Published online before print February 25, 2002, doi: 10.1161/hc1102.105261
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(Circulation. 2002;105:1354.)
© 2002 American Heart Association, Inc.
Plasma Norepinephrine Predicts Survival and Incident Cardiovascular Events in Patients With End-Stage Renal Disease
From CNR (C.Z., F.M., S.P., S.C., G.T.), Centre of Clinical Physiology and Division of Nephrology, Reggio Calabria, Italy; Division of Cardiology (F.A.B.), Morelli Hospital, Reggio Calabria, Italy; and Institute of Internal Medicine (A.C., L.S.M.), Geriatrics (G.S., B.S.), and Nephrosurgery (G.B., F.R., P.F.), University of Catania, Italy.
Reprint requests to Prof Carmine Zoccali, CNR Centro Fisiologia Clinica, Via Sbarre Inferiori 39, Reggio Cal, 89131 Italy. E-mail carmine.zoccali{at}tin.it
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Abstract |
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Background— Sympathetic tone is consistently raised in patients with end-stage renal disease (ESRD). We therefore tested the hypothesis that sympathetic activation is associated with mortality and cardiovascular events in a cohort of 228 patients undergoing chronic hemodialysis who did not have congestive heart failure at baseline and who had left ventricular ejection fraction >35%.
Methods and Results— The plasma concentration of norepinephrine (NE) was used as a measure of sympathetic activity. Plasma NE exceeded the upper limit of the normal range (cutoff 3.54 nmol/L) in 102 dialysis patients (45%). In a multivariate Cox regression model that included all univariate predictors of death as well as the use of sympathicoplegic agents and ß-blockers, plasma NE proved to be an independent predictor of this outcome (hazard ratio [1-nmol/L increase in plasma NE]: 1.07, 95% CI 1.01 to 1.14, P=0.03). Similarly, plasma NE emerged as an independent predictor of fatal and nonfatal cardiovascular events (hazard ratio [1-nmol/L increase in plasma NE] 1.08, 95% CI 1.02 to 1.15, P=0.01) in a model that included previous cardiovascular events, pulse pressure, age, diabetes, smoking, and use of sympathicoplegic agents and ß-blockers. The adjusted relative risk for cardiovascular complications in patients with plasma NE >75th percentile was 1.92 (95% CI 1.20 to 3.07) times higher than in those below this threshold (P=0.006).
Conclusions— Sympathetic nerve overactivity is associated with mortality and cardiovascular outcomes in ESRD. Controlled trials with antiadrenergic drugs are needed to determine whether interference with the sympathetic system could reduce the high cardiovascular morbidity and mortality in dialysis patients.
Key Words: nervous system, sympathetic • norepinephrine • kidney • risk factors • nervous system, autonomic
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Introduction |
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Raised sympathetic activity is now recognized as an important mechanism involved in cardiovascular complications in humans.1 Increased sympathetic activity helps raise arterial pressure, triggers arterial damage, and represents a major player in the pathogenesis of left ventricular hypertrophy. There is consistent evidence that high sympathetic tone, as measured by plasma norepinephrine (NE), predicts mortality in cardiovascular diseases such as asymptomatic left ventricular dysfunction2 and chronic congestive heart failure,3 whereas in myocardial infarction, this neurohormone is a weak predictor of adverse outcomes.4 It is unclear whether measurements of sympathetic nervous activity are associated with long-term adverse cardiovascular outcomes in chronic diseases like hypertension, diabetes, and renal failure. In theory, the measurement of sympathetic activity in these diseases may help to refine the prognosis and may be useful for patient stratification in intervention studies aimed at reducing cardiovascular complications.
The study of the relationship between sympathetic activity, survival, and incidence of cardiovascular events in end-stage renal disease (ESRD) appears to be a desirable research goal, because the high cardiovascular mortality in these patients is incompletely accounted for by traditional risk factors. Sympathetic activity is increased in patients with mild to moderate5 or end-stage renal insufficiency,6 and there is now evidence that the diseased kidneys themselves are a trigger of sympathetic overactivity.6–8 With this background in mind, we set out to study the predictive power of plasma NE for all-cause mortality and cardiovascular outcomes in a large cohort of patients without heart failure who were undergoing chronic hemodialysis.
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Methods |
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The protocol conformed to the ethical guidelines of our institutions, and informed consent was obtained from each participant.
Study Cohort
Two hundred twenty-eight hemodialysis patients (126 men and 102 women) who had been undergoing regular dialysis treatment for at least 6 months (median duration of regular dialysis treatment 43 months, interquartile range 21 to 110 months) were enrolled into the study. These patients represented 70% of the dialysis population of 4 dialysis units (a Clinical Research Center, an academic unit, and 2 affiliated centers). Enrollment into the study began in January 1997 and terminated in June 1998. Reasons for exclusion were history or clinical evidence of circulatory congestion (defined as dyspnea in addition to 2 of the following conditions: raised jugular pressure, bibasilar crackles, pulmonary venous hypertension, or interstitial edema on chest radiograph that required hospitalization or extra ultrafiltration9) and left ventricular ejection fraction <35%, intercurrent illnesses requiring hospitalization, terminal illnesses, and dementia, and in a minority (10%) of patients, unwillingness to participate or logistical reasons. Patients were being treated thrice weekly with standard bicarbonate dialysis (Na 138 mmol/L, HCO3 35 mmol/L, K 1.5 mmol/L, Ca 1.25 mmol/L, Mg 0.75 mmol/L) and cuprophan or semisynthetic membranes (dialysis filter surface area 1.1 to 1.7 m2). Dry weight was targeted in each case to achieve a normotensive edema-free state. The average urea Kt/V in these patients was 1.21±0.27. Eighty-five patients were habitual smokers (21±16 cigarettes/d). One hundred twenty-three patients were undergoing treatment with erythropoietin, and 83 were undergoing antihypertensive therapy (58 taking monotherapy with ACE inhibitors, angiotensin II type 1 receptor antagonists, calcium channel blockers, ß-blockers, or central sympathicoplegic agents and 25 undergoing double or triple therapy with various combinations of these drugs). Seventeen of the 83 patients taking antihypertensive drugs were being treated with central sympathicoplegic agents (clonidine, n=14; 
-methyldopa, n=3) and 18 were taking ß-blockers. After the initial assessment, patients were followed up for 34±15 months. During the follow-up, cardiovascular events (ECG-documented anginal episodes, myocardial infarction, heart failure, arrhythmia, transient ischemic attacks, stroke, and other complications; see Table 2) and death were accurately recorded. Each death was reviewed and assigned an underlying cause by a panel of 5 physicians. As part of the review process, all available medical information about each death was collected. This information always included study and hospitalization records. In the case of an out-of-hospital death, family members were interviewed by telephone to better ascertain the circumstances surrounding death.
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Blood Pressure Measurements
Blood pressure was estimated by averaging all predialysis arterial pressure recordings during the month before the study (total of 12 measurements; ie, 3/wk). Average predialysis arterial pressure in dialysis patients is closely related to 24-hour ambulatory blood pressure monitoring and is related to left ventricular mass at least as strongly as 24-hour ambulatory blood pressure monitoring.10
Laboratory Measurements
Blood sampling was performed between 8 and 10 AM after an overnight fast, always during a nondialysis day. After the patient had spent 20 to 30 minutes of quiet rest in a semirecumbent position, samples were taken into chilled EDTA evacuated containers, placed immediately on ice, and centrifuged within 30 minutes at -4°C, and the plasma was stored at -80°C before assay. The plasma concentration of NE was measured by a commercially available radioimmunoassay kit (Amicyl test, Immunological Laboratories). The intra-assay coefficient of variation was 7% to 15%. The upper limit of the normal range of plasma NE in our laboratory is 3.54 nmol/L, which is very close to the value (3.38 nmol/L) reported in a previous study.11
Albumin (Bromcresol Green), calcium and phosphate, cholesterol, and hemoglobin measurements were made by standard methods in the clinical laboratory. Plasma homocysteine was determined by a high-performance liquid chromatography method.12 C-reactive protein was measured with a commercially available kit (Behring, Scoppito).
Statistical Analysis
Data are reported as mean±SD (normally distributed data) or as median and interquartile range (data which deviated from the normal distribution). Comparisons between groups were made by t test or Mann-Whitney test as appropriate. Survival curves were estimated by the Kaplan-Meier product-limit method and compared with the Mantel (log-rank) test. For patients who experienced multiple events, survival analysis was restricted to the first event. The independent prognostic power of plasma NE for all-cause mortality and cardiovascular events (fatal and nonfatal) was analyzed by the Cox proportional hazards method by introduction of all covariates that were related to all-cause mortality or cardiovascular outcome on univariate analysis. Tested covariates included traditional risk factors (previous cardiovascular events, age, sex, arterial pressure, diabetes, cholesterol, and smoking), risk factors peculiar to ESRD (hemoglobin, calcium-phosphate product, and serum albumin), and nontraditional cardiovascular risk factors (C-reactive protein and homocysteine). Because sympathicoplegic agents and ß-blockers may interfere with sympathetic activity, we always forced into the Cox models the use of these drugs. The assumption of linearity for the Cox models was examined through visual inspection, and no violation of proportional hazards was found. Hazard ratios and their 95% CIs were calculated with the estimated regression coefficients and their standard errors in the Cox regression analysis. All calculations were made with a standard statistical package (SPSS for Windows version 9.0.1). All Cox proportional hazard models were of adequate statistical power (at least 9 events for each covariate in the model).
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Results |
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The main demographic and clinical characteristics of the study population are detailed in Table 1. The prevalence of diabetes mellitus in this cohort was 15% (ie, 35 of 228 patients). Eight-four patients had a history of ECG-documented anginal episodes or myocardial infarction, and 33 had experienced transient ischemic attacks or strokes.
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Median plasma NE was 2.92 nmol/L (interquartile range 1.72 to 5.57 nmol/L), and individual plasma NE exceeded the upper limit of the normal range (cutoff 3.54 nmol/L) in 102 cases (45%). No relationship was found between plasma NE and Kt/V (P=0.31) and serum creatinine (P=0.47).
NE, All-Cause Mortality, and Cardiovascular Outcomes
During the follow-up period (34±15 months), 124 fatal and nonfatal cardiovascular events occurred in 85 patients. Eighty-seven patients died; 57 deaths (ie, 66% of all deaths) were attributable to cardiovascular causes (Table 2). Plasma NE was significantly higher (P=0.04) in patients who died during follow-up (3.97 nmol/L, range 1.76 to 7.06 nmol/L) than in those who survived (2.70 nmol/L, range 1.68 to 4.63 nmol/L). Similarly, plasma NE was higher (P=0.03) in patients with incident cardiovascular events (3.99 nmol/L, range 1.88 to 6.69 nmol/L) than in those who did not have such events (2.70 nmol/L, range 1.66 to 4.63 nmol/L). Event-free survival curves in patients subdivided on the basis of the 75th percentile of plasma NE are reported in the Figure. Cumulative mortality and cumulative cardiovascular events in patients with values above this threshold were consistently higher than in those showing values below this threshold.
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Cox Proportional Hazards Models
On univariate Cox regression analysis, plasma NE (hazard ratio [1-nmol/L increase in plasma NE] 1.10, 95% CI 1.04 to 1.17, P=0.001) as a continuous variable was significantly related to all-cause mortality. In addition, age (P<0.001), male sex (P=0.02), diabetes (P=0.002), previous cardiovascular events (P<0.001), serum albumin (P=0.006), and C-reactive protein (P=0.01) were associated with death. In a multivariate Cox regression model that included all univariate predictors of survival and the use of sympathicoplegic agents and ß-blockers, plasma NE proved to be an independent predictor of this outcome (Table 3).
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Similarly, on univariate Cox regression analysis, plasma NE (hazard ratio [1-nmol/L increase in plasma NE] 1.09, 95% CI 1.02 to 1.15, P=0.006), age (P<0.001), diabetes (P=0.005), previous cardiovascular events (P<0.001), pulse pressure (P<0.001), and smoking (P=0.03) were significantly associated with fatal and nonfatal cardiovascular events, and plasma NE again emerged as an independent predictor of cardiovascular outcomes in a multivariate Cox regression model that included these covariates and the use of sympathicoplegic agents and ß-blockers (Table 4). The adjusted relative risk for cardiovascular complications in patients with plasma NE >75th percentile was 1.92 (95% CI 1.20 to 3.07) times higher than in those with normal NE concentration (P=0.006).
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Discussion |
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This study shows for the first time that sympathetic activity as assessed by the measurement of plasma NE is an independent predictor of all-cause mortality and cardiovascular morbid events in patients with ESRD without heart failure.
Sympathetic Activity in ESRD
Plasma NE measurement represents a useful guide to assess sympathetic neural activity. However, the amount of NE in the plasma is only a fraction of the amount released into the synaptic clefts and may be influenced by several factors, such as the rate of reuptake into the nerve endings or into extraneuronal cells, the density of neuroeffector junctions, and the metabolic clearance rate. Measurement of plasma catecholamines as an indicator of sympathetic neural activity demands caution in ESRD because of the complex metabolic alterations that are present in these patients. Plasma NE concentration in ESRD patients undergoing dialysis has been reported to be high13–21 or normal.22–24 Sympathetic microneurography is presently the golden standard for measuring sympathetic activity.25 In the sole study in which sympathetic activity was assessed by this technique, sympathetic nerve discharge was substantially higher in patients with ESRD than in healthy subjects.6
Although less reliable than sympathetic microneurography, the measurement of plasma NE is regarded as an adequate method to estimate sympathetic activity in prognostic studies.2 We found that plasma NE level was frankly elevated in a substantial proportion of patients, which confirms that sympathetic tone is markedly raised in ESRD. We enrolled the population without symptoms of heart failure or intercurrent illnesses from 4 dialysis units that shared common policies and clinical practices. Thus, our cohort represented a valid sample of the dialysis population without advanced cardiac complications.
NE, Survival, and Cardiovascular Outcomes
Approximately one third of patients enrolled in the present study had 1 or more cardiovascular complications. The annual death rate was 12.5%, which is similar to that of the Italian registry of dialysis and transplantation and of other European registries,26 and during the follow-up, as many as 66% of patients died of cardiovascular causes. The incidence of stroke in the present cohort was higher than that reported in the United States Renal Data System,27 and this difference should be taken into account when generalizing the results of the present study. Such high cardiovascular morbidity and mortality in large part depends on the fact that atherosclerosis and diabetes, ie, the major causes of ESRD, are risk factors for the cardiovascular system and the kidney as well. However, traditional (ie, Framingham) risk factors do not fully explain the exceedingly high cardiovascular mortality of these patients.28 Anemia, hyperhomocysteinemia, inflammation, malnutrition and hypoalbuminemia, and hyperphosphatemia28–30 have now emerged as primary cardiovascular risk factors in patients with advanced renal disease. The need for observational studies to better characterize the risk profile of dialysis patients and to identify new risk factors has been set recently as a research priority by an expert panel of the National Kidney Foundation in the United States.31
Sympathetic factors are involved in the progression of cardiovascular structural alterations such as left ventricular hypertrophy and arterial remodeling,1 and high sympathetic activity may promote atherosclerosis.32 The importance of high sympathetic tone in cardiovascular complications has a solid scientific basis that is also supported by intervention studies.33 We found by multiple forms of analysis that NE was associated with death and cardiovascular outcomes. Importantly, the relationship between this marker of sympathetic activity and outcomes remained significant on multivariate analysis that controlled for other significant risk factors, including previous cardiovascular complications, as well as use of sympathicoplegic agents and ß-blockers. Plasma NE concentration above the 75th percentile of the distribution in the present study population was associated with a 92% excess risk for cardiovascular complications. This risk is of an order of magnitude similar to that conveyed by a 1-g/L increase in the serum concentration of fibrinogen or that associated with a 20-mm Hg increase in diastolic pressure.29 However, measurement of plasma NE is a much less reproducible marker of sympathetic function than direct sympathetic nerve discharge measurement.25 Therefore, due to regression dilution bias,34 plasma NE may substantially underestimate the true link between sympathetic activity and cardiovascular risk in dialysis patients.
Factors responsible for sympathetic activation in ESRD are still incompletely understood, and augmented sympathetic activity in dialysis patients may depend, at least in part, on compromised cardiac function. Although we cannot exclude that mild degrees of asymptomatic left ventricular dysfunction might have contributed to raised plasma NE in our patients, it is unlikely that this factor is a major component, because we excluded from the study patients with EF <35% and those with clinical evidence of congestive heart failure. The cardiovascular risk associated with plasma NE that we observed in ESRD was less than that reported in the SOLVD (Studies of Left Ventricular Dysfunction) trial2 in patients with asymptomatic heart failure. It appears likely but remains to be proved that in the dialysis population as a whole, the risk conveyed by sympathetic activation is much higher than that demonstrated from the present study, because clinical manifestations of congestive heart failure and systolic dysfunction are present in 
30% of patients.35
High NE predicts cardiovascular complications in ESRD. Increased sympathetic nerve traffic and circulating catecholamines might render uremic patients susceptible to a series of cardiovascular complications ranging from left ventricular hypertrophy to arrhythmia.36 Controlled trials with antiadrenergic drugs are needed to establish whether interference with the sympathetic system reduces the high cardiovascular morbidity and mortality of dialysis patients.
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Acknowledgments |
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This study was supported in part by a grant from the Regional Health Authority of Calabria (Fondi finalizzati per l’insufficienza renale cronica Regione Calabria, 1997). We are grateful to Dr Isabella Fermo (S. Raffaele Hospital, Milan) for the measurement of plasma total homocysteine concentration. The Cardiovascular Risk Extended Evaluation in Dialysis (CREED) Investigators are as follows: Giuseppe Enia, MD, Vincenzo Panuccio, MD, Rocco Tripepi, Technician, Carmela Marino, Technician, Vincenzo Candela, MD, Carlo Labate, MD, Filippo Tassone, MD.
Received November 9, 2001; revision received January 7, 2002; accepted January 7, 2002.
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C. Zoccali, F. Mallamaci, F. A. Benedetto, G. Tripepi, P. Pizzini, S. Cutrupi, and L. Malatino Urotensin II and Cardiomyopathy in End-Stage Renal Disease Hypertension, February 1, 2008; 51(2): 326 - 333. [Abstract] [Full Text] [PDF]
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S. Genovesi, O. Bracchi, P. Fabbrini, E. Luisetto, M. R. Vigano, D. Lucini, M. Malacarne, A. Stella, and M. Pagani Differences in heart rate variability during haemodialysis and haemofiltration Nephrol. Dial. Transplant., August 1, 2007; 22(8): 2256 - 2262. [Abstract] [Full Text] [PDF]
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 P. J. Blankestijn SYMPATHETIC HYPERACTIVITY--A HIDDEN ENEMY IN CHRONIC KIDNEY DISEASE PATIENTS Perit. Dial. Int., June 1, 2007; 27(Supplement_2): S293 - S297. [Abstract] [Full Text] [PDF]
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M. P. Schlaich, E. A. Lambert, P. A. Sobotka, G. W. Lambert, and M. D. Esler Sympathetic Hyperactivity in Hypertensive Chronic Kidney Disease Patients Is Reduced During Standard Treatment Hypertension, May 1, 2007; 49(5): e27 - e27. [Full Text] [PDF]
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J. Neumann, G. Ligtenberg, I. H.T. Klein, P. Boer, P. L. Oey, H. A. Koomans, and P. J. Blankestijn Sympathetic Hyperactivity in Hypertensive Chronic Kidney Disease Patients Is Reduced During Standard Treatment Hypertension, March 1, 2007; 49(3): 506 - 510. [Abstract] [Full Text] [PDF]
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 C. Otte, T. C. Neylan, S. S. Pipkin, W. S. Browner, and M. A. Whooley Depressive Symptoms and 24-Hour Urinary Norepinephrine Excretion Levels in Patients With Coronary Disease: Findings From the Heart and Soul Study Am J Psychiatry, November 1, 2005; 162(11): 2139 - 2145. [Abstract] [Full Text] [PDF]
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J. Neumann, G. Ligtenberg, L. Oey, H. A. Koomans, and P. J. Blankestijn Moxonidine Normalizes Sympathetic Hyperactivity in Patients with Eprosartan-Treated Chronic Renal Failure J. Am. Soc. Nephrol., November 1, 2004; 15(11): 2902 - 2907. [Abstract] [Full Text] [PDF]
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P. J. Blankestijn Sympathetic hyperactivity in chronic kidney disease Nephrol. Dial. Transplant., June 1, 2004; 19(6): 1354 - 1357. [Full Text] [PDF]
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F. Mallamaci, G. Tripepi, R. Maas, L. Malatino, R. Boger, and C. Zoccali Analysis of the Relationship between Norepinephrine and Asymmetric Dimethyl Arginine Levels among Patients with End-Stage Renal Disease J. Am. Soc. Nephrol., February 1, 2004; 15(2): 435 - 441. [Abstract] [Full Text] [PDF]
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C. Zoccali, F. Mallamaci, and G. Tripepi Novel Cardiovascular Risk Factors in End-Stage Renal Disease J. Am. Soc. Nephrol., January 1, 2004; 15(90010): S77 - 80. [Abstract] [Full Text]
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I. H.H.T. Klein, G. Ligtenberg, J. Neumann, P. L. Oey, H. A. Koomans, and P. J. Blankestijn Sympathetic Nerve Activity Is Inappropriately Increased in Chronic Renal Disease J. Am. Soc. Nephrol., December 1, 2003; 14(12): 3239 - 3244. [Abstract] [Full Text] [PDF]
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C. T. Chan, P. J. Harvey, P. Picton, A. Pierratos, J. A. Miller, and J. S. Floras Short-Term Blood Pressure, Noradrenergic, and Vascular Effects of Nocturnal Home Hemodialysis Hypertension, November 1, 2003; 42(5): 925 - 931. [Abstract] [Full Text] [PDF]
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R. Dikow and E. Ritz Cardiovascular complications in the diabetic patient with renal disease: an update in 2003 Nephrol. Dial. Transplant., October 1, 2003; 18(10): 1993 - 1998. [Full Text] [PDF]
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C. Zoccali, F. Mallamaci, G. Tripepi, F. A. Benedetto, S. Parlongo, S. Cutrupi, D. Iellamo, G. Bonanno, F. Rapisarda, P. Fatuzzo, et al. Prospective Study of Neuropeptide Y as an Adverse Cardiovascular Risk Factor in End-Stage Renal Disease J. Am. Soc. Nephrol., October 1, 2003; 14(10): 2611 - 2617. [Abstract] [Full Text] [PDF]
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 J. A L Calbet Chronic hypoxia increases blood pressure and noradrenaline spillover in healthy humans J. Physiol., August 15, 2003; 551(1): 379 - 386. [Abstract] [Full Text] [PDF]
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G. Cice, L. Ferrara, A. D'Andrea, S. D'Isa, A. Di Benedetto, A. Cittadini, P. E. Russo, P. Golino, and R. Calabro Carvedilol increases two-year survivalin dialysis patients with dilated cardiomyopathy: A prospective, placebo-controlled trial J. Am. Coll. Cardiol., May 7, 2003; 41(9): 1438 - 1444. [Abstract] [Full Text] [PDF]
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M. Hausberg, M. Kosch, P. Harmelink, M. Barenbrock, H. Hohage, K. Kisters, K. H. Dietl, and K. H. Rahn Sympathetic Nerve Activity in End-Stage Renal Disease Circulation, October 8, 2002; 106(15): 1974 - 1979. [Abstract] [Full Text] [PDF]
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C. Zoccali, F. Mallamaci, G. Tripepi, S. Parlongo, S. Cutrupi, F. A. Benedetto, A. Cataliotti, and L. S. Malatino Norepinephrine and Concentric Hypertrophy in Patients With End-Stage Renal Disease Hypertension, July 1, 2002; 40(1): 41 - 46. [Abstract] [Full Text] [PDF]
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