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Cashion, Ann K.3; Hathaway, Donna K.3,5,6; Milstead, E. Jean3; Reed, Laura4; Gaber, A. Osama5

The 18Th Annual Meeting Of The American Society Of Transplantation, May 15-19, 1999, Chicago, Illinois: Clinical Transplantation

Background. Transplantation has been shown to improve cardiorespiratory reflex measures of autonomic function. However, there are limited data on how kidney or kidney-pancreas transplantation influence continuous autonomic modulation of heart rate and the clinical utility of 24-hr heart rate variability (HRV) monitoring.

Methods. Ninety nondiabetic kidney and 30 diabetic kidney-pancreas transplant recipients underwent 24-hr Holter monitoring before and again at 6 and 12 months posttransplantation. Tapes were submitted for determination of HRV including interbeat variability (the proportion of adjacent R-R intervals having a difference <50 msec, the SD of all R-R intervals for the entire recording, and the SD of the averages of R-R intervals calculated over 5-min blocks for the entire recording) which is associated with vagal function, sudden death, and circadian function, respectively. Power spectral analysis quantified total neural, sympathetic, and parasympathetic modulation of the heart in ln (msec2).

Results. Nondiabetic kidney recipients showed improvement (P≤0.05) in the SD of the averages of R-R intervals calculated over 5-min blocks (83.2 vs. 95.7 msec) and the SD of all R-R intervals (94.5 vs. 104.4 msec) by 6 months and all groups showed improvement by 12 months. Kidney-pancreas recipients also showed improved total neural (4.35 vs. 4.64) and sympathetic modulation (2.70 vs. 3.13). Kidney-pancreas recipients had significantly poorer values for each measure (P≤0.05) at all time points.

Conclusions. Cardiac autonomic neuropathy arises in the presence of uremia and diabetes, with severe dysfunction seen when these conditions occur concomitantly. Improvement in cardiac autonomic function follows both kidney and kidney-pancreas transplantation with more pronounced improvement in the circadian measures. Therefore, circadian measures of 24-hr HRV could be used to monitor the restoration of cardiac autonomic function.

Colleges of Nursing and Medicine and the Department of Surgery, Transplant Division, The University of Tennessee, Memphis, Tennessee 38163

1 Presented in abstract form at the 18th Annual Meeting of the American Society of Transplantation, May 15-19, 1999, Chicago, IL.

2 Supported by grant RO1 NR03871 from the National Institutes of Health.

3 College of Nursing, University of Tennessee.

4 Transplant Division, University of Tennessee.

5 College of Medicine, Department of Surgery, Transplant Division, University of Tennessee.

6 Address correspondence to: Donna K. Hathaway, PhD, College of Nursing, 877 Madison Av., Suite 641, University of Tennessee, Memphis, TN 38163.

Received 15 June 1999.

Accepted 25 August 1999.

Cardiac autonomic neuropathy has been associated with increased morbidity and risk for sudden cardiac death in patients with diabetes (1-3), uremia (1, 4), and kidney and kidney-pancreas transplant (5-7). Although standard cardiorespiratory reflex tests used to evaluate cardiac autonomic function demonstrate improved function after transplantation, this improvement occurs slowly (6, 8) and may not be evident for as long as 4 years (9). Diminished 24-hr heart rate variability (HRV*), a newer measure of cardiac autonomic function, is believed to be a more sensitive measure of cardiac autonomic function and able to detect dysfunction earlier than standard reflex tests. In addition, measures obtained from 24-hr HRV tests have been found to identify increased risk for sudden death independent of other risk factors (10). Because it is unknown if patients experience improvement in patterns of 24-hr HRV after kidney and kidney-pancreas transplantation, we undertook this investigation to determine the utility of this test and its ability to document early changes in autonomic neuropathy.

Numerous studies have used two standard cardiorespiratory reflexes, change in heart rate with deep breathing and with valsalva maneuver, to evaluate cardiac autonomic function in normal (11-13), uremic (14, 15), diabetic (16, 17), and transplant populations (6, 8). Both measures assess a complex reflex arc reflecting a "beat to beat" balance of sympathetic and parasympathetic activity that can easily be altered by physical and/or emotional stress (16). Although cardiorespiratory reflexes are easy to administer, noninvasive, and are, therefore, a popular investigative tool (16), they have two major limitations. First, the patient must be willing and able to cooperate with the protocol. If the patient is unable to do so (e.g., the patient is too ill or does not understand the procedure), reliability of the measure can be affected. Second, although procedures are standardized, stimuli could evoke different mechanisms in different individuals, thus yielding results that may not always reflect the same dysfunction (18) raising questions regarding the validity of the tests.

Because changes in cardiorespiratory reflex measures in transplant patients are often minimal and inconsistent and because these tests reflect response to an isolated laboratory stressor, not response to day to day activity, 24-hr HRV with power spectral analysis has gained interest as an alternative method for evaluating autonomic function. Heart rate variability monitoring is a noninvasive method that has the potential to assess earlier stages of cardiac autonomic dysfunction than evoked measures (19-21), in addition to examining circadian rhythmicity (22).

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After Institutional Review Board approval, cardiac autonomic function evaluations were conducted at pretransplant and again at 6 and 12 months postkidney (n=90) and kidney-pancreas (n=30) transplant. Patients were included if they were older than 18 years of age and had end-stage renal disease, regardless of dialysis status. Patients were excluded from the study if they were pregnant or found to have a coexisting neurological deficit that alters autonomic function. On the day of testing, a consent form was signed and an ambulatory Holter monitor applied. Participants were asked to wear the Holter monitor for 24 hr and to document their activities during that time in the diary provided.

24-hr HRV measures. Analysis of 24-hr ambulatory Holter monitor tapes was completed by Marquette Electronics Laser SXP Ambulatory ECG Analysis and Editing Systems (version 5.8 software) and Series 8500 Holter recording system. Each QRS complex was digitized at a rate of 128 samples per second, R waves were identified, and templates were applied to prevent inaccurate HRV interpretation. The analyzed data file was then scanned and manually edited to locate and correct any errors in QRS labeling that would adversely affect measurement of HRV. Tapes were required to have ≥20 hr of analyzable data and generally had ≥23 hr of analyzable data. Using these data files, 24-hr HRV with power spectral analysis was calculated.

The HRV calculations are placed in two general domains. The time domain is derived directly from the R-R intervals and is based on their means and SD. Measures in the time domain category include the SD of all R-R intervals (SDNN) and the SD of the averages of R-R intervals calculated over 5-min blocks, for the entire recording (SDANN) (23). The SDNN has been found to be associated with sudden cardiac death (24). The SDANN is considered the best measure of overall autonomic balance and represents circadian rhythmicity of autonomic function (25), in addition to estimating long-term components of HRV (26). The second time domain category is based on differences between adjacent R-R intervals and includes the proportion of adjacent R-R intervals having a difference >50 msec (pNN50) (23) and reflects alterations in autonomic function that are primarily vagally mediated (26, 27).

Frequency-domain measures are calculated by fast Fourier transformation and reflect neural modulation of heart rate. The waveforms generated by the transformation of R-R intervals are than analyzed to determine the relative contribution of various waveform frequencies. These measures have been previously described (28) and are briefly presented. Frequency waveforms describe and are used to quantify the amount of total (0.01-1.00 Hz), low (0.04-0.15 Hz), and high (0.15-0.40 Hz) power (29). Total power waveforms reflect a combination of all cyclic components responsible for variability (23). Low frequency (LF) waveforms estimates sympathetic modulation along with some parasympathetic modulation, although high frequency (HF) waveforms, also known as the respiratory frequency, represent parasympathetic modulation (30, 31). Twenty-four-hour HRV frequency measures were found to be diminished in studies of patients with diabetes (19, 21), uremia (1, 28), and both uremia and diabetes (1, 28, 32).

Quality assurance data provided by the manufacturer illustrate mathematically correct results after submission of known electronically generated cardiac signals (29). The Holter monitor, before each 24-hr recording, records 8 min of calibration signals and these signals can be evaluated by the technician before HRV analysis. The recorder also uses a phase lock loop to stabilize the time basis and accuracy has been established to within ±1 sec/24-hr period. Robustness of locating the fudicial point on the R wave is enhanced by the software's template matching ability. This technology has been successfully used in clinical studies evaluating alterations in autonomic regulatory mechanisms in patients with heart disease (33), cardiac transplantation (34), diabetic autonomic neuropathy and uremia (28), and kidney transplantation (35).

Twenty-four-hour measures are highly stable in both normal subjects (36), postmyocardial infarction patients (37), and patients with ventricular arrhythmias (38). Thus, it is thought that 24-hr HRV measures may be ideal for assessing intervention therapies (23), such as transplantation (39), exercise (40), and deep breathing relaxation techniques (41).

Data analysis. One-way analyses of variance with preplanned multiple comparison using least square means were used to test for differences among study groups and from pre- to posttransplant. [Chi]2 and t tests were used to determine equivalence of groups as appropriate. A priori level of significance was set at P≤0.05.

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Characteristics of the study sample are displayed in Table 1 and indicate that kidney and kidney-pancreas transplant recipients were similar in age and gender. Differences in race and months of dialysis reflect the distribution and treatment characteristics of the study population. Most of our kidney-pancreas recipients are Caucasian, although approximately 50% of our uremia patients are African-American. These characteristics have not, however, previously been found to influence HRV (1). Study results (Table 2) suggest that non-diabetic renal failure patients awaiting kidney transplant have diminished 24-hr HRV measures, but these values are still within the lower limits of normal based on our laboratory's healthy control values. At 6 months posttransplant, the kidney transplant recipients have significantly improved (P≤0.05) measures of circadian fluctuation (SDANN, SDNN), although other 24-hr measures slightly diminished though not to a significant degree. By 12 months posttransplant all measures of 24-hr HRV have increased from pretransplant with circadian measures continuing to show significant (P≤0.05) improvement.

Table 1

Table 1

Table 2

Table 2

Pretransplant baseline values of the kidney-pancreas recipients are severely diminished with the SDNN approaching values (<50 msec) associated with sudden cardiac death in myocardial infarction patients (24). At 6 months post kidney-pancreas transplant, improvement is seen in all measures except for pNN50 and HF, both of which are thought to reflect parasympathetic modulation. This pattern continues at 12 months with significant (P≤0.05) improvement demonstrated in circadian measures, total power, and LF, although parasympathetic modulation (pNN50) remains diminished. Although improvement is documented for most measures, only one measure, the SDANN, reaches a value within normal range of our healthy controls.

Overall, measures of 24-hr HRV suggest a trend toward improvement in cardiac autonomic function by 12 months posttransplant in both study groups. However, kidney-pancreas transplant recipients have significantly (P≤0.05) poorer HRV at all time points. At 12 months posttransplant, both nondiabetic-kidney and kidney-pancreas recipients show significant (P≤0.05) improvement in circadian measures, although the kidney-pancreas group also demonstrates significant (P≤0.05) improvement in all measures except those reflective of parasympathetic modulation.

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The metabolic derangements manifested by uremia, especially when in combination with diabetes, can result in neurological changes that include demyelination of preganglionic parasympathetic and sympathetic fibers with nerve lesion formation (42, 43) and loss of microvasculature leading to cell hypoxia (44, 45) with neuronal cell degeneration and slowing of neurotransmission. Dysautonomia is difficult to measure and quantify due to the dual innervation of the autonomic nervous system (sympathetic and parasympathetic pathways), the numerous reflex arcs involved, and the anatomic dispersion of autonomic nerve fibers (44). Even with these measurement obstacles, quantification of dysautonomia using cardiorespiratory reflex tests that evaluate heart rate response to physiologic stressors has been reported in the literature since the 1950s (16, 46-48). The primary cardiorespiratory reflex tests are change in heart rate with deep breathing and with valsalva maneuver.

Twenty-four-hour monitoring of HRV with power spectral analysis has gained interest as an alternative method to cardiorespiratory reflex tests for evaluating cardiac autonomic function. Cardiorespiratory reflex tests detect parasympathetic abnormalities in renal failure patients who have significant dysautonomia (16), although 24-hr HRV detects earlier deterioration in autonomic function in addition to examining circadian rhythmicity (19-22). In addition, power spectral analysis allows quantification of cardiac autonomic function into parasympathetic and sympathetic modulation. Unfortunately, studies investigating HRV of kidney transplant recipients (35, 49) are scarce even though cardiovascular events are the leading cause of morbidity in diabetic kidney or kidney-pancreas transplant recipients (50), occurring despite potential recipients being rejected due to poor pretransplant cardiac evaluations. In addition, sudden death accounts for as much as 15% of all deaths in kidney or kidney-pancreas recipients (51-53).

Our study findings show that patients with uremia experience various degrees of dysautonomia, and those with diabetes in addition to uremia have the greatest dysfunction. In addition to having poorer overall HRV, the kidney-pancreas group displayed severely diminished circadian function (SDNN and SDANN) at pretransplant, which identified these patients as being at-risk for sudden death based on previous research (1). Other study results (22) have also shown a marked reduction in day/night sympathovagal balance in 54 diabetic subjects by using 24-hr HRV frequency measures. Because significant improvement in circadian function is noted early posttransplantation (at 6 months for kidney recipients), those recipients not showing circadian improvement could be further evaluated and monitored for cardiac risk.

Although significant improvement is documented in measures of circadian function (SDNN and SDANN), our study results did not show significant improvement in time or frequency domain measures reflecting parasympathetic modulation (pNN50 and HF) for either study group. Another study (35) that evaluated patients at 4 months postkidney transplantation obtained similar results, except they also report a significant increase in the frequency measure representing parasympathetic modulation (HF). This difference in findings could be a reflection of small sample size and of rigid patient selection criteria (35), although we used more liberal criteria. Diminished parasympathetic modulation is of concern because although the etiology of sudden death is unknown, it is thought to be associated with the loss of this function (54, 55). Although the frequency domain measure reflecting parasympathetic modulation did not improve post-transplant, significant improvement in the measure reflecting all cyclic components (total power) and in sympathetic modulation (LF) occurred for kidney-pancreas recipients by 12 months.

In summary, study groups experienced improvement in 24-hr HRV after kidney and kidney-pancreas transplantation supporting the role of transplantation in improving cardiac autonomic function. At 12 months posttransplant the kidney-pancreas recipients, who had significantly poorer measures of HRV than nondiabetic recipients at each time point, showed significant improvement in more HRV measures than nondiabetic kidney recipients. Only kidney recipients showed a trend toward improvement in parasympathetic function by 12 months. Improvement after transplantation was seen the earliest in and is most pronounced for measures of circadian function, particularly the SDNN, which has been associated with sudden death.

Acknowledgments. The authors thank Monique Johnson and Pat Joplin for data collection and management skills.

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