Cyclosporin A Impairs the Nocturnal Blood Pressure Fall in Renal Transplant Recipients
In renal transplant recipients, hypertension and a diminished nocturnal blood pressure fall are frequently found. To investigate whether this diminished nocturnal blood pressure fall is related to the use of cyclosporin A or to other factors, such as the use of glucocorticoids, we measured 24-hour ambulatory blood pressure in 18 renal transplant recipients both before and 16 weeks after conversion from cyclosporin A to azathioprine. Renal blood flow and glomerular filtration rate were estimated from 131I-hippurate and 125I-iothalamate clearances, respectively, and plasma concentrations of renin, atrial natriuretic peptide, norepinephrine, prostaglandin E2, and thromboxane B2 were determined. During cyclosporin A treatment, mean 24-hour blood pressure was 117±3 mm Hg, and the nocturnal fall in blood pressure was 4±9 mm Hg. A nondipping diurnal blood pressure pattern was present in 13 patients. After conversion to azathioprine, mean 24-hour blood pressure decreased to 109±3 mm Hg (P<.001), the nocturnal fall increased to 9±6 mm Hg, and the number of patients with a nondipping diurnal blood pressure pattern decreased to 9. The nocturnal fall in heart rate (17±10 beats per minute) during cyclosporin A did not change after conversion. Body weight and plasma concentrations of norepinephrine and renin did not change. Plasma concentrations of prostaglandin E2 and thromboxane B2 decreased after conversion, as did plasma atrial natriuretic peptide. Renal blood flow and glomerular filtration rate increased after conversion. In conclusion, cyclosporin A appears to be involved in the disturbance of the circadian blood pressure rhythm in renal transplant recipients. Although the precise mechanism is unclear, the elevated plasma atrial natriuretic peptide and slightly suppressed plasma renin concentrations suggest that intravascular volume expansion may contribute to the observed hemodynamic alterations.
The normally occurring nocturnal decline in BP has been reported to be absent or attenuated in heart, liver, and kidney transplant recipients.1 2 3 4 5 6 7 Existing evidence suggests that the use of glucocorticoids is associated with this hemodynamic abnormality. Van den Borne et al5 found that glucocorticoid therapy dose dependently attenuated or abolished the nocturnal fall in BP in liver transplant recipients. Furthermore, the same group of authors also showed that the reappearance of the normal nocturnal decline in BP in cardiac transplant recipients was related to the reduction of the dose of glucocorticoids after transplantation.8 Moreover, a reduced or absent nocturnal decline in BP has been observed in patients with endogenous or exogenous hypercortisolism.9
The use of CsA is frequently accompanied by the development of hypertension.4 7 Several causative mechanisms have been postulated, including an increase in sympathetic nerve activity, a decrease in renal function, disturbance of the synthesis and release of prostaglandins and endothelin-1, and sodium retention.10 11 12 13 14 Apart from inducing hypertension, CsA, alone or in combination with glucocorticoids, may contribute to the attenuation of the nocturnal decline in BP after transplantation.
To gain more insight into the role of CsA in the attenuation of the nocturnal decline in BP, we studied kidney transplant recipients during CsA- and AZA-based immunosuppressive regimens. In both instances, the dose of glucocorticoids was kept at a constant level.
Patients were recruited from renal transplant recipients enrolled in a prospective randomized clinical trial designed to evaluate the effects on long-term graft function and incidence of rejection episodes of two different immunosuppressive regimens, ie, prednisone combined with CsA or prednisone combined with AZA. For this trial, CsA-treated renal transplant recipients who were at least 6 months after transplantation were randomly allocated to either continuation of CsA treatment or conversion from CsA- to AZA-based immunosuppression.
For the present study, renal transplant recipients were selected who did not have preexisting hypertension with a clinic BP of 150/95 mm Hg or higher during antihypertensive treatment and who were allocated to conversion from CsA to AZA. Patients with diabetes mellitus, previous graft rejection, or signs of autonomic neuropathy were excluded. The first 18 consecutive patients fulfilling these criteria and willing to give written informed consent were studied. About 50% of the patients who were converted from CsA to AZA did not meet all criteria, mainly because of preexisting hypertension that could not be attributed to the use of CsA.
The first study was performed while patients were on CsA therapy and the second study 16 weeks later when patients were on AZA therapy. During both studies, the patients used the same prednisone dose. All antihypertensive medication (β-blockers in 13 patients and calcium channel blockers in 8) was discontinued 3 days before the studies. On both study days, patients arrived in the cardiovascular research laboratory after an overnight fast. On arrival, they were weighed and then a small catheter (Venflon, Viggo Spectramed) was inserted into a forearm vein of each arm for infusion of radiopharmaceuticals and blood sampling. After renal function studies, patients were fitted with the equipment for 24-hour ambulatory BP monitoring and were discharged from the hospital. The study protocol was approved by the local Medical Ethics Committee, and all procedures were performed in accordance with institutional guidelines.
Effective renal plasma flow and GFR were estimated from the urinary clearances of 131I-hippuran and 125I-thalamate (Amersham International plc) as previously described.15 The mean of two calculated clearances of 131I-hippurate and 125I-thalamate was used for further analysis. During the renal function studies, arterial pressure was measured by an automated oscillometric device (AccuTorr2, Datascope Corp). RBF was calculated by dividing effective renal plasma flow by (1−hematocrit). RVR was calculated by dividing mean arterial pressure by RBF. Before the start of the renal function studies, a blood sample was taken for determination of CsA 12-hour trough blood levels (CycloTrac SP, IncStar Corp).
During the renal function studies, blood was sampled for measurement of plasma concentrations of norepinephrine, ANP, renin, PGE2, and TxB2 after patients had rested supine for 30 minutes. Plasma norepinephrine concentration was measured by fluorometric detection after high-performance liquid chromatographic separation as described previously.16 Plasma ANP concentration was measured by means of a commercially available radioimmunoassay kit.17 Plasma renin concentration was measured by an immunoradiometric assay as previously described.18 Plasma PGE2 and TxB2 concentrations were measured by a commercially available competitive enzyme immunoassay with a monoclonal antibody directed against PGE2 and specific anti-TxB2 polyclonal antibodies (Cayman Chemical).
Twenty-four-Hour BP Monitoring
For ambulatory BP monitoring, the oscillometric SpaceLabs model 90207 monitor was used. BP was measured in the nondominant arm. From 7 am to 10 pm, ambulatory BP was measured at 20-minute intervals and from 10 pm to 7 am at 30-minute intervals. To correct for asynchronous day-night patterns between patients, daytime was defined as the period between 9 am and 10 pm, and nighttime was defined as the period between 1 and 6 am. With the use of these criteria, all patients were awake during daytime and asleep during nighttime. From the hourly averages of ambulatory BP recordings, daytime, nighttime, and 24-hour averages of systolic, diastolic, and mean BPs and heart rate were calculated for each patient.
Data are presented as mean±SD. For comparison of means, Student's two-tailed paired t test was used. A value of P≤.05 was considered to indicate statistical significance.
Twelve male and six female kidney transplant recipients, aged 39±13 years, were studied. The time after transplantation when the first study was performed ranged from 6 to 89 months (mean, 24 months). At the time of the first study, the daily CsA dose was 5.4±1.4 mg/kg, resulting in a CsA whole blood trough concentration of 250±66 mg/L. At the time of the second study, the mean daily dose of AZA was 1.8±1.4 mg/kg. During both studies, each patient used an identical daily dose of prednisone (range, 7.5 to 12.5 mg; mean, 10.4 mg). Body weight was similar during CsA and AZA. Conversion from CsA to AZA was not complicated by episodes of graft rejection in the period between the studies.
During CsA, all patients were treated with antihypertensive drugs, whereas after conversion to AZA, only four patients used antihypertensive treatment. The mean number of antihypertensive drugs (calcium channel blockers and/or β-blockers) per patient decreased from 1.3±0.5 before to 0.3±0.6 after conversion (P<.05).
Twenty-four-Hour BP Recordings
Reliable ambulatory BP recordings were obtained in all patients, allowing us to use 92±4% of all readings of the first and 90±8% of the second recordings for analysis. As anticipated, ambulatory BP was higher during CsA than during AZA treatment. The nocturnal decline in BP during CsA but not during AZA treatment was almost completely abolished (Fig 1⇓). During CsA, only four patients had a nocturnal decline of mean BP of more than 10 mm Hg, whereas during AZA treatment, this number increased to nine patients. After conversion, the nocturnal decline in mean BP increased from 3.9 to 9.9 mm Hg (P<.05), and the ratio of nighttime to daytime mean BP decreased from 0.96±0.08 to 0.91±0.06 (P<.01) (Fig 2⇓). Unlike BP, ambulatory heart rate and its nocturnal decline were similar during both immunosuppressive regimens (Fig 1⇓).
After conversion, RBF and GFR moderately increased and RVR decreased (Table⇓). The nocturnal fall in mean BP and the level of 24-hour mean BP were not significantly correlated with absolute values of RBF, GFR, or RVR nor with changes of these parameters after conversion.
Plasma concentrations of renin and norepinephrine were within the normal ranges of our laboratory. Plasma norepinephrine concentration did not change after conversion, but plasma renin concentration tended to decrease. The plasma concentrations of PGE2 and TxB2 decreased (Table⇑). During both immunosuppressive regimens, plasma ANP concentrations were about twofold increased compared with the normal reference values of our laboratory. After conversion from CsA to AZA, plasma ANP concentration moderately decreased (P<.05) (Table⇑). None of the hormonal parameters was significantly correlated with the decline in nocturnal mean BP or the level of 24-hour mean arterial pressure.
Our study confirms the results of previous studies showing that CsA treatment increases BP in renal transplant recipients.10 12 14 In addition, it shows that the use of CsA may contribute to the loss of the nocturnal fall in BP in these patients. The ratio between nighttime and daytime mean arterial pressure decreased after conversion, indicating that on average a more physiological diurnal BP profile was present during AZA treatment.
The mechanism by which CsA impairs the nocturnal fall in BP is unclear. A decrease in sympathetic tone and increase in vagal tone are considered to be important for the normally occurring nocturnal decline in BP.19 Administration of CsA has been reported to be associated with an increase in muscle sympathetic nerve activity in heart transplant recipients and in patients with myasthenia gravis.10 Therefore, an increase in sympathetic tone might have contributed to the blunted diurnal BP rhythm in our patients as well. However, neither basal plasma norepinephrine concentration as an approximate index of sympathetic tone nor the nocturnal decrease in heart rate as an indirect parameter of sympathetic-vagal balance was affected by CsA in the present study. After conversion, the plasma concentrations of PGE2 and TxB2 decreased, but these changes were not significantly correlated with any of the BP parameters. Other investigators have reported that prostaglandins do not appear to play an important role in the development of CsA-associated systemic hypertension, which contrasts with their well-established effects in the renal vasculature during CsA treatment.20
GFR was moderately reduced and RVR markedly increased during CsA therapy compared with the AZA-based regimen. An attenuation of the nocturnal fall in BP has been observed in patients with advanced renal insufficiency and end-stage renal disease on hemodialysis.6 This abnormal diurnal BP variation has been linked to the sodium and fluid retention occurring in these conditions. One may wonder whether such a mechanism was also operative in our patients during CsA treatment. Although body weight did not change, plasma ANP concentration was higher and plasma renin concentration tended to be lower during CsA than during AZA treatment, suggesting that some degree of intravascular fluid retention was present during CsA treatment. A significant increase in plasma ANP concentrations in healthy men after a high oral dose of CsA has also been reported by Sturrock et al.14 The elevated plasma ANP concentration may also be related to glucocorticoid-induced sodium retention, which can be held responsible for the residual nondipping that was observed in 9 of 18 patients during AZA. Furthermore, in vitro studies have shown that glucocorticoids have the ability to enhance the cardiac release of ANP.21
A loss of the nocturnal fall in BP after organ transplantation has been reported by several investigators.1 2 5 7 It has been suggested that after cardiac transplantation, the denervated state of the transplanted heart accounts for this hemodynamic abnormality, and the regain of the nocturnal decline in BP is explained by reinnervation.8 Other investigators have reported that the reappearance of the nocturnal decline in BP in heart transplant recipients is correlated with the reduction of the glucocorticoid dose.5 8 Earlier studies suggest that the nocturnal decline in BP is attenuated or abolished in patients with exogenous or endogenous hypercortisolism.9 Thus, glucocorticoids and cardiac denervation seem to be important determinants of the attenuation of the nocturnal decline in BP after heart transplantation. In the present study, we show that in addition to these factors, the use of CsA is associated with a blunted diurnal BP rhythm. It is still unclear which single factor contributes most to the disturbance of 24-hour BP control in transplant recipients.
As a consequence of the treatment protocol, CsA therapy was replaced by AZA therapy and not vice versa. Therefore, the patients were always examined in the same order, which might have influenced the study outcome. During both recordings, 24-hour heart rate profiles were very similar, suggesting that no important differences in sleep quality or nighttime physical activity occurred. Studies on the reproducibility of ambulatory BP recordings have not shown a consistent difference between successive recordings.22 23 24 An order effect usually leads to a slightly higher BP during the initial phase of the first recording. Since in our study the recordings were started at 1 pm, this effect would have resulted in a larger day-night difference during CsA than during AZA therapy; however, the opposite was found.
In the present study, we assessed intravascular volume status by noninvasive measures, which consistently pointed toward volume expansion during CsA. Because of ethical considerations, we were unable to expand our study with more invasive procedures such as cardiac catheterization or additional radioisotope studies, which also have particular methodological problems.
In conclusion, we found that in addition to other factors, treatment with CsA per se is associated with a loss of the nocturnal decline in BP in renal transplant recipients. The clinical relevance of our findings remains speculative for the moment. In patients with essential hypertension or secondary forms of hypertension, a loss of diurnal BP variability is associated with an increased incidence of left ventricular hypertrophy and cardiovascular morbidity.25 In renal transplant recipients, a close relationship between 24-hour BP and the development of left ventricular hypertrophy has been found.26 Recently, it has been reported that conversion from CsA to AZA resulted in improved graft and patient survival and a trend toward a lower cardiovascular mortality.27 Further studies are needed to evaluate the potentially beneficial long-term effects of conversion from CsA to AZA and the relationship between 24-hour BP variation and cardiovascular morbidity and mortality in this patient group.
Selected Abbreviations and Acronyms
|ANP||=||atrial natriuretic peptide|
|GFR||=||glomerular filtration rate|
|RBF||=||renal blood flow|
|RVR||=||renal vascular resistance|
Reprint requests to M.A. van den Dorpel, MD, Department of Internal Medicine I, University Hospital Dijkzigt, Dr Molewaterplein 40, 3015 GD Rotterdam, Netherlands.
- Received October 3, 1995.
- Revision received October 26, 1995.
- Accepted March 26, 1996.
Reeves RA, Shapiro AP, Thompson ME, Johnsen AM. Loss of nocturnal decline in blood pressure after cardiac transplantation. Circulation. 1986;73:401-408.
Idema RN, Van den Meiracker AH, Balk AHHM, Bos E, Schalekamp MADH, Man in 't Veld AJ. Abnormal diurnal variation of blood pressure, cardiac output, and vascular resistance in cardiac transplant patients. Circulation. 1994;90:2797-2803.
Textor SC. De novo hypertension after liver transplantation. Hypertension. 1993;22:257-267.
Van den Borne P, Gelin M, Van de Stadt J, Degaute J-P. Circadian rhythms of blood pressure after liver transplantation. Hypertension. 1993;21:398-405.
Imai Y, Abe K, Sasaki S, Minami N, Nihei M, Munakata M, Murakami O, Matsue K, Sekino H, Miura Y, Yoshinaga K. Altered circadian blood pressure rhythm in patients with Cushing's syndrome. Hypertension. 1988;12:11-19.
Wenting GJ, Tan-Tjiong HL, Derkx FHM, Man in 't Veld AJ, Schalekamp MADH. Split renal function after captopril in unilateral renal artery stenosis. Br Med J. 1984;288:886-890.
Van der Hoorn FAJ, Boomsma F, Man in't Veld AJ, Schalekamp MADH. Determination of plasma catecholamines in human plasma by high performance liquid chromatography: comparison between a new method with fluorescence detection and an established method with electrochemical detection. J Chromatogr. 1989;487:17-27.
Derkx FHM, De Bruin RJA, Van Gool JMG, Rosmalen FMA, Van Hoek M-JC, Beerendonk CCM, Schalekamp MADH. A novel assay of plasma prorenin using a renin inhibitor. J Hypertens. 1993;11(suppl 5):S240-S241.
Kahtri IM, Freis ED. Hemodynamic changes during sleep. J Appl Physiol. 1967;22:867-873.
Pickering TG. Ambulatory Monitoring and Blood Pressure Variability. London, UK: Science Press; 1990:9.3-9.4.
Verdecchia P, Porcellati C, Schillaci G, Borgioni C, Ciucci A, Battistelli M, Guerrreri M, Gatteschi C, Zampi I, Santucci A, Santucci C, Reboldi G. Ambulatory blood pressure: an independent predictor of prognosis in essential hypertension. Hypertension.. 1994;24:793-801.
Hollander AAMJ, van Saasse JLCM, Kootte AMM, van Dorp WT, van Bockel HJ, van Es LA, van der Woude FJ. Beneficial effects of conversion from cyclosporin to azathioprine after kidney transplantation. Lancet. 1995:345:610-614.