ORIGINAL ARTICLES. Revisiting Autonomic Dysfunction in End-Stage Renal Disease Patients

ORIGINAL ARTICLES Revisiting Autonomic Dysfunction in End-Stage Renal Disease Patients Jocemir R. Lugon 1, Elias A. Warrak 1, Adriano S. Lugon 1, Bruno A. Salvador 2, Antonio C. L. Nobrega 2 1 Department of Clinical Medicine and 2 Department of Physiology, Universidade Federal Fluminense, Niterói-RJ, Brazil. Background: Autonomic dysfunction is frequent in endstage renal disease (ESRD) patients, but both the relative involvement of the parasympathetic and sympathetic branches and the role of antihypertensive drugs in this setting are still controversial. The present study addressed these issues employing a battery of standard noninvasive cardiovascular autonomic tests. Methods: Sympathetic (S) function was evaluated by responses of both systolic blood pressure (BP) to passive tilting and diastolic BP to handgrip; parasympathetic (P) function, through the respiratory sinus arrhythmia test and the heart rate response to the 4-s unloaded exercise test. Additional tests influenced by both branches of the autonomic system (P þ S) were accomplished by the assessment of heart rate response to the Valsalva maneuver, handgrip, and tilting. Results: Studied subjects belonged to one of the three groups: not requiring BP medications (n ¼ 11; 8 men, 3 women); receiving antihypertensive therapy (n ¼ 36; 21 men, 15 women); and apparently healthy controls (n ¼ 15; 10 men, 5 women). When the variables grouped according to the branch of the autonomic nervous system predominantly probed were analyzed, only the frequency of impaired sympathetic autonomic responses was higher in compared to controls (55 vs. 23%, P ¼ 0.040). In contrast, when receiving were compared to controls, the differences became significant in S, P, and P þ S tests (46 vs. 23%, P ¼ 0.045; 22 vs. 3%, Correspondence to: Jocemir R. Lugon, R. Haddock Lobo 369/309, 20260-131 Tijuca Rio de Janeiro-RJ, Brazil. email: jocerl@hospital.huap.uff.br This study was presented at ASN/ISN World Congress of Nephrology, San Francisco, California, USA, October 2001. P ¼ 0.020; and 34 vs. 13%, P ¼ 0.010, respectively). With the criterion of more than one positive finding in any of the variables examined for diagnosing autonomic dysfunction, the prevalence of autonomic dysfunction was 20% in controls, 64% in (P ¼ 0.005 vs. controls), and 67% in receiving (P ¼ 0.043 vs. controls). Conclusions: ESRD continues to be associated with a high prevalence of autonomic dysfunction. receiving were found to have detectable impairment in the entire autonomic system in contrast to those in whom inadequate responses were restricted to the sympathetic branch. Hemodial Int. 2003; 7(3):198 203. Key words Hemodialysis, end-stage renal disease, autonomic dysfunction, blood pressure drugs Introduction Autonomic dysfunction is known to be common in endstage renal disease (ESRD) patients [1 3] and may contribute to dialysis-related hypotensive episodes [4,5]. Moreover, autonomic dysfunction has also been associated with other fatal and nonfatal cardiovascularevents[6,7]. In the past decades the treatment offered to ESRD patients undergoing maintenance hemodialysis has improved substantially. Anemia is now better controlled [8]. Side effects of the new-generation blood pressure (BP) drugs are less prominent. Modern machinery is provided with devices that yield precise ultrafiltration control. Available membranes are more biocompatible and efficient with higher permeability to both water and solutes [9]. These changes were accompanied by a focus on the dialysis prescription and adequacy of dialysis dose, resulting in an increase of survival and better 198

Hemodialysis International, Vol. 7, No. 3, 2003 quality of life [10]. Whether these advances have influenced the prevalence of autonomic dysfunction is uncertain, and the relative importance of parasympathetic and sympathetic branches and the role of antihypertensive drugs in autonomic dysfunction in dialysis patients are still controversial. Sympathetic and parasympathetic systems play complementary roles in the regulation of the cardiovascular system. The extent of influence of ESRD on each branch of the system may not be equivalent and may result in different patterns of autonomic dysfunction. Moreover, antihypertensive drugs may reflexively inhibit or activate the sympathetic and/or the parasympathetic systems modifying the autonomic regulation. Accordingly, the present study was designed to address these issues employing standard noninvasive cardiovascular autonomic tests. Methods Patients with ESRD were recruited from three dialysis centers in Rio de Janeiro, Brazil. Informed consent was obtained and the protocol approved by the ethical committee of the Medical School. Chronic medications, including those for blood pressure control, were continued during the study. All who were determined by the investigators to be capable of performing the battery of tests who did not have any of the exclusion criteria were enrolled. To qualify, patients had to be receiving dialysis for at least 6 months and had to be 18 to 70 years old. Patients with diabetes mellitus, Hansen s disease, and amyloidosis or presenting for examination with systolic BP 190 mm Hg and/or diastolic BP 120 mm Hg were excluded. Patients were treated using dialysis machines equipped with a programmable ultrafiltration control device (Model 2008S or 4008B, Fresenius Medical Care AG, Bad Homburg, Germany). The dialysis program consisted of three sessions of 3.5- to 4.5-hr duration per week, blood flow of 350 450 ml/min, bicarbonatebuffered dialysate ([Ca 2þ ], 3.5 meq/l) at 500 ml/min, and low-flow hollow-fiber dialyzers. Reverse osmosis was used to provide water treatment. The autonomic tests were carried out on a nondialysis day. A paired control group of healthy volunteers recruited among medical doctors, students, and laboratory personnel was also examined. Subjects were instructed to refrain from smoking and drinking coffee for at least 2 hr before the tests. Once in the laboratory they received a full explanation about the procedures and purpose of the study and underwent a clinical examination that included resting blood pressure determination. They were allowed to practice the techniques of the tests for 10 min and to rest thereafter for 15 min. An additional rest period of 5 min in the supine position was requested before beginning the tests. During evaluations, heart rate was Lugon et al. continuously monitored by telemetry (Polar Vantage, Electric Oy, Finland) and the BP was measured with a calibrated aneroid sphygmomanometer. Sympathetic evaluation Passive tilting and change in systolic BP (reference value [RV] 10 mm Hg). After 5 min in the supine position, the subjects were passively tilted over 20 s to 70 using a manual-driven table. The systolic BP was measured every 30 s for 5 min. Static handgrip and change in diastolic BP (RV 3 25 mm Hg). In the sitting position, the maximal voluntary contraction (MVC) of the dominant hand was determined as the peak force achieved in three attempts. The subjects were then asked to sustain 30% of MVC as long as possible. The diastolic BP was measured every 30 s throughout the sustained contraction. Parasympathetic evaluation Respiratory sinus arrhythmia (RV 1.1). The subject was oriented to perform two controlled 12-s-long respiratory cycles (6 s for inspiration and expiration) with maximal changes in pulmonary volumes (from residual volume to total lung capacity). The heart rate response was measured by the ratio between the longest R-R interval during expiration and the shortest one during inspiration. Four-second exercise test [11] (RV 1.1). The subject executed a fast unloaded cycling on a cycle ergometer for 4 s, from the fourth to the eighth second, of a 12-s maximal inspiratory apnea. The heart rate response to exercise was measured by the ratio between the last R-R interval immediately before the onset of exercise and the shortest R-R interval during exertion. Combined sympathetic and parasympathetic evaluation Valsalva maneuver (RV 1.20). While seated, subjects were instructed to blow against a closed circuit connected to an aneroid manometer to generate 40 mm Hg for 15 s. The heart rate response was determined by the ratio (Valsalva index) between the longest R-R interval after the maneuver and the shortest one during the expiratory strain. Static handgrip and heart rate response (RV 3 10 bpm). Static handgrip (performed as above) and heart rate response were measured by the difference between the peak value during sustained contraction and the one obtained at rest. Passive tilting and heart rate response (RV 1.1). Passive tilting (performed as above) and heart rate response were assessed by the ratio between the longest R-R interval around the 30th second and the shortest R-R interval around the 15th second starting from the moment the upright position was reached. For statistical analysis the unpaired t test was used to compare independent numeric data and Fisher s Exact 199

Autonomic Dysfunction in ESRD Hemodialysis International, Vol. 7, No. 3, 2003 TABLE I test was used to compare discrete variables. Significance was set at the level of P < 0.05. Results General features of patients and controls. receiving N 15 11 36 Gender (M/F) 10/5 8/3 21/15 Age (years) a 43 10 46 13 44 12 Race (B/W) 7/8 8/3 25/11 Time on dialysis (months) n.a. 42 29 59 37 Primary renal disease Nephrosclerosis n.a. 5 16 Chronic n.a. 1 9 glomerulonephritis Lupus nephropathy n.a. 1 1 APKD n.a. 1 2 Other n.a. 1 5 Unknown n.a. 2 3 a Mean SD. n.a. ¼ not applicable. The first 52 who agreed to participate in the study were enrolled. Complete data were obtained in 47. Fifteen of 17 initially recruited controls accomplished the autonomic test battery. The general features of the patients and controls are presented in Table I. Eleven did not receive BP medications. Groups did not differ in age and distribution of either gender or race. had been receiving dialysis for 59 37 and 42 29 months, respectively (with and without, n.s.). Of those patients receiving treatment for hypertension, 21 were receiving one BP drug, 7 receiving two drugs, 6 receiving three drugs, and 1 receiving four drugs. Drug families were as follows: ACE inhibitor 20, a2-agonist 15, b-blocker 10, calcium channel blocker 6, vasodilator 5, AT-1 antagonist 1, and diuretic 1. Findings regarding the variables that predominantly evaluate the sympathetic branch of the autonomic nervous system are presented in Table II. Inadequate systolic BP responses to passive tilting were seen in 13% of controls, 36% of, and 39% of receiving. Similar inadequate responses of the diastolic BP in the handgrip test occurred in 31, 73, and 53% of controls and the two patient groups, respectively. When data from the two sympathetic tests were pooled, the frequencies of inadequate response in both groups of were found to be statistically higher than in controls (55 vs. 23%, P ¼ 0.040, relative risk [RR] 2.08; 95% CI 1.12 3.88 for ESRD patients ; and 46 vs. 23%, P ¼ 0.045, RR 1.31, 95% CI 1.03 1.66 for receiving ). Data pertaining to the predominant evaluation of the parasympathetic branch of the autonomic nervous system are summarized in Table III. On the respiratory sinus arrhythmia test, values were in the accepted normal range in all of the controls, 82% of not receiving, and 83% of the receiving. When considering the 4-s unloaded exercise test, responses in the normal range were seen in 94, 91, and 72% of subjects, respectively. Again, a statistically significant difference was observed when the two parasympathetic tests were analyzed altogether. Here, the frequency of abnormal responses was higher in ESRD patients receiving when compared to controls (22 vs. 3%, P ¼ 0.020, RR 1.43, 95% CI 1.18 1.73). Results of the three variables influenced by both sympathetic and parasympathetic branches of the autonomic nervous system are presented in Table IV. The tilting index was abnormal in none of the controls, 18% of, and 8% of receiving ; the Valsalva index in 6, 9, and 39%, respectively; and the variation of heart rate on handgrip test in 31, 36, and 56%, respectively. The frequency of impaired responses in the Valsalva test was significantly higher in receiving BP drugs compared to both controls (P ¼ 0.003, RR 2.02, 95% CI 1.31 3.13) and BP drugs (P ¼ 0.013, RR 1.71, 95% CI 1.14 2.56). When TABLE II Frequency (f ) of abnormalities on tests that predominantly evaluate the sympathetic autonomic system a. TABLE III Frequency (f) of abnormalities on tests that predominantly evaluate the parasympathetic autonomic system a. receiving ESRD receiving Change in systolic BP on 2 (13) 4 (36) 14 (39) passive tilting (>10 mm Hg) Change in diastolic BP on 5 (31) 8 (73) 19 (53) handgrip (<25 mm Hg) All 7 (23) 12 (55) b 33 (46) b a Data are presented as f(%). b P < 0.05 vs. controls. Respiratory sinus (0) 2 (18) 6 (17) arrhythmia (<1.10) 4-s unloaded exercise 1 (6) 1 (9) 10 (28) test (<1.10) All 1 (3) 3 (14) 16 (22) b a Data are presented as f(%). b P < 0.05 vs. controls. 200

Hemodialysis International, Vol. 7, No. 3, 2003 TABLE IV Frequency (f) of abnormalities on tests that evaluate both the sympathetic and the parasympathetic autonomic system a. receiving Tilting index (<1.10) (0) 2 (18) 3 (8) Valsalva index (<1.20) 1 (6) 1 (9) 14 (39) b Variation of heart rate 5 (31) 4 (36) 20 (56) on handgrip (<10) All 6 (13) 7 (21) 37 (34) c a Data are presented as f(%). b P< 0.05 vs. controls and ESRD. c P< 0.05 vs. controls. these tests were analyzed as a group, the frequency of inadequate responses in BP drugs was significantly different from controls (34 vs. 13%, P ¼ 0.010, RR 1.33, 95% CI 1.11 1.33). In view of the number of positive findings in the control group, additional analyses were performed in an attempt to discern a combination that would be the most discriminative between and controls (Table V). The finding of more than one positive test in any of the variables examined for diagnosis of autonomic dysfunction was found to be the best predictor of autonomic dysfunction. Using this criterion, controls had impaired autonomic function in 20% of cases, ESRD patients in 64% of cases (P ¼ 0.005 vs. controls, RR 1.78, 95% CI 1.17 2.71), and receiving in 67% of cases (P ¼ 0.043 vs. controls, RR 2.80, 95% CI 1.09 7.17). When both ESRD groups were analyzed together, impaired responses were seen in 66% (P ¼ 0.003 vs. controls, RR 1.60, 95% CI 1.14 2.24). Discussion Autonomic dysfunction has been known to be a frequent abnormality in [1 4] but its role in the high cardiovascular mortality of is still a matter of controversy [12,13]. Some authors have reported a high incidence of cardiac arrhythmias in hemodialysis patients with associated autonomic dysfunction in standard tests, including paroxysmal atrial TABLE V Frequency (f) of cases with one or fewer and more than one altered autonomic test. Inadequate responses not receiving receiving 1 12 (80) 4 (36) 12 (33) >1 3 (20) 7 (64) b 24 (67) b a Data are presented as f (%). b P < 0.05 vs. controls. Lugon et al. fibrillation, ventricular ectopy, and ventricular tachycardia [6]. The importance of baroreceptor sensitivity impairment has been emphasized in the increased risk of death following myocardial infarction [14]. Finally, the prolongation of QT interval found in patients with impaired heart rate response to respiration and the Valsalva maneuver has been associated with sudden cardiac death [15]. In a study of 104 diabetic and 184 nondiabetic patients awaiting renal or combined renal pancreatic transplantation and with the use of power spectral analysis techniques to detect autonomic dysfunction, it was demonstrated that only one of the five deceased patients displayed normal values for all eight autonomic function measurements employed [7]. The present study was prospectively designed to assess the prevalence of sympathetic and parasympathetic dysfunction in receiving current standard hemodialysis treatment and the role of BP drugs in the autonomic dysfunction found. Changes in systolic BP in passive tilting and in diastolic BP in static handgrip were used as the sympathetic tests; respiratory sinus arrhythmia and the 4-s exercise test were used as the parasympathetic tests; and finally the Valsalva index and the heart rate responses to both static handgrip and tilting were used as the tests that probed both branches of the autonomous nervous system. Overall, defective sympathetic responses were found more frequently than parasympathetic ones in either or controls, suggesting that they were more sensitive but less specific. Despite that, inadequate responses always tended to be more frequent in the two groups of for every category of tests. Individually, the Valsalva index, which evaluates both branches of the autonomic system, was found to be the most sensitive parameter for detecting autonomic dysfunction in. Its frequency of abnormality was higher in receiving compared to either controls or. However, when dealing with autonomic tests, the starting point is that the diagnosis of autonomic dysfunction should not be based on the results of a single test. Using a battery of tests may be more reliable and informative [16]. When the frequencies of abnormal results in each category of tests for the three studied groups were analyzed, our findings suggested that ESRD alone was a significant determinant of impaired responses but only for the sympathetic branch of the autonomous nervous system. Sympathetic hyperactivity is known to be present in [17] and experimental animals [18] starting early in the course of chronic renal failure [19]. It is thought to be mediated by signals arising in the failing kidney [20]. However, these observations do not conflict with the present finding of predominant impairment of sympathetic responses in : first, 201

Autonomic Dysfunction in ESRD Hemodialysis International, Vol. 7, No. 3, 2003 because defective regulation of autonomic function is thought to involve mainly the afferent loop [21,22] and, second, because baseline hyperactivity may indeed contribute to impair adaptation to acute hemodynamic challenges such as those employed during autonomic testing. In other words, despite the tonic increased sympathetic activity, have reduced phasic sympathetic modulation. ESRD in combination with was a significant determinant of inadequate responses in every category of tests. Consistent with our findings, the initial hypothesis of an early and predominant involvement of the parasympathetic system [23 25] has recently been challenged [24,26]. The small number of patients in the present study makes inferences as to the effects of particular classes of antihypertensive drugs on the autonomic response difficult to make. However, the majority of antihypertensive drugs, if not all, are associated with perturbations of autonomic function. Some of them, such as beta blockers and a2-agonists, for example, have a mechanism of action intrinsically linked to impairment of sympathetic response [11,27]. In addition, drugs that diminish the production or the action of angiotensin II, which is known to activate catecholamine release in synapses, are associated with a reduction of sympathetic hyperactivity [28]. Except for one patient who was only taking nifedipine, all the others were receiving at least one of drugs known to be associated with attenuation of sympathetic activity or response. It is our view that the presence of such drugs may have unmasked otherwise undetectable defective parasympathetic responses. This may not be a unique situation considering that a similar finding was reported following clonidine administration to patients with essential hypertension [29]. To better assess the prevalence of autonomic dysfunction in we resorted to an analysis in which the frequency of one, more than one, more than two, and more than three positive tests were calculated for the three studied groups. Consistent with other findings, these results were more discriminative when the criterion of more than one positive test was used for the diagnosis [16]. From this perspective, abnormal numbers reached 64% for patients, 67% for those receiving such drugs, and 20% for controls. This last number is still somewhat high for a healthy control group, considering that a previous study employing a similar battery of autonomic tests has suggested a specificity of 94% [16]. The limited sample size could account for this, in part. In spite of the results in controls, the prevalence of autonomic dysfunction in in the present study remains quite impressive, being three times higher in both groups of in comparison to controls. In addition, the prevalence of inadequate autonomic responses in the present study are consistent with previous reports in which numbers vary from 50% to 100% [4,13,26]. In summary, autonomic dysfunction remains highly prevalent in undergoing current standard hemodialysis treatment. receiving BP drugs were found to have detectable impairment in the entire autonomic system in contrast to those in whom inadequate responses were restricted to the sympathetic branch. Whether represent an additional risk to autonomic dysfunction in ESRD patients or simply facilitate the detection of an underlying parasympathetic defect remains to be determined. References 1 Goldenberg S, Thompson A, Guha A, Kramer N, Parrish A. Autonomic nervous dysfunction in chronic renal failure. Clin Res. 1971; 19:531 535. 2 Hennessy WJ, Siemsen AW. Autonomic neuropathy in chronic renal failure. Clin Res. 1968; 16:385 387. 3 Malik S, Winney RJ, Ewing DJ. Chronic renal failure and cardiovascular autonomic function. Nephron. 1986; 43:191 195. 4 Ewing DJ, Winney R. Autonomic function in patients with chronic renal failure on intermittent dialysis. Nephron. 1975; 15:424 429. 5 Calvo C, Maule S, Mecca F, Quadri R, Martina G, Cavallo Perin P. The influence of autonomic neuropathy on hypotension during hemodialysis. Clin Auton Res. 2002; 12:84 87. 6 Jassal SV, Coulshed SJ, Douglas JF, Stout RW. Autonomic neuropathy predisposing to arrhythmias in hemodialysis patients. Am J Kidney Dis. 1997; 30:219 223. 7 Hathaway DK, Cashion AK, Milstead EJ, Winsett RP, Cowan PA, Wicks MN, Gaber AO. Autonomic dysregulation in patients awaiting transplantation. Am J Kidney Dis. 1998; 32:221 229. 8 IV. NKF-K/DOQI clinical practice guidelines for anemia of chronic kidney disease. Am J Kidney Dis 2001 37(1 suppl 1):S182 S238. 9 Parker TF 3rd. Technical advances in hemodialysis therapy. Semin Dial. 2000; 13:372 377. 10 Hingorani S, Watkins SL. Dialysis for end-stage renal disease. Curr Opin Pediatr. 2000; 12:140 145. 11 Araújo CGS, Nóbrega ACL, Castro CLB. Heart rate response to deep breathing and 4-seconds of exercise before and after pharmacological blockade with atropine and propranolol. Clin Auton Res. 1992; 2:35 40. 12 Lazarus JM, Denker BM, Owen WF Jr. Hemodialysis. In: Brenner BM, Rector FC, eds. The Kidney, 5th ed. Philadelphia: Saunders, 1995; 2472. 13 Henrich WL. Hemodynamic instability during hemodialysis. Kidney Int. 1986; 30:605 612. 14 La Rovere M, Specchia G, Montana A, Schwartz P. Baroreceptor sensitivity, clinical correlates and cardiovascular mortality amongst patients with a first myocardial infarction: a prospective study. Circulation. 1988; 78:816 824. 202

Hemodialysis International, Vol. 7, No. 3, 2003 15 Krivoshiev S, Vazelov E, Koteva A, Zlatarska S, Antonov S, Kirjakov Z. Does uraemic autonomic neuropathy increase the risk of sudden cardiac death? Nephrol Dial Transplant. 1989; 4:75 77. 16 Vita G, Princi P, Savica V, Bellinghieri G, Puglisi RM, Marabello L, Messina C. Uremic autonomic dysfunction evaluated by pattern recognition analysis. Clin Nephrol. 1991; 6:290 293. 17 Augustyniak RA, Tuncel M, Zhang W, Toto RD, Victor RG. Sympathetic overactivity as a cause of hypertension in chronic renal failure. J Hypertens. 2002; 20:3 9. 18 Ye S, Zhong H, Yanamadala V, Campese VM. Renal injury caused by intrarenal injection of phenol increases afferent and efferent renal sympathetic nerve activity. Am J Hypertens. 2002; 15:717 724. 19 Tinucci T, Abrahao SB, Santello JL, Mion D Jr. Mild chronic renal insufficiency induces sympathetic overactivity. J Hum Hypertens. 2001; 15:401 406. 20 Hausberg M, Kosch M, Harmelink P, Barenbrock M, Hohage H, Kisters K, Dietl KH, Rahn KH. Sympathetic nerve activity in end-stage renal disease. Circulation. 2002; 106:1974 1979. 21 Rostand SG, Brunzell JD, Cannon RO 3rd, Victor RG. Cardiovascular complications in renal failure. J Am Soc Nephrol. 1991; 2:1053 1062. 22 Vita G, Messina C, Savica V, Bellinghieri G. Uraemic autonomic neuropathy. J Auton Nerv Syst. 1990; 30(suppl):S179 S184. Lugon et al. 23 Chu TS, Tsai TJ, Lee SH, Yen TS. Evaluation of cardiovascular autonomic function tests in dialysis patients. J Formos Med Assoc. 1993; 92:237 240. 24 Vita G, Bellinghieri G, Trusso A, Constantino G, Santoro D, Monteleone F, Messina C, Savica V. Uremic neuropathy studied by spectral analysis of heart rate. Kidney Int. 1999; 56:232 237. 25 Campese VM. Orthostatic hypotension: idiopathic and uremic. Kidney Int. 1988; 34(suppl 25): S152 S155. 26 Esforzado Armengol N, Amenos AC, Bono Illa M, Gaya Bertran J, Calls Ginesta J, Rivera Fillat F. Autonomic nervous system and adrenergic receptors in chronic hypotensive heamodialysis patients. Nephrol Dial Transplant. 1997; 12:939 944. 27 Coupland NJ, Bailey JE, Wilson SJ, Horvath R, Nutt D. The effects of clonidine on cardiovascular responses to standing in healthy volunteers. Clin Auton Res. 1995; 5:171 177. 28 Ma X, Chapleau MW, Whiteis CA, Abboud FM, Bielefeldt K. Angiotensin selectively activates a subpopulation of postganglionic sympathetic neurons in mice. Circ Res. 2001; 88:787 793. 29 Lazzeri C, La Villa G, Mannelli M, Janni L, Barletta G, Montano N, Franchi F. Effects of clonidine on power spectral analysis of heart rate variability in mild essential hypertension. J Auton Nerv Syst. 1998; 74:152 159. 203