Regression of left ventricular hypertrophy by at₁ receptor blockade in renal transplant recipients

Abstract

AT₁ receptor antagonists control blood pressure (BP) effectively and reduce left ventricular hypertrophy in patients with essential hypertension. Because left ventricular hypertrophy is very common in renal transplant recipients, we examined the cardiovascular effects and the safety profile of the AT₁ receptor antagonist losartan in hypertensive renal transplant recipients. In 20 renal transplant recipients with stable renal graft function 50 mg of losartan was added to the preexisting antihypertensive treatment (no angiotensin-converting enzyme inhibitors) at least 6 months after renal transplantation. Twenty-four–hour ambulatory BP, two-dimensional-guided M-mode echocardiography, and duplex sonography, as well as renal function, red blood cell count, cyclosporine A and FK 506 levels, erythropoetin, and angiotensin II concentration were determined at baseline and after 6 months of therapy. With 24-h ambulatory BP measurement, systolic blood pressure (SBP) was reduced by 7.5 2.4 mm Hg and diastolic blood pressure (DBP) by 4.5 ± 1.8 mm Hg (P< .01 and P< .05, respectively). Posterior, septal, and relative wall thickness decreased by 0.95 ± 0.2 mm, 0.91 ± 0.2 mm and 0.04 ± 0.01 mm, respectively (all P< .001). Left ventricular mass index decreased by 18.1 ± 4.7 g/m² (P< .01). Ejection fraction and midwall fractional fiber shortening as systolic parameters and the relation of passive-to-active diastolic filling of the left ventricle were unaltered. Serum creatinine and cyclosporine A concentration remained stable in all patients. Hemoglobin and hematocrit decreased by 1.0 ± 0.3 g/dL and 3.6% ± 0.9%, respectively (P< .002 and P< .001) without a change in serum erythropoetin level. In renal transplant recipients the AT₁ receptor antagonist losartan reduces left ventricular hypertrophy without altering systolic or diastolic function. It is safe with regard to renal function and immunosuppression, but slightly decreases hemoglobin level.

Losartan, renal transplantation, left ventricular hypertrophy, erythropoesis

L eft ventricular (LV) hypertrophy has been identified as an indicator of poor prognosis in patients with essential hypertension and with secondary hypertension.^1–3 With regression of LV hypertrophy an improvement of the overall and cardiovascular prognosis has been shown in patients with essential hypertension.^4,5

In a recent meta-analysis, which included only studies with double-blind randomized controlled study design, angiotensin-converting enzyme (ACE) inhibitors evolved as the most potent drug class with respect to reduction of LV mass in essential hypertension.⁶ These data confirm the well-known role of the renin-angiotensin system in the pathogenesis of hypertension and LV hypertrophy.^7,8 However, ACE inhibition has specific side effects, activates alternative pathways for the conversion of angiotensin I in angiotensin II, and leads to an accumulation of bradykinin and substance P.^9–11

The angiotensin II receptor antagonists with losartan as first drug clinically introduced are effective antihypertensive agents with a safety and tolerance profile comparable to placebo.¹² In addition, a reduction of LV mass can be achieved, as has been demonstrated recently in 77 patients with essential hypertension after a 22-month therapy with losartan.¹³ The antihypertensive properties of losartan have been confirmed in patients with renal transplantation with no changes in renal graft function or any interference with immunosuppressive drugs being observed.¹⁴

Despite the high prevalence of LV hypertrophy in renal transplant recipients, little is known about its regression under therapy. Thus far few studies focused on the reduction of LV mass in renal transplant recipients, mostly investigating the effects of calcium channel blockers.¹⁵ The purpose of our study was to evaluate the cardiovascular effects and the safety profile with special regard to renal function and immunosuppression of the AT₁ receptor antagonist losartan in hypertensive renal transplant recipients.

Methods

Study design

The study design was open prospective. However, investigators evaluating echocardiograms, 24-h ambulatory BP, and endocrine parameters were blinded with regard to the examination time point and the clinical data of the patients. Eligible patients received 50 mg of losartan once daily for 26 weeks in addition to their antihypertensive treatment. ACE inhibitors and AT₁ receptor blockers other than losartan were not allowed 6 months before and throughout the study. If at any follow-up visit BP was not sufficiently controlled or symptomatic hypotension developed, the preexisting antihypertensive treatment was modified according to the discretion of the patient’s nephrologist. Clinical, laboratory, and echocardiographic evaluation as well as ambulatory BP measurement were performed at baseline and after 26 weeks.

Study population

Twenty patients with a history of successful renal transplantation of more than 6 months, a stable renal graft function for 3 months, and a serum creatinine concentration ≤2.0 mg/dL were consecutively recruited at our outpatient clinic, if unsatisfactorily controlled arterial hypertension was present. Patients were eligible if casual BP was ≤95 mm Hg diastolic and ≤160 mm Hg systolic at two consecutive outpatient visits. Patients with stenosis of the renal transplant artery (excluded by duplex sonography), valvular heart disease, chronic heart failure (New York Heart Association function class III–IV) or any other severe concomitant disease were excluded. Demographics and clinical data are given in Table 1.

Table 1.

demographics of the patients (n = 20)

Characteristics
Sex (male/female)	14/6
Age (yr)	45 ± 2
Weight (kg)	74.3 ± 2.5
Height (cm)	170 ± 2
Body mass index (kg/m2)	25.6 ± 0.7
Time posttransplantation (months)*	36 (6–192)
Number of antihypertensive drugs*	2 (1–5)

*

Median with range.

Laboratory workup

Hemoglobin, erythrocyte count, serum sodium, potassium, creatinine, urea and uric acid, blood glucose, serum lipids (including triglycerides, total cholesterol, high-density lipoprotein and low-density lipoprotein cholesterol), plasma cyclosporine A and FK-506 levels were determined at baseline, and after 4 and 26 weeks of treatment. An additional safety measurement of serum creatinine and plasma cyclosporine A or FK-506 concentration was performed at week 2. Serum erythropoetin and plasma angiotensin II were measured at baseline and after 26 weeks. In between visits were scheduled according to the discretion of the patient’s nephrologist.

Ambulatory blood pressure monitoring

Ambulatory BP was recorded noninvasively for 24 h (Spacelab 90207, Redmont, WA) on a routine working day (for details see Ref.¹⁶). Recordings were taken every 15 min from 6.01 AM to 10:00 PM and every 30 min from 10:01 PM to 6:00 AM. A built-in error-correction was used (excluding 1% of readings successfully completed) and profiles were added manually (excluding an additional 0.5% of readings successfully completed) to exclude erroneous readings.

Echocardiography

Two-dimensional guided M-mode echocardiography was performed using a 3.5-MHz probe (Hitachi EUB 565, Ecoscan Hitachi Ultraschall, Lübbecke, Germany). Echocardiograms were recorded in the III–IV left intercostal space lateral to the sternal border with the patient recumbant in the supine or half left-sided position. All traced echocardiograms were videotaped and read independently by two physicians unaware of the patients identity and the examination date. Septal and posterior wall thickness and end-diastolic diameter were measured according to the recommendations of the American Society of Echocardiography (ASE).¹⁷ Relative wall thickness, a parameter for concentric LV hypertrophy, was determined by dividing posterior wall thickness by half the end-diastolic diameter.¹⁸

Left ventricular mass was calculated according to the ASE and then corrected following the suggestions of Devereux and associates.¹⁸ The ratio of maximal velocity of the active-to-passive filling of the LV (Vmax A/E) and the ratio of the velocity time integral of the active to passive filling of the LV (VTI A/E), measured by Doppler sonography, were used to evaluate diastolic filling of the left ventricle.¹⁹ Ejection fraction (EF) and midwall fiber fractional shortening (midwall FFS) were used as parameters for LV systolic function.

Statistics

All statistical analyses were made using SPSS software. Paired Student t test and linear regression analysis were used where indicated. Two-tailed P values are given throughout the text. All data are expressed as mean ± standard error of the mean.

Results

Efficacy

All patients completed 26 weeks of treatment. At baseline patients were on one to five (median 2) antihypertensive drugs with β-blockers used by 16 patients, calcium channel blockers by 13, diuretics by 7, α-blockers by 6, and centrally sympatholytic drugs used by 5 patients. Throughout the study no change in the number or doses of antihypertensive drugs occurred. After 26 weeks of additional treatment with losartan a reduction of casual diastolic blood pressure by 5.6 ± 2.4 mm Hg (P < .05), but not of casual systolic blood pressure (SBP) was observed. Twenty-four-hour SBP and DBP was reduced by 7.5 ± 2.4 and 4.5 ± 1.8 mm Hg, respectively (all P < .05) (Table 2). The decrease in ambulatory BP was most marked at nighttime with 14.4 ± 3.3 mm Hg systolic and 8.2 ± 3.1 mm Hg diastolic, respectively (P < .02 and P < .05, respectively).

Table 2.

BLOOD PRESSURE AND ECHOCARDIOGRAPHIC DATA OF RENAL TRANSPLANT RECIPIENTS (N = 20) AT BASELINE AND AFTER 26 WEEKS OF LOSARTAN TREATMENT

Characteristics	Baseline	Week 26	P
Blood pressure
Casual SBP (mm Hg)	140 ± 4.9	136 ± 3.3	NS
Casual DBP (mm Hg)	90 ± 2.5	84 ± 1.6	.036
Heart rate (beats/min)	71 ± 3.7	65 ± 3.0	.046
24-h SBP (mm Hg)	139 ± 3.2	131 ± 3.5	.011
24-h DBP (mm Hg)	87 ± 1.9	83 ± 2.0	.029
Echocardiography
Left atrial diameter (mm)	41.7 ± 0.9	40.4 ± 1.0	.094
Diastolic posterior wall thickness (mm)	11.0 ± 0.4	10.1 ± 0.3	.001
Diastolic septal wall thickness (mm)	11.8 ± 0.4	10.9 ± 0.3	.001
Diastolic left ventricular diameter (mm)	51.3 ± 1.1	51.2 ± 0.9	NS
Relative wall thickness	0.43 ± 0.02	0.39 ± 0.01	.003
Left ventricular mass (g)	294 ± 22	262 ± 16	.01
Left ventricular mass index (g/m2)	162 ± 11.6	144 ± 8.4	.001
Vmax A/E	0.76 ± 0.05	0.73 ± 0.06	NS
VTI A/E	0.42 ± 0.04	0.43 ± 0.03	NS
EF (%)	66.8 ± 2.2	67.3 ± 3.1	NS
Midwall FFS (%)	16.3 ± 0.7	17.4 ± 1.0	NS

SBP = systolic blood pressure; NS = not significant; DBP = diastolic blood pressure; Vmax = maximal velocity; VTI = velocity time integral; EF = ejection fraction; midwall FFS = midwall fiber fractional shortening.

Echocardiography

By the end of week 26 posterior and septal wall thickness decreased by 0.95 ± 0.2 and 0.91 ± 0.2 mm, respectively (P < .001). Relative wall thickness as a parameter of concentric LV hypertrophy decreased by 0.04 ± 0.01 (P < .001), whereas left ventricular diastolic diameter did not. Left ventricular mass index decreased from 162 ± 11.6 to 144 ± 8.4 g/m², P < .01. At the end of the study LV mass index was normalized (men <135 g/m², women <110 g/m²) in nine patients compared with four patients at baseline (χ² test, P = .025). The reduction of LV mass index was not correlated to the corresponding changes in casual and 24-h ambulatory BP (data not given).

The diastolic LV filling determined by Vmax A/E and VTI A/E remained unchanged throughout the study, whereas left atrium tended to decrease. Ejection fraction as a parameter for global systolic function and mid FFS as a parameter for myocardial contractility were preserved throughout the study (Table 2).

Clinical safety profile

Tolerability

No patient was withdrawn from the study medication and no side effects were reported by the patients. No first dose hypotension was observed.

Renal function

Mean serum creatinine concentration remained stable throughout the study, whereas mean serum urea concentration showed a slight increase by 7.3 ± 2.4 mg/dL (P < .01). There was an increase in serum creatinine concentration higher than 0.5 mg/dL in any patient. No rejection episode or indication for renal biopsy due to suspected rejection occurred. Mean serum potassium concentration increased by 0.24 ± 0.1 mmol/L (P < .01), but in all patients serum potassium level remained below the upper normal limit of 5.5 mmol/L. Serum uric acid concentration showed a slight, but statistically not significant decrease by the end of the study.

Erythropoesis

The hemoglobin concentration and the hematocrit decreased significantly by 1.0 ± 0.3 g/dL and 3.6% ± 0.9%, respectively (P < .002 and P < .001, respectively) at week 26. The decrease was not correlated to serum creatinine concentration. In two of the patients, continuing losartan beyond the end of the study, the hemoglobin level declined further with one patient developing symptomatic anemia. After reduction of the losartan dose, the hemoglobin level increased in these patients.

The serum erythropoetin concentration remained unchanged throughout the study. In addition no correlation between the changes in hemoglobin level or hematocrit and the changes in erythropoetin or angiotensin II concentrations was found.

Immunosuppression

Blood levels of cyclosporine A and FK-506 did not change during the study period, and no dose adjustment was necessary in any patient (all data in Table 3).

Table 3.

LABORATORY VALUES OF RENAL TRANSPLANT RECIPIENTS (N = 20) AT BASELINE AND AFTER 26 WEEKS OF LOSARTAN TREATMENT

Characteristics	Baseline	Week 26	P
Hemoglobin (g/dL)	14.7 ± 0.3	13.7 ± 0.4	.002
Hematocrit (%)	44.1 ± 1.0	40.5 ± 1.2	.001
Creatinine (mg/dL)	1.28 ± 0.11	1.30 ± 0.10	NS
Urea (mg/dL)	46.8 ± 4.9	54.1 ± 4.6	.006
Uric acid (mg/dL)	8.03 ± 0.47	7.68 ± 0.38	.09
Potassium (mmol/L)	4.05 ± 0.05	4.29 ± 0.09	.007
Cyclosporine A level (ng/mL)	121.2 ± 7.9	125.5 ± 4.4	NS
FK-506 level (ng/mL)	7.48 ± 1.51	8.08 ± 0.41	NS
Erythropoetin (ng/mL)	15.0 ± 1.3	14.1 ± 1.1	NS
Angiotensin II (pg/mL)	7.1 ± 1.0	15.7 ± 2.7	.01

Abbreviation as in Table 2.

Discussion

The primary aim of our study was to analyze the impact of AT₁ receptor antagonists on LV hypertrophy in renal transplant recipients with stable graft function. We found that losartan reduces LV mass in renal transplant recipients, predominantly by a decrease in LV wall thickness. Our results are in accordance with the literature demonstrating the capability of losartan and other AT₁ receptor antagonists to reduce LV mass in animals and in patients with essential hypertension.^13,20,21,22 In face of the prognostic importance of LV hypertrophy, which is documented for patients with essential hypertension,^3,4,23 reduction of LV mass appears to be also desirable in renal transplant recipients. Of note, LV hypertrophy is a risk factor for cardiovascular events and total mortality in patients on renal replacement therapy.^2,24

Blood pressure control was improved by the additional treatment with losartan in hypertensive renal transplant recipients. This was true for casual and ambulatory BP control especially at nighttime and confirms the long-lasting effect of the drug with an only once daily regimen.²⁵ Despite the fact that losartan was given in addition to the preexisting antihypertensive therapy, no first dose hypotension was observed reflecting the safety of losartan with regard to clinical practice. Because arterial hypertension highly predicts long-term graft survival, sufficient BP control into the normotensive range appears to be mandatory especially in renal transplant recipients.^26,27

In this study design we cannot determine whether the reduction of LV mass is only attributable to better BP control or whether an additional BP independent effect is encountered. However, the lack of a significant correlation between the reduction of LV mass and the corresponding changes in BP suggests that at least in part BP independent effects of losartan might have contributed to the clearcut reduction of LV mass. In accordance to studies in patients with essential hypertension,¹³ losartan was well tolerated by renal transplant recipients. With respect to renal function and immunosuppressive therapy losartan was safe as shown recently in other studies.¹³

In contrast to most results in hypertensive patients with unimpaired¹⁴ and impaired renal function,²⁸ we observed a significant and in at least one patient a clinically relevant decrease of the hemoglobin level in response to losartan. This is in accordance with reports on an amelioration of post-transplant erythrozytosis by losartan.²⁹ Several but not all studies reported a decrease in hemoglobin concentration in renal transplant recipients treated with losartan.^14,30,31 The discrepancies might be explained partly by the different duration of the trials, as an anemic effect was only demonstrated in studies with longer treatment duration. Experiments with rats have suggested a decrease of serum erythropoetin in response to AT₁ blockade as the main factor of a decrease in hematocrit.³² However, we did not find a significant decrease in serum erythropoetin concentrations, nor any relation to the concomitant change of angiotensin II levels. Nevertheless, any interrelationship between angiotensin II and erythropoetin on a cellular level could be responsible, but the precise pathogenetic mechanism as to how erythropoetin regulation is impaired is still a matter of debate.³³ There is only one trial comparing the effects of ACE inhibitors and AT₁ receptor antagonists in renal transplant recipients. In that trial a similar decrease in hematocrit was reported in response to either drug, suggesting a similar mechanism for suppression of erythropoesis for both drug classes.³¹

In conclusion, losartan effectively reduced LV hypertrophy and ameliorated BP control in renal transplant recipients without influencing renal function and immunosuppressive therapy. However, hemoglobin concentration was slightly diminished.