Loss of nocturnal blood pressure fall after liver transplantation during immunosuppressive therapy

AJH 1995; 8:598-605

Loss of Nocturnal Blood Pressure Fall After Liver Transplantation During Immunosuppressive Therapy Sandra J. Taler, Stephen C. Textor, Vincent J. Canzanello, Daniel J. Wilson, Russell H. Wiesner, and Ruud A. Krom

Hypertension, which develops after organ transplantation during immunosuppression with cyclosporine (CSA), is often associated with a loss of nocturnal decrease in blood pressure. Few data correlate circadian blood pressure patterns before transplant with those observed at fixed time points after transplant, or address the role of alternate immunosuppressive agents such as FK506. FK506 is unrelated structurally to CSA and less often leads to hypertension early after transplant. The present study compared nocturnal blood pressure patterns in patients with end-stage liver disease (ESLD) before transplant to those of transplant recipients receiving either FK506 (0.15 mg/kg/day) plus prednisone or CSA (2 to 3 mg/kg/day) plus prednisone and azathioprine after orthotopic liver transplantation. Overnight ambulatory blood pressure profiles were studied in 13 pretransplant ESLD patients and in 34 patients (FK506: n = 13; CSA: n = 21) treated with different steroid doses (24 __- 11 mg/day FK506; 34 +- 3 mg/day CSA), according to protocol, 4 weeks (range, 2 to 7 weeks) after liver transplant. Mean blood pressure and heart rate values from awake and nocturnal 5-h time blocks were compared to 13 normotensive control subjects. Patients with ESLD were normotensive and maintained a normal nocturnal

blood pressure fall (125 -!-- 3/74 _ 2 mm Hg awake; 1 0 9 _ 3/60 _ 2 mm Hg nocturnal). Awake ambulatory blood pressures were higher in CSA patients than in FK506 patients (148 - 3 / 9 5 - 2 v 128 -+ 3 / 7 8 - 2 m m Hg, respectively; P < .01), despite reduced glomerular filtration rates in both transplant groups. Both immunosuppressive regimens led to a loss of nocturnal blood pressure fall, as compared to ESLD patients or normotensive controls. Nocturnal heart rates were higher in ESLD and transplant patients, but decreased from awake levels similarly in all groups. These data demonstrate that despite high heart rates, ESLD patients maintain normal circadian blood pressure patterns before transplantation with disturbances of circadian blood pressure appearing soon after liver transplantation with either FK506 (plus glucocorticoid) or CSA (plus glucocorticoid) immunosuppression. These disturbances are not limited to patients developing hypertension. Am J Hypertens 1995;8:598-6O5

Received July 21, 1994. AcceptedJanuary31, 1995. From the Divisionsof Hypertension(SJT, SCT, VJC,DJW), Gastroenterology( ~ ) , and TransplantSurgery(RAK),MayoClinic, Rochester, Minnesota. These studies were supported by a Grant-in-Aidfromthe Amer-

ican Heart Association (#91-0127-10) and National Institutes of Health General ClinicalResearch Grant MO1-RR-585. Address correspondenceand reprint requests to SandraJ. Taler, MD, Divisionof Hypertensionand InternalMedicine,MayoClinic, 200 First Street Southwest, Rochester, MN 55905.

© 1995 by the American Journal of Hypertension, Ltd.

KEY WORDS: Hypertension, FK506, tacrolimus, cyclosporine, transplantation, nocturnal fall, circadian rhythm, prednisone, ambulatory blood pressure monitoring, end-stage liver disease.

0895-7061/95/$9.50 0895-706I (95)00077-3

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lterations in blood pressure control and adrenergic nerve activity in patients with end-stage liver disease (ESLD) are well recognized. Most patients with ESLD have a hyperdynamic circulation, characterized by high cardiac output with low systemic vascular resistance. 1,2 The latter is attributed to vasodilation within the mesenteric vasculature. 3 Exaggerated sympathetic adrenergic nerve activity is characteristic of this condition, 4 manifested by increased heart rate and renal vasoconstriction. After liver transplantation, complex hemodynamic changes evolve. A rise in systemic vascular resistance occurs within days to weeks. 2 The rise in resistance commonly produces a rise in blood pressure to clinically hypertensive levels (> 140/90 m m Hg), a finding particularly common since the introduction of cyclosporine A (CSA) as a primary immunosuppressive agent. Hypertension developing after organ transplantation is usually characterized by disturbed circadian rhythms, with a loss or reversal of the normal nocturnal fall in blood pressure. 5 The mechanisms underlying this loss of nocturnal pressure fall are not well understood. Conclusions about the role of cardiac innervation, glucocorticoid doses, adrenergic activation, and the specific role of CSA are limited by incomplete data regarding circadian patterns before transplant and collection of data at varied time points after transplantation. FK506 (tacrolimus), a macrolide antibiotic recently approved as an alternative immunosuppressive agent, is unrelated structurally to CSA but with nearly identical immunosuppressive actions. Despite having hormonal and renal effects in parallel to those of CSA, the incidence of hypertension after transplantation with FK506 is lower (22% to 28%) as compared to CSA (78%) within 1 year after transplantation. 2'6 The present study was undertaken to examine circadian patterns of blood pressure and heart rate in patients with ESLD before transplant and during the early time period (1 month) after liver transplantation comparing CSA- and FK506-based immunosuppressive regimens.

A

METHODS Patient P o p u l a t i o n Forty-seven patients were studied; 13 pretransplant candidates with ESLD and 34 transplant recipients studied early after orthotopic liver transplantation (mean, 4.1 -- 0.2 weeks; range, 2 to 7 weeks). Causes of liver failure were similar in all groups (Table 1). Clinical and laboratory characteristics are summarized in Table 2. To characterize circadian blood pressure patterns in ESLD, 13 consecutive liver transplant candidates (9 men, 4 women) were studied by overnight ambulatory blood pressure monitoring (ABPM). Two patients were taking low

TABLE 1. CAUSES OF HEPATIC FAILURE IN ESLD PATIENTS AND LIVER TRANSPLANT RECIPIENTS Number of Patients Diagnosis

Primary sclerosing cholangitis Primary biliary cirrhosis Chronic active hepatitis (B or C) Alcoholic cirrhosis e~l-antitrypsin deficiency Wilson's disease Cryptogenic cirrhosis

ESLD

CSA

FK506

4 1 3 2 0 0 3

6 2 7 3 1 1 1

4 3 2 1 1 0 2

dose corticosteroids (prednisone, 7.5 and 12.5 mg/ day). For the transplant recipients, ABPM was performed after hospital discharge and before introduction of antihypertensive medications. Thirteen patients were receiving FK506 (8 men, 5 women) and 21 CSA (15 men, 6 women). After liver transplantation, a standardized immunosuppression protocol was used as described previously. 2 For patients treated with FKS06, immunosuppression consisted of 0.075 mg/kg FK506 administered intravenously as a continuous infusion every 12 h (daily dose, 0.15 mg/ kg), followed by oral doses of 0.15 mg/kg/day. Prednisone was administered at 100 rag/day and tapered to 10 mg/day during the first month. For patients treated with CSA, immunosuppression consisted of intravenous CSA (2 to 3 mg/kg as a continuous infusion beginning on the second day after transplant, followed by oral dosage adjustment to maintain trough blood levels between 250 and 400 mg/dL as measured by whole blood HPLC), prednisone (200 mg/day on a tapering schedule during the first month to 20 mg/day), and azathioprine (2 mg/kg/day). Measurements of blood pressure and renal function were performed in the transplant hypertension clinic and the General Clinical Research Center of this institution as described previously. 2'7 The procedures and protocol for this study were approved by the institutional review board of the Mayo Clinic. Informed, written consent was obtained. Ambulatory blood pressure measurements were obtained using an 18-h ABPM protocol (model 90207; SpaceLabs, Hillsboro, OR, or Pressurometer-IV; Del Mar Avionics, Irvine, CA) from 4 PM on day I until 10 AM on day 2. This 18-h monitoring period was selected to determine awake and inactive nocturnal blood pressure profiles without interfering with other posttransplant studies during morning and early afternoon hours. Each monitor consisted of an appropriately sized inflatable cuff, worn on the nondominant arm, connected by an air hose to a small portable pump worn on the patient's shoulder or belt and programmed to inflate the cuff at preset intervals. Blood Protocol

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TABLE 2. CLINICAL A N D LABORATORY CHARACTERISTICS OF ESLD PATIENTS A N D LIVER T R A N S P L A N T RECIPIENTS Characteristics

Male:female Mean age (years) Pretransplant BP (mm Hg) Systolic Diastolic At study: Body weight (kg) Medication dosage (rag/day) Prednisone (mean) Prednisone (median) FK506 CSA Blood level FK506 (ng/dL) CSA (mg/dL) Serum creatinine (~mol/L) (normal, 53-106) GFR (iothalamate clearance, mL/min/1.73 m2)~ Serum albumin (g/L) (normal, 35--50) AST (~kat/L) (normal, 0.20-0.52)

ESLD (n = 13)

CSA (n = 21)

FK506 (n = 13)

9:4 50 -+ 3

15:6 44 + 2

8:5 54 -+ 3*

125 --- 3 74 + 2

117 + 3 69 + 2

113 + 6 69 -+ 3

78.5 + 4

69.5 + 2

72.1 + 5

34 -+ 3 30

24 + 11t 12.5t 9.8 + 1.5

681 + 53 11.9 -+ 2.4 97 87.2 27 1.33

+-- 9 +-- 11.1 -- 1§ --- 0.23§

313.2 106 69.7 31 0.65

-- 22 -+ 9 + 8.3 + 1 -+ 0.13

141 57.4 31 0.62

- 9t --- 5.3 + 1 - 0.13

Mean +- SEM, *P < .05 compared to CSA; t P < .01 compared to CSA; §P < .05 compared to CSA and FKS06. ~:Normal range in normotensive control subjects on normal sodium intake 125 +- 18 mL/min/1.73 m 2. ESLD, End stage liver disease; GFR, glomerular filtration rate; AST, aspartate aminotransferase.

pressure a n d heart rate were m e a s u r e d automatically and stored e v e r y 10 rain d u r i n g awake h o u r s and e v e r y 20 min d u r i n g nocturnal hours. The Del Mar unit detected Korotkoff s o u n d s b y an auscultatory m e t h o d using a m i c r o p h o n e t a p e d over the corres p o n d i n g brachial artery; the SpaceLabs unit measured blood pressure b y an oscillometric m e t h o d . Patients were advised to continue their activities d u r i n g the recording period, but asked to allow the arm to h a n g quietly b y their side d u r i n g each m e a s u r e m e n t to minimize interference by arm m o v e m e n t s . To e n s u r e reliable m e a s u r e m e n t s in each subject, blood pressure m e a s u r e m e n t s m a d e in sitting and standing positions w e r e calibrated against m a n u a l auscultatory m e a s u r e m e n t s at the outset. If the difference b e t w e e n the averages of the systolic or diastolic pressures, m e a s u r e d simultaneously by both m e t h o d s , e x c e e d e d 8 m m Hg, the cuff and microp h o n e were repositioned a n d the p r o c e d u r e repeated until a d e q u a t e concordance of readings was achieved (Del Mar unit) or a n o t h e r a t t e m p t at calibration was tried using the auscultatory unit rather than the oscillometric m e t h o d . The technicians w h o p e r f o r m e d these measurements had undergone appropriate training and testing, including audiometric examination, to e n s u r e their ability to measure blood pressure accurately. Before final analysis, the r e c o r d e d data were edited as follows. The following readings w e r e c o m p u t e r flagged for review a n d interpretation: systolic read-

ings ->245 m m Hg or <20 m m Hg, diastolic readings <20 m m Hg, n o n s e n s e readings w h e r e systolic readings were within 10 m m H g of diastolic readings or systolic differences of ->50 m m Hg, diastolic differences of ->30 m m Hg f r o m the immediately p r e c e d i n g or following values. A 5-h period from late a f t e r n o o n into early e v e n i n g w h e n the patient was awake a n d active was selected from each ABPM record (Figure 1). A s e c o n d 5-h period was selected from late night or early m o r n i n g w h e n the patient was at rest in bed, based on patient diaries and clock time. A 2-h interval b e t w e e n the awake and nocturnal data periods was excluded from analysis as a transition period b e t w e e n activity a n d rest. To be included in the analysis, each data set r e q u i r e d a m i n i m u m of 24 a w a k e b l o o d p r e s s u r e readings, and 12 nocturnal blood pressure readings within the 5-h time periods. N o r m o t e n s i v e subjects, m a t c h e d b y age and sex to the FK506 patients, w e r e selected for c o m p a r i s o n from a registry of patients p r e v i o u s l y s t u d i e d b y ABPM. s These subjects u n d e r w e n t 24-h ABPM using similar e q u i p m e n t and protocols. Statistical Methods Results of all s t u d i e s w e r e stored on a database using CLINFO. Data w e r e expressed as m e a n -+ SEM. C o m p a r i s o n s b e t w e e n multiple g r o u p s were p e r f o r m e d b y analysis of variance. Specific g r o u p comparisons were p e r f o r m e d using Duncan's multiple c o m p a r i s o n test. I m m u n o s u p p r e s -

AJH-JUNE 1995-VOL. 8, NO. 6

N O C T U R N A L BP AFTER T R A N S P L A N T

entire range of comparison determined by BlandAltman analysis.

250

2OO

== ~ 150 1,o

5O

Awake:

Nocturnal:

134/83 mm Hg

113/59 mm Hg

iiiiiiill iiii i;iiiiiiiiii iiiiiiiiiiiiiiiiiiiiii iiiiiiiiill .v.

0

40

6p

8p

10p |2m

(A)

2a

4a

6a

8a

lea

2'p

12n

4'p

Real time data

Nocturnal: 163/107 mm Hg

Awake:

152/106 mm Hg

"~ 150' n "l- 140 I00@mll

sol

6p

8p

IGp 12ra 2a

(B)

4a

6a

I

I

I

I

I

lOa 12n

2p

4p

Real time data

250

2OO

I~

Awake:

Nocturnal:

110/66 mm Hg

111/63mm Hg

.........

5010:'~ 4p

(c)

6p

8p

100 12m 2a

4a

601

", *

,

6a

8a

.

.

.

10a 12n

. 2p

4p

Real time data

FIGURE 1. Examples of 18-h ABPM in a representative (A) ESLD patient and (B) CSA- and (C) FK506-treated transplant recipients. Five-hour blocks were selected to determine awake and nocturnal blood pressures. A 2-h transition period was excluded.

sant drug doses and laboratory comparisons between transplant regimens and transplant recipients were p e r f o r m e d using parametric and nonparametric methods as appropriate. Mean values for blood pressure and heart rate from the awake 5-h time block were compared to mean values from the nocturnal 5-h time block in all subjects. To examine the use of 5-h time blocks for awake and nocturnal pressures, we compared 5-h time blocks to entire awake and nocturnal time periods in the control subjects from 24-h ABPM recordings using both linear regression and Bland-Altman analysis. 9 Regression analysis of systolic and diastolic blood pressure and heart rate from the 5-h segments and longer periods agreed closely (r -> 0.93 in all instances) with a minimal error (4%) detected over the

RESULTS

Clinical and laboratory characteristics of the ESLD patients were similar to those of the transplant groups and are summarized in Table 2. Transplant recipients receiving CSA were younger than those receiving FK506. No differences were evident between blood pressures in the ESLD patients and pretransplant blood pressures of the transplant recipients. Low albumin and elevated transaminase levels in the ESLD patients were consistent with advanced liver disease. One month after transplantation, daily prednisone doses were lower in FK506-treated patients compared to the CSA group as designed by protocol (mean dose, 24 + 11 mg/day v 34 +- 3 rag/day; median dose, 12.5 v 30 mg/day, respectively). Excluding two patients (one treated with FK506 and one treated with CSA) taking bolus corticosteroids for treatment of rejection, mean doses were similar to median doses (mean dose, 13 - 1 mg/day FK506 v 32 + 2 mg/day CSA). Glomerular filtration rates in ESLD patients and both FK506 and CSA groups were less than those of normotensive subjects studied under similar conditions. 2 Serum creatinine values were higher in the FK506-treated patients t h a n in the CSA-treated group. Serum albumin and aspartate aminotransferase did not differ between transplant groups.

Ambulatory Blood Pressure Measurements Awake and nocturnal blood pressures and heart rates are summarized in Table 3 and illustrated in Figure 1. The ESLD patients studied had blood pressures that did not differ from normotensive subjects either awake or at night. Despite higher resting heart rates, average nocturnal falls in systolic (15 +- 2 mm Hg) and diastolic (14 -+ 2 mm Hg) blood pressures were similar to normotensive subjects (Figures 1A, 2A). In contrast, 1 month after transplantation in the CSA group the blood pressures were increased compared to the blood pressures before transplant and higher than those in FKS06-treated patients (Figure 1B, C; Table 3). Nocturnal blood pressures did not decrease in either the CSA group ( - 1 - 2 mm H g / - 4 --2mmHgvcontrol, -16 + 3mmHg/-10-+ 2mm Hg, P < .05) or the FKS06 group ( - 3 + 2 mm H g / - 4 -+ 2 mm Hg v control, - 16 -+ 3 mm H g / - 10 + 2 mm Hg, P < .05) (Figure 2A). Hence, nocturnal blood pressures in both CSA and FK506 groups were elevated compared to control subjects and ESLD patients before transplant (Table 3). Heart Rate Heart rates were elevated throughout the monitoring period in ESLD patients and in both transplant groups. Nocturnal heart rates decreased, however, to similar degrees in all groups, regardless

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TABLE 3. BLOOD PRESSURES A N D HEART RATES D U R I N G AWAKE A N D N O C T U R N A L AMBULATORY BLOOD PRESSURE MONITORING Pretransplant

Awake Systolic BP (mm Hg) Diastolic BP (mm Hg) Heart rate (beats/min) Nocturnal Systolic BP (ram Hg) Diastolic BP (mm Hg) Heart rate (beats/min) Nocturnal Fall (nocturnal-awake) Systolic BP (ram Hg) Diastolic BP (mrn Hg) Heart rate (beats/min)

Early Posttransplant (2-7 wk)

ESLD (n = 13)

CSA (n = 21)

FKS06 (n -- 13)

125 _-. 3 74 + 2 87+ 3t

148 + 3* 95 + 2* 91+ 3t

128 + 3 78 + 2 85 + 4t

124 + 3 74-+ 1 74-+ 3

109 _+ 3 60 + 2 80 --+ 2t"

147 + 3* 92-+ 2* 77 + 3t"

125 -+ 4* 74 + 3* 76 + 3"1

108 -+ 3 64+ 2 63 + 2

-1 + 2~ - 4 -+ 2~ -14-+2

- 3 + 21: - 4 + 21: -9+-2

-16 - 3 -10 + 2 -10-+2

-15 + 2 -14 -+ 2 -7+2

Nl Subjects (n = 13)

Mean +- SEM. *P < .01 v all other groups; ~'P < .01 v normal subjects; J;P < .01 v ESLD and normal subjects.

ESLD, end stage liver disease.

of blood pressure or immunosuppressive regimen (Figure 2B, Table 3).

pressure despite elevated heart rates. Early after liver transplantation, CSA-treated patients had elevated arterial pressures and lost the normal nocturnal presDISCUSSION sure fall. Remarkably, FK506-treated patients also lost Results from this study indicate that patients with the nocturnal pressure fall, despite normal average ESLD demonstrate normal circadian patterns of blood blood pressures and lower daily glucocorticoid doses. This study used 5-h time segments obtained from 18-h ABPM recordings to avoid interfering with s I morning activities required by clinical care after trans0 plantation. The use of 5-h time blocks in our studies O. m A to reflect awake and nocturnal blood pressure and heart rate patterns was supported by close agreement ~, E between such time blocks and larger time periods obg -,o z tained from 24-h recordings in healthy subjects. Fur-15 thermore, the degree of fall in our normotensive subjects using this method of ABPM analysis was similar -20 ESLD CSA FKS06 Normal to values reported by others using 24-h recordings. s'w Other studies also demonstrate close agree(A) * P < .01 vs ESLD and normal subjecls ment between short-term ABPM blocks and 24-h monitoring. 11,12 5The loss of nocturnal pressure fall after transplan0tation may have important and possibly adverse imrr T plications. Loss of nocturnal fall in blood pressure in essential and secondary hypertensive patients is as-o . ~ -10 sociated with higher incidence of cardiovascular comZ plications. Sustained nocturnal elevations correlate -15 with left ventricular h y p e r t r o p h y , 13 lacunar infarcts, 14 and microalbuminuria. 15 Atherosclerotic car-20 (B) ESLD CSA FKS06 Normal diovascular disease is the leading cause of late morbidity and mortality in organ transplant recipients. FIGURE 2. Day-night blood pressure (A) and heart rate (B) The rapidity with which hypertensive target organ differences before and after liver transplantation. Both CSA, azaeffects develop after transplantation may relate to this thioprine, prednisone and FK506, prednisone treated patients failed to demonstrate a nocturnal pressure fall, in contrast to the lack of nocturnal decline. In cardiac transplant recipESLD patients and normal subjects. Nocturnal heart rates fell to ients, the rapid development of left ventricular hya similar degree in all groups. pertrophy 16'17 has been attributed to posttransplant

AJH-JUNE 1995-VOL. 8, NO. 6

hypertension; however, evidence to date is not conclusive. 18"19 Whether similar consequences result from loss of nocturnal blood pressure fall in patients w h o remain normotensive, such as those taking FK506, is not known. Our results confirm and extend previous reports of disturbed circadian blood pressure variation after transplantation. Initial studies in cardiac transplant recipients emphasized that circadian blood pressure patterns are similar to those of patients with autonomic insufficiency, s'2° The investigators implicated cardiac denervation as the cause. Lower levels of circulating catecholamines at night account for nocturnal decline in heart rate, even early after transplant. 2° The fact that some patients regain a nocturnal pressure fall later has been interpreted as "reinnervation. ''21'22 However, an identical loss of nocturnal pressure variation after liver and renal transplantation argues against a primary role for cardiac denervation. Some researchers 23-25 suggest that enhanced sympathetic adrenergic stimulation after transplantation may explain both the development of posttransplant hypertension and the loss of circadian pressure variation. Several of our observations challenge this interpretation. First, despite high heart rates and cardiac outputs, 1'2 our patients with ESLD demonstrated normal nocturnal blood pressure falls. Other investigators have demonstrated increased sympathetic nerve traffic and circulating catecholamines in ESLD. 4 These data indicate that enhanced sympathetic nerve activity need not eliminate circadian blood pressure patterns. Second, the loss of diurnal patterns we observed after liver transplantation occurred during a period in which Floras et al 4 demonstrated a fall in sympathetic nerve traffic as recorded in the peroneal nerve. Third, loss of nocturnal pressure pattern was equally demonstrable in FK506 patients whose blood pressures were not elevated, despite experimental evidence 23"26 that FK506 and CSA affect nerve traffic to a similar degree. Hence, these studies suggest that neither the degree of sympathetic adrenergic activation nor the absolute levels of arterial pressure are closely related to circadian patterns of blood pressure after transplantation. The effects of the corticosteroid dose on diurnal pressure pattern are difficult to determine precisely. There is evidence that excess glucocorticoid, either of endogenous or exogenous source, affects circadian blood pressure rhythm. Reports in patients with Cushing's syndrome demonstrate a loss of nocturnal pressure fall, with preserved fall in heart rate, 27'2s analogous to the posttransplant patterns reported here. Exogenous glucocorticoid treatment induces a nocturnal rise or loss of the usual fall in blood pressure. 29 Daytime heart rates are higher in glucocorticoid-treated patients than in essential hypertensives,

NOCTURNALBP AFTERTRANSPLANT 603

yet the nocturnal fall in heart rate is preserved. Corticosteroid administration, like Cushing's syndrome, may lead to disturbance of the normal hypothalamicpituitary-adrenal periodicity and its action on the autonomic nervous system by modulating synthesis of sympathetic neurotransmitters and vascular response to catecholamines. 28'29 Previous studies of posttransplant blood pressure patterns are confounded by inclusion of data obtained at widely varying time points (up to several years) after transplantation. In most cases, steroid doses are decreased as patients achieve stable graft function, also at varying time points. Hence, the effects of steroid dose after transplant cannot be readily separated from the effects of time after transplant. Van de Borne et a121 reported maintenance of normal circadian blood pressure variation in a group of cardiac transplant recipients receiving low dose corticosteroids, and demonstrated recovery of circadian rhythm in a second group by 7 months after transplant, correlating with the decrease in corticosteroid dose. Additional studies in liver transplant recipients indicate that 59% have normal nocturnal blood pressure falls when studied late after transplantation, correlating with lower mean doses of glucocorticoids. 3° Our results were obtained early after transplantation in liver transplant recipients receiving different steroid doses as part of the design of their immunosuppressive regimen. It is of interest that two of the ESLD patients were taking daily corticosteroids in doses (7.5 and 12.5 rag/day) comparable to the transplant recipients at i month after surgery. Despite taking steroids, nocturnal pressure fall was preserved. Within the transplant recipient groups, nocturnal falls in blood pressure were universally absent despite different steroid doses. However, it should be emphasized that all patients were taking pharmacologic doses of glucocorticoids in a fashion that precluded normal diurnal variation. A role for steroids that reflects a "threshold p h e n o m e n o n " cannot be excluded from these data. Because the loss of nocturnal fall was o b s e r v e d in n o r m o t e n s i v e patients treated with FK506, our results further argue against a unique role for CSA in this regard. Both transplant groups had reduced glomerular filtration rates, which have been associated with impaired sodium excretion. 2"31 Studies in patients with various degrees of renal failure and volume expansion for other reasons demonstrate a loss of nocturnal blood pressure fall. 32'33 Hence, both FK506 and CSA recipients likely experience relative volume expansion during a transition period between marked pretransplant vasodilatation and posttransplant systemic vasoconstriction. We interpret our results with overnight blood pressure monitoring to reflect volume expansion occurring during this transition, suggesting that baroreceptor reflexes do not induce sufficient va-

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sodilatation to lower arterial pressure in the face of persistently exaggerated cardiac outputs. Several studies suggest that normal circadian patterns redevelop in some transplant recipients at a later time. Whether regaining nocturnal blood pressure patterns represents a return of baroreceptor sensitivity, resolution of volume expansion, or other factors cannot be addressed with the present data. Multiple processes may occur. Several studies indicate that CSA-induced hypertension continues to represent a relatively volume expanded state long term, compared to patients treated only with azathioprine and corticosteroids. 34"3s Long-term studies regarding both circadian blood pressure patterns and volume status of patients treated with FK506 are not yet available. Taken together, our results demonstrate that patients with ESLD before transplantation maintain normal circadian blood pressure patterns but lose nocturnal blood pressure variation during the early period after liver transplantation whether treated with FK506 or CSA immunosuppression. It is likely that this loss of circadian rhythm reflects several complex hemodynamic, adrenergic, and hormonal mechanisms during the transition from ESLD to the posttransplant state. Further studies to elucidate the roles of volume and altered endothelial function in this process are warranted as our results establish that loss of nocturnal fall after transplantation is not limited to CSA administration. Furthermore, these studies dissociated nocturnal regulation of blood pressure itself from the absolute level of blood pressure.

8.

9.

10.

11.

12.

13.

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15.

16.

17.

REFERENCES

1. Murray JF, Dawson AM, Sherlock S: Circulatory changes in chronic liver disease. Am J Med 1958;24: 358-367. 2. Textor SC, Wiesner R, Wilson DJ, et al: Systemic and renal hemodynamic differences between FK506 and cyclosporine A in liver transplant recipients. Transplantation 1993;55:1332-1339. 3. Benoit JN, Korthuis RJ, Granger DN, Battarbee HD: Splanchnic hemodynamics in acute and chronic portal hypertension, in Bomzon A, Blendis LM (eds): Cardiovascular Complications of Liver Disease. Boca Raton, CRC Press, 1990, pp 179-206. 4. Floras JS, Legault L, Morali GA, et al: Increased sympathetic outflow in cirrhosis and ascites: direct evidence from intraneural recordings. Ann Intern Med 1991;114:373-380. 5. Reeves RA, Shapiro AP, Thompson ME, Johnsen AM: Loss of nocturnal decline in blood pressure after cardiac transplantation. Circulation 1986;73:401408. 6. Todo S, Fung JJ, Tzakis A, et al: One hundred ten consecutive primary orthotopic liver transplants under FK506 in adults. Transplant Proc 1991;23:13971402. 7. Textor SC, Wilson DJ, Lerman A, et al: Renal hemo-

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