but it may also adversely affect prognosis independently of its effect on blood pressure. The purpose of this review is to summarize available knowledge on the role of the sympathetic nervous system in the pathogenesis of renal hypertension, its clinical relevance, and the consequences of this knowledge for the choice of treatment.

Pathogenesis and treatment of hypertension in polycystic kidney disease.

PURPOSE OF REVIEW: Hypertension is common in patients with autosomal dominant polycystic kidney disease. It may contribute to cardiovascular risk and to progression of renal failure. RECENT FINDINGS: Apart from fluid overload and renin activation, hypertensive patients with autosomal dominant polycystic kidney disease also have increased sympathetic activity, regardless of renal function. Sympathetic hyperactivity not only contributes to the hypertension but may also increase cardiovascular risk independent of blood pressure. SUMMARY: Treatment for normalizing blood pressure and sympathetic activity should be started early in the course of the disease.

Sympathetic nerve activity is inappropriately increased in chronic renal disease.

The hypothesis that in hypertensive patients with renal parenchymal disease sympathetic activity is "inappropriately" elevated and that this overactivity is a feature of renal disease and not of a reduced number of nephrons per se is addressed. Fifty seven patients with renal disease (various causes, no diabetes, all on antihypertensive medication) were studied, age range 18 to 62, creatinine clearance 10 to 114 ml/min per 1.73 m(2). Antihypertensives were stopped, but diuretics were allowed, to prevent overhydration. Matched control subjects were also studied. The effect of changes in fluid status was examined in seven patients while on and after stopping diuretics and in eight control subjects while on low- and high-sodium diet. Seven kidney donors were studied before and after unilateral nephrectomy. Sympathetic activity was quantified as muscle sympathetic nerve activity (MSNA) in the peroneal nerve. Mean arterial pressure, MSNA, and plasma renin activity were higher in patients than in control subjects, respectively (115 +/- 12 and 88 +/- 11 mmHg, 31 +/- 15 and 18 +/- 10 bursts/min, and 500 [20 to 6940] and 220 [40 to 980] fmol/L per s; P < 0.01 for all items). Extracellular fluid volume (bromide distribution) did not differ. Seven patients were studied again after stopping diuretics. MSNA decreased from 34 +/- 18 to 19 +/- 18 bursts/min (P < 0.01). Eight healthy subjects were studied during low- and high-sodium diet. MSNA was 26 +/- 12 and 13 +/- 7 bursts/min (P < 0.01). The curves relating extracellular fluid volume to MSNA were parallel in the two groups but shifted to a higher level of MSNA in the patients. In the kidney donors, creatinine clearance reduced by 25%, but MSNA was identical before and after donation. It is concluded that in hypertensive patients with renal parenchymal disease, sympathetic activity is inappropriately high for the volume status and that reduction of nephron number in itself does not influence sympathetic activity.