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The effect of kidney transplantation on autonomic nervous dysfunction in patients with chronic renal failure
The Effect of Kidney Transplantation on Autonomic Nervous Dysfunction in Patients With Chronic Renal Failure R. Kveder, A. Kanolus, A.F. Bren, J. Kovac, and S. Sega
A
UTONOMIC nervous dysfunction (AND) is wellrecognized complication of chronic renal failure (CRF). Abnormalities of vagal function with possible combined sympathetic disturbances have been reported most commonly.1–3 Few reports dealing with the effects of kidney transplantation on AND found in the literature make this subject rather contradictory. Some of the authors found some improvement4 or even almost complete normalization of AND after kidney transplantation in non– diabetic neuropathy,5,6 although others found no improvement of autonomic indices in nondiabetic neuropathy in patients with end-stage renal disease (ESRD).7 The aim of our study was to investigate the degree and the course of AND in patients with ESRD after successful kidney transplantation. PATIENTS AND METHODS Patients Nineteen patients with successful kidney transplantation participated in this study. There were 12 females, 7 males, average age 37.8 (33 to 42.6, 95% confidence interval) years, uremia duration 11.4 years (9.2 to 13.6), duration after transplantation 2.53 years (1.8 to 3.3), serum creatinine 119 mol/L (102 to 136). All patients were treated with methylprednisolone and cyclosporine. Patients with diabetes mellitus were excluded. All patients were in stable clinical condition at autonomic testing. Informed consent had been obtained from all patients. They were requested to refrain from smoking and taking medications or drugs that might interfere with autonomic function. The results of AN testing were compared to the results of age- and sex-matched healthy controls.
Methods Valsalva Maneuver. The subject was studied in the sitting position maintaining an expiratory pressure of 40 mm Hg for 10 seconds by blowing through a mouthpiece attached to a mercury manometer. The test was repeated twice. The Valsalva ratio was calculated as the ratio of the longest R–R interval after the manoeuvre to the shortest R–R interval during the manoeuvre. The highest value was included in the analysis. Deep Breathing. The subject was breathing at a rate of 6 breaths per minutes while sitting. Expiratory–inspiratory ratio (“deep breathing ratio”) was calculated as the maximal R–R interval during expiration to the minimal R–R interval during inspiration. Sustained Handgrip. The subject was asked to exert 30% of maximal voluntary contraction for 5 minutes on a handgrip dynamometer using the dominant arm. The highest increase in diastolic
blood pressure was considered. The ratio of the average R–R interval during a 15-second period before testing to the minimal R–R interval during the test was calculated (“handgrip ratio”). Orthostatic Test. After adequate rest (6 minutes) in supine position the blood pressure was measured with an automatic sphygmomanometer. The subject was than asked to stand up within 3 to 5 seconds and to remain motionless for 5 minutes. Blood pressure was recorded immediately before standing, after 15 seconds of standing, and each minute until the end of the test. The test was repeated after 5 minutes of supine rest. The change in systolic blood pressure from rest value to the value at 1 minute after standing was used for analysis. Ratio of the maximal R–R interval to the minimal R–R interval after standing (“orthostatic ratio”) was calculated. The highest difference in blood pressure and highest ratio was accepted. Spectral Analysis of Heart Rate Variability. ECG and respiratory activity were monitored for each subject in relaxed supine position for 6 minutes and 6 minutes while quietly standing. The recorded signals were fed into analog-to-digital channels of a personal computer. A fast discrete Fourier transformation was used to calculate the amplitude and power spectrum of fluctuations in heart rate and respiration. The output of the analysis consisted of a plot of time series and amplitude spectrum. Integrals over relevant frequency bands mainly in the very low-frequency range (0.001 to 0.05 Hz; VLF), in the low frequency range (0.05 to 0.15 Hz; LF), and in the high-frequency range–respiratory peak (0.15 to 0.45 Hz; HF) were computed.
Statistics SPSS for Windows 6.0 (SPSS Corporation 1993) statistical package was used to perform the statistical analysis. The results are expressed as mean with 95% confidence interval (CI). One-way analysis of variance was the main statistical method to test the means. Kruskal-Wallis test was used for not normally distributed data. P ⬍ .05 was considered significant.
RESULTS AND DISCUSSION
Main results are summarised in Table 1. Comparison of the results of AN testing in transplanted patients with the results in 33 hemodialysis patients showed significantly higher values of Valsalva ratio (1.49 versus 1.28, P ⬍ .05), From the Department of Nephrology and Department of Neurology, University Medical Centre, Ljubljana, Slovenia. Address reprint requests to Assist Prof Radoslav Kveder, MD, PhD, University Medical Centre, Department of Nephrology, Zaloska 7, 1000 Ljubljana, Slovenia.
0041-1345/01/$–see front matter PII S0041-1345(01)02462-9
© 2001 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
3394
Transplantation Proceedings, 33, 3394–3395 (2001)
AUTONOMIC NERVOUS DYSFUNCTION
3395
Table 1. Autonomic Function Estimated With Classic Cardiocirculatory Tests and Heart Rate Variability Expressed as the Integral of the Heart Rate Amplitude Spectrum in Supine and Standing Position in Patients After Kidney Transplantation and in Healthy Controls Parameter
Patients Mean
Valsalva ratio Deep breathing ratio Hand grip ratio Orthostatic test ⌬SBP ratio Frequency range: supine VLF LF HF Frequency range: standing VLF LF HF
Controls 95% CI
F
Mean
95% CI
1.49 1.38 1.19
1.35–1.63 1.30 –1.46 1.15–1.23
1.78 1.57 1.37
1.58 –1.98 1.49 –1.65 1.29 –1.45
5.50 9.40† 19.0†
⫺8.8 1.14
⫺12.6 –5.1 1.10 –1.18
6.4 1.59
1.2–2.1 1.49 –1.69
32.40† 72.20†
2.45 2.27 3.04
1.88 –3.02 1.66 –2.88 1.96 – 4.12
1.63 2.01 2.35
1.2–2.06 1.44 –2.58 1.53–3.17
4.65* 0.34 0.95
2.43 1.83 1.85
1.84 –3.02 1.26 –2.40 1.26 –2.44
2.89 3.43 2.39
2.05–3.73 2.51– 4.35 1.65–3.13
0.76 8.39† 1.25
F, F value; SBP, systolic blood pressure (mm Hg). *P ⬍ .05. † P ⬍ .01.
deep breathing ratio (1.38 versus 1.22, P ⬍ .01), in hand grip ratio (1.19 versus 1.13, P ⬍ .01). There was no difference in orthostatic ratio (1.14 versus 1.16). Heart rate variability determinations were significantly higher in LF as well as in HF band in patients after transplantation in supine (P ⬍ .05), but not in standing position. When we compared, AN parameters in two groups of transplanted patients, that did not differ in age, renal function, serum PTHi, and average cyclosporine concentrations (ⱕ3 years and ⬎3 years after transplantation), only the values of deep breathing ratio turned out to be significantly higher (1.31 versus 1.48, P ⬍ .05) in the second group. All other parameters showed no significant differences. The pathogenesis of AND in patients with ESRD has not been clarified yet. Most of the authors agree that pathogenesis is multifactorial and probably related to uremia.2,8 One should expect restitution of AN function after successful kidney transplantation, and some of the results in the literature has indeed shown almost complete normalisation of the AN system testing after kidney transplantation.5,6 Our results did not confirm such statements. We found definite abnormality in AN function (at least two tests abnormal) in 31% of patients and borderline dysfunction (at least one test abnormal) in 63.2%. The comparison with
age- and sex-matched healthy controls has shown the significant differences in all parasympathetic tests and most of the sympathetic. The results of spectral analysis of heart rate variability pointed at higher sympathetic activity in renal transplant patients as well as to some degree of persistent depression of baroreceptor feedback control. When we compared the two groups of patients according to different time elapsed after transplantation we could not find any significant differences between groups though most of the parameters of AND has shown the tendency to improve with the longevity of normal renal function. REFERENCES 1. Ewing DJ, Winney R: Nephron 15:424, 1975 2. Campese VM, Romoff MS, Levitan D, et al: Kidney Int 20:246, 1981 3. Vita G, Princi P, Savica V, et al: Clin Nephrol 36:290, 1991 4. Agarwal A, Anannd IS, Sakhuja V, et al: Kidney Int 40:489, 1991 5. Mallamaci F, Zoccalli C, Ciccarelli M, et al: Clin Nephrol 25:175, 1986 6. Yildiz A, Sever MS, Demirel S, et al: Nephron 80:57, 1998 7. Solders G, Persson A, Wilczek H: Transplantation 4:616, 1986 8. Vita G, Bellinghieri G, Trusso A, et al: Kidney Int 56:232, 1999
A
UTONOMIC nervous dysfunction (AND) is wellrecognized complication of chronic renal failure (CRF). Abnormalities of vagal function with possible combined sympathetic disturbances have been reported most commonly.1–3 Few reports dealing with the effects of kidney transplantation on AND found in the literature make this subject rather contradictory. Some of the authors found some improvement4 or even almost complete normalization of AND after kidney transplantation in non– diabetic neuropathy,5,6 although others found no improvement of autonomic indices in nondiabetic neuropathy in patients with end-stage renal disease (ESRD).7 The aim of our study was to investigate the degree and the course of AND in patients with ESRD after successful kidney transplantation. PATIENTS AND METHODS Patients Nineteen patients with successful kidney transplantation participated in this study. There were 12 females, 7 males, average age 37.8 (33 to 42.6, 95% confidence interval) years, uremia duration 11.4 years (9.2 to 13.6), duration after transplantation 2.53 years (1.8 to 3.3), serum creatinine 119 mol/L (102 to 136). All patients were treated with methylprednisolone and cyclosporine. Patients with diabetes mellitus were excluded. All patients were in stable clinical condition at autonomic testing. Informed consent had been obtained from all patients. They were requested to refrain from smoking and taking medications or drugs that might interfere with autonomic function. The results of AN testing were compared to the results of age- and sex-matched healthy controls.
Methods Valsalva Maneuver. The subject was studied in the sitting position maintaining an expiratory pressure of 40 mm Hg for 10 seconds by blowing through a mouthpiece attached to a mercury manometer. The test was repeated twice. The Valsalva ratio was calculated as the ratio of the longest R–R interval after the manoeuvre to the shortest R–R interval during the manoeuvre. The highest value was included in the analysis. Deep Breathing. The subject was breathing at a rate of 6 breaths per minutes while sitting. Expiratory–inspiratory ratio (“deep breathing ratio”) was calculated as the maximal R–R interval during expiration to the minimal R–R interval during inspiration. Sustained Handgrip. The subject was asked to exert 30% of maximal voluntary contraction for 5 minutes on a handgrip dynamometer using the dominant arm. The highest increase in diastolic
blood pressure was considered. The ratio of the average R–R interval during a 15-second period before testing to the minimal R–R interval during the test was calculated (“handgrip ratio”). Orthostatic Test. After adequate rest (6 minutes) in supine position the blood pressure was measured with an automatic sphygmomanometer. The subject was than asked to stand up within 3 to 5 seconds and to remain motionless for 5 minutes. Blood pressure was recorded immediately before standing, after 15 seconds of standing, and each minute until the end of the test. The test was repeated after 5 minutes of supine rest. The change in systolic blood pressure from rest value to the value at 1 minute after standing was used for analysis. Ratio of the maximal R–R interval to the minimal R–R interval after standing (“orthostatic ratio”) was calculated. The highest difference in blood pressure and highest ratio was accepted. Spectral Analysis of Heart Rate Variability. ECG and respiratory activity were monitored for each subject in relaxed supine position for 6 minutes and 6 minutes while quietly standing. The recorded signals were fed into analog-to-digital channels of a personal computer. A fast discrete Fourier transformation was used to calculate the amplitude and power spectrum of fluctuations in heart rate and respiration. The output of the analysis consisted of a plot of time series and amplitude spectrum. Integrals over relevant frequency bands mainly in the very low-frequency range (0.001 to 0.05 Hz; VLF), in the low frequency range (0.05 to 0.15 Hz; LF), and in the high-frequency range–respiratory peak (0.15 to 0.45 Hz; HF) were computed.
Statistics SPSS for Windows 6.0 (SPSS Corporation 1993) statistical package was used to perform the statistical analysis. The results are expressed as mean with 95% confidence interval (CI). One-way analysis of variance was the main statistical method to test the means. Kruskal-Wallis test was used for not normally distributed data. P ⬍ .05 was considered significant.
RESULTS AND DISCUSSION
Main results are summarised in Table 1. Comparison of the results of AN testing in transplanted patients with the results in 33 hemodialysis patients showed significantly higher values of Valsalva ratio (1.49 versus 1.28, P ⬍ .05), From the Department of Nephrology and Department of Neurology, University Medical Centre, Ljubljana, Slovenia. Address reprint requests to Assist Prof Radoslav Kveder, MD, PhD, University Medical Centre, Department of Nephrology, Zaloska 7, 1000 Ljubljana, Slovenia.
0041-1345/01/$–see front matter PII S0041-1345(01)02462-9
© 2001 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
3394
Transplantation Proceedings, 33, 3394–3395 (2001)
AUTONOMIC NERVOUS DYSFUNCTION
3395
Table 1. Autonomic Function Estimated With Classic Cardiocirculatory Tests and Heart Rate Variability Expressed as the Integral of the Heart Rate Amplitude Spectrum in Supine and Standing Position in Patients After Kidney Transplantation and in Healthy Controls Parameter
Patients Mean
Valsalva ratio Deep breathing ratio Hand grip ratio Orthostatic test ⌬SBP ratio Frequency range: supine VLF LF HF Frequency range: standing VLF LF HF
Controls 95% CI
F
Mean
95% CI
1.49 1.38 1.19
1.35–1.63 1.30 –1.46 1.15–1.23
1.78 1.57 1.37
1.58 –1.98 1.49 –1.65 1.29 –1.45
5.50 9.40† 19.0†
⫺8.8 1.14
⫺12.6 –5.1 1.10 –1.18
6.4 1.59
1.2–2.1 1.49 –1.69
32.40† 72.20†
2.45 2.27 3.04
1.88 –3.02 1.66 –2.88 1.96 – 4.12
1.63 2.01 2.35
1.2–2.06 1.44 –2.58 1.53–3.17
4.65* 0.34 0.95
2.43 1.83 1.85
1.84 –3.02 1.26 –2.40 1.26 –2.44
2.89 3.43 2.39
2.05–3.73 2.51– 4.35 1.65–3.13
0.76 8.39† 1.25
F, F value; SBP, systolic blood pressure (mm Hg). *P ⬍ .05. † P ⬍ .01.
deep breathing ratio (1.38 versus 1.22, P ⬍ .01), in hand grip ratio (1.19 versus 1.13, P ⬍ .01). There was no difference in orthostatic ratio (1.14 versus 1.16). Heart rate variability determinations were significantly higher in LF as well as in HF band in patients after transplantation in supine (P ⬍ .05), but not in standing position. When we compared, AN parameters in two groups of transplanted patients, that did not differ in age, renal function, serum PTHi, and average cyclosporine concentrations (ⱕ3 years and ⬎3 years after transplantation), only the values of deep breathing ratio turned out to be significantly higher (1.31 versus 1.48, P ⬍ .05) in the second group. All other parameters showed no significant differences. The pathogenesis of AND in patients with ESRD has not been clarified yet. Most of the authors agree that pathogenesis is multifactorial and probably related to uremia.2,8 One should expect restitution of AN function after successful kidney transplantation, and some of the results in the literature has indeed shown almost complete normalisation of the AN system testing after kidney transplantation.5,6 Our results did not confirm such statements. We found definite abnormality in AN function (at least two tests abnormal) in 31% of patients and borderline dysfunction (at least one test abnormal) in 63.2%. The comparison with
age- and sex-matched healthy controls has shown the significant differences in all parasympathetic tests and most of the sympathetic. The results of spectral analysis of heart rate variability pointed at higher sympathetic activity in renal transplant patients as well as to some degree of persistent depression of baroreceptor feedback control. When we compared the two groups of patients according to different time elapsed after transplantation we could not find any significant differences between groups though most of the parameters of AND has shown the tendency to improve with the longevity of normal renal function. REFERENCES 1. Ewing DJ, Winney R: Nephron 15:424, 1975 2. Campese VM, Romoff MS, Levitan D, et al: Kidney Int 20:246, 1981 3. Vita G, Princi P, Savica V, et al: Clin Nephrol 36:290, 1991 4. Agarwal A, Anannd IS, Sakhuja V, et al: Kidney Int 40:489, 1991 5. Mallamaci F, Zoccalli C, Ciccarelli M, et al: Clin Nephrol 25:175, 1986 6. Yildiz A, Sever MS, Demirel S, et al: Nephron 80:57, 1998 7. Solders G, Persson A, Wilczek H: Transplantation 4:616, 1986 8. Vita G, Bellinghieri G, Trusso A, et al: Kidney Int 56:232, 1999