Cardiovascular disease is the dominant cause of death in renal transplant recipients (1,2). One known cardiovascular risk factor is hypertension, which is highly prevalent both before and after renal transplantation affecting 70%–90% of the recipients (3–6). Hypertension, among other factors such as anemia, fluid overload, the presence of arteriovenous (AV) fistula, and hyperparathyroidism, may cause left ventricular hypertrophy (LVH), a commonly observed complication observed in end-stage renal disease patients (>60%) and also an important independent determinant of mortality (7–10). In chronic uremia, there are multiple predisposing factors to LVH (11). After a successful renal transplantation, most of these predisposing factors are usually eliminated. However, hypertension tends to persist especially in calcineurin-inhibitor treated recipients (3–6).
The effect of renal transplantation on LVH is a subject of controversy. Prospective echocardiographic studies have demonstrated regression of LVH after successful renal transplantation (12–15), whereas others have not observed such an effect (16,17). Blood pressure (BP) seems to play a determinant role in LVH evolution after successful renal transplantation (16,17).
Studies in nonuremic hypertensive subjects suggest that, at equivalent blood pressure control, angiotensin converting enzyme (ACE) inhibitors may be more potent than β-blockers and diuretics in the reduction of LVM and that calcium channel blockers (CCB) have an effect in the intermediate range (18). Some authors have suggested that reversal of structural vascular changes during antihypertensive therapy is more dependent on the blockade of the renin-angiotensin-aldosterone system than on the lowering of the systemic blood pressure (19,20). To our knowledge, no study has been performed in transplant recipients addressing the use of ACE inhibitors or CCBs focusing on regression of LVH after transplantation.
In the present study, we prospectively examined the morphologic and functional cardiac parameters after transplantation in hypertensive renal transplant recipients receiving cyclosporin. The patients were randomized to double-blind treatment with lisinopril or controlled-release nifedipine treatment early after renal transplantation. Echocardiography was performed at 8–10 weeks (baseline) and after 12 months (follow-up) of antihypertensive treatment.
MATERIALS AND METHODS
From January of 1995 to April of 1997, 287 renal transplant recipients were considered eligible for the study, 68 remained normotensive as defined by a diastolic blood pressure of ≤95 mmHg. Of the 219 hypertensive patients, 32 received a CCB/ACE inhibitor due to isolated systolic BP, 21 refused to participate, and 12 received an ACE inhibitor for heart failure. The remaining 154 patients were randomized according to protocol. All patients gave informed consent to participate. Eligible patients were over 18 years of age and had recently received a renal transplant. Exclusion criteria were known hypersensitivity to either of the study drugs, myocardial infarction in the previous 6 months, donor age under 10 years of age, or stenosis of the graft renal artery.
The study design was a randomized single-center, double-blind, double-dummy, parallel group comparative study. The patients who presented with hypertension within the first 3 weeks after transplantation were asked to participate in the study. All blood pressure measurements (also by the local nephrologist) were performed after a minimum of 10 min of rest with the patient sitting. An average of three measurements taken at intervals of 3 min was calculated. Blood pressures were measured on the arm without arteriovenous fistula. If the patients did not have a patent brachial arteriovenous fistula, the arm with the higher blood pressure readings was determined at entry into the study and used for all additional measurements. At inclusion, blood pressure was measured at three different times with a minimum of 12 hr between the first and the last measurement. Patients with persistent hypertension who had given written informed consent were randomized to receive 1 tablet controlled-release nifedipine (30 mg once daily) plus placebo or 1 tablet lisinopril (10 mg once daily) plus placebo. Treatment allocation was performed using a predetermined, computer-generated randomization scheme. Patients were randomly allocated to one of two treatment groups in blocks of 10 with no stratification. The randomization ratio was 1/1. The dose was doubled when necessary, target diastolic blood pressure being below 90 mmHg. Other antihypertensive drugs were added as indicated. Concomitant use of ACE inhibitors, angiotensin II receptor blockers, or CCBs was not allowed.
Echocardiography was performed twice. Baseline recordings were performed in a stable phase after 8–10 weeks on study medication to avoid the tendency of volume retention in the early posttransplant period. Echocardiographic measurements were repeated 12 months after transplantation (follow-up) in renal transplant recipients still on study medication.
All patients were assessed for drug safety, tolerance, and efficacy in an outpatient setting at the National Hospital during the first 2 months after transplantation. Thereafter, patients were followed by their local nephrologist. All changes in medication and any adverse events were reported to the National Hospital and consistently recorded. The final follow-up evaluation was performed at the National Hospital approximately 1 year after randomization.
A Vingmed CFM 750 ultrasonic device system (GE Vingmed Sound, Horten, Norway) with a duplex mechanical annular array probe was used. Signals from the last 10 sec are stored in an internal replay memory where they can be recalled or transferred to external computers. The patients were examined in the lateral recumbent position after 15 min of rest. Standard ultrasonic techniques and acoustic windows were used to visualize the heart. Dimensions were determined by M-mode echocardiography. Pulsed, continuous, and color Doppler echocardiography in at least three planes were used to assess valvar function. Recordings at baseline and follow-up were performed by the same examiner (PEB) and were transferred as digital data to a PowerMac computer (Apple Computer Inc, Cupertino, CA) for later analysis. In our laboratory, the intraobserver variability is below 12% for LVM.
After conclusion of the study, each recording was coded and interpreted at random by a second experienced observer who was unaware of the subject identification and clinical characteristics (HI). Recordings from each patient were analyzed simultaneously to ensure consistent measurement technique using a dedicated analysis program (Echopac, GE Vingmed Sound). Dimensions of the left ventricle were measured using the convention of the American Society of Echocardiography using the mean of three consecutive heart beats (21). The two-dimensional left ventricular endocardium was traced at end diastole and peak systole in cine loops of apical four chamber and two chamber views, and the correct position of the tracings were controlled by running the cine loops.
Left ventricular mass (LVM) was calculated (22) as:
0.83[(IVS + LVDd + PW)3 − LVDd3]g
where IVS is diastolic dimension of intraventricular septum, LVDd is left ventricular diastolic dimension, and PW is diastolic dimension of posterior wall, in centimeters. LVM was normalized for body surface area, left ventricular mass index (LVMI) and LVH was defined as LVMI>134 g/m2 in men and 110 g/m2 in women (23). An algorithm using the biplane Simpson rule calculated left ventricular ejection fraction (EF).
All patients recruited received baseline triple immunosuppression with CsA (Sandimmune Neoral), prednisolone, and azathioprine from the day of transplantation. Oral CsA therapy was started either before or just after the transplantation. Initial CsA dose was 10 mg/kg per day. Target trough CsA whole blood concentration was 300–400 μg/L for weeks 1–2, 250–350 μg/L for weeks 3–4, and 150–250 μg/L for weeks 5–8. From week 9–26, the target CsA concentration was 125–200 μg/L, and from week 27, a concentration of 100–150 μg/L was targeted. Oral prednisolone was started on day 1 at 80 mg/day. Initially, it was tapered 10 mg/day until 20 mg was reached. Further reduction of 5 mg/day was performed every 4 weeks until 10 mg/day was reached. Initial azathioprine dose was ≥2 mg/kg per day and tapered to 1 mg/kg per day after 1 month.
The end point for this study was the change in echocardiographic parameters from baseline to follow-up after 1 year of treatment with nifedipine versus lisinopril in hypertensive renal transplant recipients receiving CsA.
Data are reported as mean±SD. Treatment groups were compared for demographic characteristics using the Student’s two-sample test (approximately normally distributed data), the Wilcoxon two-sample test (non-normally distributed data), or the Fisher’s exact test for categorical data. For the efficacy analysis, treatment groups were compared using analysis of covariance with baseline as the covariate for the change in echocardiographic findings. Statistical significance was defined as P <0.05. With 60 patients in each treatment group, significance level of 0.05, and assumed SD of 19, the study would have 80% power to detect a difference in LVMI between treatment groups of 10 g/m2.
One hundred fifty-four renal transplant recipients were included in the study (n=78 on nifedipine, n=76 on lisinopril). Hypertension usually occurred early after transplantation and treatment started on average 3 days after transplantation (range, 1–22 in the nifedipine group, 1–16 in the lisinopril group). One hundred twenty-three renal transplant recipients (80%) completed 1 year of antihypertensive treatment. Baseline demographics are presented in Table 1. The reasons for premature withdrawals are presented in Table 2. There were three graft losses due to rejection, all in the lisinopril group.
Echocardiographic results at baseline and at follow-up are presented in Table 3. Seven of the included patients had technically inadequate echocardiograms and were excluded from the final evaluation, and results from 116 patients are presented. None of the patients had severe valvular disease. No significant differences between baseline measurements of the two groups were present. At baseline 66% of the patients had LVH in the nifedipine group and 63% in the lisinopril group. After 1 year of treatment, the myocardial mass was considerably reduced by 15% (P <0.0001) in both groups, from 153.3±44.4 to 130.8±37.5 g/m2 in the nifedipine group and from 142.2±35.4 to 120.9±34.0 g/m2 in the lisinopril group. These reductions in myocardial mass were statistically not different in the two treatment groups. At the end of 1 year, 45% of the recipients still had LVH in the nifedipine group and 41% in the lisinopril group.
No change in diastolic diameter of the left ventricle occurred during the treatment period, and the ejection fraction remained unchanged. The reduction in myocardial mass was due to a significant fall in the thickness of both interventricular septum and posterior wall. The decrease in wall thickness was similar in both treatment groups. These results were unchanged when normalizing the results for body surface area.
Blood pressure was controlled equally well in both study groups (Table 4). If high dose of the study drug was insufficient to achieve a diastolic BP≤90 mmHg, additional antihypertensive treatment was started (Table 5). The preferred first add on drug was a β-blocking agent. Some patients in addition received a loop-diuretic, which can significantly increase the antihypertensive effect of lisinopril and to a lesser extent nifedipine. There was no difference in type of additional antihypertensive treatment given patients during the study.
Hemoglobin values increased in both groups during the study period. The increase from baseline was most pronounced in the nifedipine group (11.3±1.4 to 13.8±2.0 g/L vs. 11.0±1.4 to 12.5±1.7 g/L in the lisinopril group, P <0.01 between groups at final visit). There was no statistically significant difference between serum creatinine values at baseline echocardiography (nifedipine 134±33 μmol/L vs. lisinopril 147±34 μmol/L). During the treatment period, there was a significant decrease in serum creatinine in the nifedipine group (125±32 μmol/L, P <0.01) but serum creatinine remained unchanged in the lisinopril group (144±45 μmol/L).
All patients were on standard immunosuppressive treatment with cyclosporine, prednisolone, and azathioprine at the time of randomization (see Methods and Patients section for details). The dosage of immunosuppressive medication and trough blood concentrations of CsA were the same in both groups at any period during the study (data not shown). Two patients were switched from CsA to tacrolimus during the study (one in each group).
No serious adverse event could be related to the study drugs. Transient hyperkalemia (not leading to hospitalization) was reported in 22 patients receiving lisinopril, significantly higher than 8 patients treated with nifedipine (P <0.05). However, only one patient in the lisinopril group was withdrawn from the study due to hyperkalemia. Fourteen patients treated with nifedipine and 3 patients treated with lisinopril (P <0.05) reported peripheral ankle edema. Two patients, both treated with nifedipine, withdrew from the study due to ankle edema. Two patients experienced cough, both were in the lisinopril group. Both continued in the study and considered the cough as a minor problem. Four patients experienced episodes of angina pectoris during the study period (one in the nifedipine group and three in the lisinopril group). No patients experienced a myocardial infarction.
The aim of this study was to compare the effects on LVH of an ACE inhibitor and a CCB in treatment of hypertensive renal transplant recipients. The results demonstrate that LVH is common in these patients. By controlling hypertension with lisinopril or controlled release nifedipine, there is a 15% reduction of LVMI after 1 year of treatment in both groups. This reduction in myocardial mass was due to reduced thickness of the left ventricular wall. To the best of our knowledge, the present study is the first controlled, blinded study to directly compare effects of different antihypertensive drugs on LVH in hypertensive renal transplant recipients.
It is well known that hypertension is associated with reduced kidney survival in patients with chronic renal disease (24,25) and after renal transplantation (1,26,27). LVH is a frequent finding in patients in both settings (7,9,24,25). In addition, LVH is a blood pressure-independent risk factor for cardiovascular morbidity and mortality both in essential hypertension and in end-stage renal disease (28,29). Koren et al. (28) showed that cardiovascular death occurred in a higher proportion of patients with than without LVH (14% compared with 0.5%, P <0.001). Similarly, cardiovascular complications are more common in renal transplant recipients with hypertension (1). These facts underline the importance of treatment of both hypertension and LVH after renal transplantation.
Whether antihypertensive drugs differ with regard to their ability to reduce left ventricular mass has been a matter of debate. In particular, the question has been raised whether certain antihypertensive drugs reduce myocardial hypertrophy beyond the effect of lowering blood pressure. Meta-analyses have shown that ACE inhibitors may be more potent than β-blockers and diuretics in the reduction of LVM and that CCB had an effect in the intermediate range (18,20). It is possible that the effects of antihypertensive drugs on myocardial hypertrophy are different in renal transplant patients and hypertensive patients with normal kidney function because sodium retention and relatively lower levels of plasma renin is a common finding in patient with posttransplant hypertension (30).
Before transplantation, there are many factors which may influence left ventricular morphology and function: hypervolemia, hypercirculation due to anemia and/or arteriovenous fistulae, uremic toxins, hypertension, electrolyte imbalance (11). Most of these factors are normally corrected during the first weeks after transplantation with the exception of persisting hypertension and arteriovenous fistulas. In earlier studies, fistula patency has not shown to influence left ventricular mass or function after renal transplantation (14,15,17). Therefore, persisting hypertension remained the conceivable dominant risk factor in the patients included in the study. Baseline measurements were performed in a stable phase 2–3 months after renal transplantation and not at the time of renal transplantation. This was done to avoid the influence on echocardiographic measurements of confounding factors such as uremia per SE, anemia, fluctuating kidney function during rejection episodes and negative effects of high-dose immunosuppressive drugs. If the baseline examination had been performed earlier, one would expect even greater reduction in myocardial mass but with more confounders from the drug effect per se.
Teruel et al. (14) studied the regression of LVH during the early time period after transplantation and found that there was a substantial decrement in LVMI during the first 3 months after transplantation. After this time-period, LVMI did not change. When the patients were split into hypertensive patients and normotensive patients, there was virtually no change in the hypertensive group from 3 months (169±48 g/m2) to 12 months (160±40 g/m2) posttransplant. However, none of the hypertensive patients in their study received CCB or ACE inhibitors (14). The normotensive group on the other hand showed a reduction in LVM (from 149±46 g/m2 to 120±27 g/m2) during the same time-period. In the present study, hypertensive recipients on CCB or ACE show a significant regression in LVM similar to normotensive patients in the study by Teruel et al. (14).
A limitation of our study is the lack of a normotensive “control” group to evaluate the “natural” progression of LVH after transplantation. However, few recipients remain normotensive after renal transplantation (3–6). Others have tried to address this problem. Peteiro et al. (15) performed echocardiographic measurements at the time of transplantation and 10 months later in 30 renal transplant recipients. Patients with a decrease in blood pressure after renal transplantation showed a reduction in LVM. Patients who remained hypertensive after renal transplantation experienced no change in LVM. In a study by Parfrey et al. (11), a multivariate analysis showed that, after transplantation, only blood pressure predicted change in LVM with a 2.1 g/m2 fall in LVMI for each mmHg fall in mean arterial pressure. Baseline echocardiography was performed within 12 months before renal transplantation (in a state of hypervolemia and uremia) and a follow-up echocardiography was performed within a year after transplantation. In the present study, the baseline echocardiography was performed 8–10 weeks after renal transplantation. We are not able to confirm that there is a correlation between the reduction in blood pressure and the reduction in left ventricular mass index (data not shown) during the study period. This indicates that treatment of hypertension is only one of many important factors affecting left ventricular mass after renal transplantation. It is conceivable that both study drugs in our study reduced LVM due to their effects on blood pressure and that the effect was consistent with an equally good blood pressure control in the two groups. It should also be noted that no patient became hypotensive or stopped taking the study medication from the time of the baseline echocardiography until the 1 year echocardiography was performed.
In conclusion, this study demonstrates that hypertension and LVH are common features early after renal transplantation. There is a significant improvement of left ventricular mass index in the first year of transplantation in patients with well controlled hypertension. Reduction of left ventricular mass index is observed to a similar extent in hypertensive patients treated with lisinopril or nifedipine. The ultimate impact on cardiovascular morbidity and mortality remains to be shown.
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© 2001 Lippincott Williams & Wilkins, Inc.
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