Sympathetic Nerve Activity Is Inappropriately Increased in Chronic Renal Disease INGE H.H.T. KLEIN,* GERRY LIGTENBERG,* JUTTA NEUMANN,* P. LIAM OEY, † HEIN A. KOOMANS,* and PETER J. BLANKESTIJN* Departments of *Nephrology and † Clinical Neurophysiology, University Medical Center Utrecht, The Netherlands Abstract. The hypothesis that in hypertensive patients with renal parenchymal disease sympathetic activity is “inappropri- ately” 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 di- uretics were allowed, to prevent overhydration. Matched con- trol 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 be- fore 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 par- allel 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 inappropri- ately high for the volume status and that reduction of nephron number in itself does not influence sympathetic activity. Hypertension is common in chronic renal disease. Its preva- lence varies between 30 and 100% depending on the target population, cause of renal disease, and level of renal function (1,2). Volume overload and activation of the renin system have long been recognized as main pathogenetic players. There is some indication that sympathetic nervous activity is also involved. Experimental data have indicated that the pres- ence of parenchymal injury results in neurogenic hypertension (3). Muscle sympathetic nerve activity (MSNA) is increased in both dialysis and predialysis patients, whereas bilaterally ne- phrectomized patients have MSNA identical to control subjects (4 – 6). Recently, we reported that MSNA is increased in hy- pertensive patients with polycystic kidney disease and still normal kidney function (7). Thus, the available data indicate that renal parenchymal changes can cause sympathetic hyper- activity. Sympathetic activity increases with age (7–9) and is feedback-regulated by baroreflex control and volume status (10). In patients with chronic renal disease, volume status may vary substantially. Therefore, it is critical that this be taken into account when assessing sympathetic activity in individual patients. The overall hypothesis for the present studies was that sympathetic activity is “inappropriately” increased in patients with renal parenchymal disease. In view of the above men- tioned, the specific aims were (1) to establish that sympathetic activity is increased in relation to the volume status of these patients and (2) to establish that sympathetic hyperactivity is a feature of chronic renal disease and not of reduced number of nephrons but intact parenchymal structure. Materials and Methods Subjects Patients with hypertension (i.e., using antihypertensive drugs and/or BP 140/90 mmHg when off medication) and with chronic renal disease (creatinine clearance 10 ml/min and stable in the last 3 mo) could enter the study. Patients with clinically manifest heart disease (congestive heart failure, ischemic heart disease, or atrial fibrillation) or diabetes or patients who were on steroids were ex- cluded. Renal disease was diagnosed by ultrasound studies (in case of polycystic kidney disease), intravenous urograms, or kidney biopsy. Healthy control subjects were matched for age, gender, and body mass index. Kidney donors were studied before and after unilateral ne- Received July 1, 2003. Accepted September 13, 2003. Correspondence to Dr. Peter J. Blankestijn, Department of Nephrology, Room F03.226, University Medical Center, P.O. Box 85500, 3508 GA Utrecht, The Netherlands. Phone: +31-30-2507336; Fax: +31-30-2543492; E-mail: p.j.blankestijn@azu.nl 1046-6673/1412-3239 Journal of the American Society of Nephrology Copyright © 2003 by the American Society of Nephrology DOI: 10.1097/01.ASN.0000098687.01005.A5 J Am Soc Nephrol 14: 3239–3244, 2003