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.
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.
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