ACE Inhibitors and Persistent Left Ventricular Hypertrophy After Renal Transplantation: A Randomized Clinical Trial

Transplantation ACE Inhibitors and Persistent Left Ventricular Hypertrophy After Renal Transplantation: A Randomized Clinical Trial Ernesto Paoletti, MD,1 Paolo Cassottana, MD,2 Marco Amidone, MD,1 Maurizio Gherzi, MD,1 Davide Rolla, MD,1 and Giuseppe Cannella, MD, PhD1 Background: Interventional studies of left ventricular hypertrophy (LVH) in renal transplant recipients are scarce and to date evaluated only patients immediately after renal transplantation. Study Design: Randomized controlled trial that assessed the effectiveness of angiotensin-converting enzyme (ACE) inhibitors in regressing persistent LVH after successful transplantation. Setting & Participants: 70 renal transplant recipients (47 men; age, 30 to 68 years) without diabetes previously randomly assigned to either cyclosporine or tacrolimus therapy, with LVH persisting 3 to 6 months after transplantation. Intervention: Subjects were randomly assigned to either lisinopril (ACE-inhibitor group; 36 patients) or no therapy (control group; 34 subjects). Outcomes: Main outcome was change in left ventricular mass index (LVMi) at month 18. Results: A consistent decrease in both systolic (SBP) and diastolic blood pressure (DBP) was observed in both groups (between-group differences, ⫺1.7 ⫾ 3.3 mm Hg; 95% confidence interval [CI], ⫺4.8 to 8.2; P ⫽ 0.6 for SBP; 0.3 ⫾ 2.2 mm Hg; 95% CI, ⫺4.8 to 4.1; P ⫽ 0.9 for DBP), whereas LVMi regressed more in the ACE-inhibitor group (between-group difference, 10.1 ⫾ 16.3 g/m2.7; 95% CI, 4.2 to 16.1; P ⬍ 0.01). A significant interaction of ACE inhibitors with cyclosporine in affecting LVMi change was shown by means of post hoc multiple regression analysis (P ⬍ 0.01; differences between cyclosporine and tacrolimus group, 13.3 ⫾ 3.9 g/m2.7; 95% CI, 5.3 to 21.2; P ⬍ 0.01 in the ACE-inhibitor group; 3.7 ⫾ 4.2 g/m2.7; 95% CI, ⫺4.7 to 12.2; P ⫽ 0.4 in the control group). Limitations: Single-center study with small sample size. Interaction of ACE inhibitors with cyclosporine treatment emerged from post hoc analysis. Conclusion: A prolonged course of ACE-inhibitor therapy is effective in regressing the persistent LVH of renal transplant recipients by mechanisms independent of effects on BP. This regression seems to be at least in part the effect of an interaction between ACE inhibitors and cyclosporine. Am J Kidney Dis 50:133-142. © 2007 by the National Kidney Foundation, Inc. INDEX WORDS: Left ventricular hypertrophy; renal transplant recipients; angiotensin-converting enzyme (ACE) inhibitors; cyclosporine; tacrolimus.

L

eft ventricular hypertrophy (LVH) after renal transplantation is highly prevalent1 and is associated with decreased patient survival rates,2 contributing to the continued high incidence of cardiovascular morbidity and mortality in renal transplant recipients.3 LVH can be regressed, although not normalized, after renal transplantation4 mainly by means of antihypertensive

therapy, and angiotensin-converting enzyme (ACE) inhibitors proved to be effective.5,6 In patients with end-stage renal disease (ESRD), a long-lasting course of ACE-inhibitor therapy was shown to regress LVH by mechanisms independent of hemodynamic effects on blood pressure (BP).7,8 However, interventional studies of LVH in renal transplant recipients

From the 1Divisione di Nefrologia, Dialisi e Trapianto, and 2Divisione di Cardiologia. Azienda Ospedaliera Universitaria S. Martino, Genova, Italy. Received November 1, 2006. Accepted in revised form April 13, 2007. Originally published online as doi: 10.1053/j.ajkd.2007.04.013 on June 1, 2007. Trial registration: http://isrctn.org; study number: ISRCTN94487168. Part of this study was presented orally at the 2007 World Congress of Nephrology, Rio de Janeiro, Brazil, April 21-25, 2007, and published in abstract form in the Proceedings of the Congress.

Address correspondence to Ernesto Paoletti, MD, Divisione di Nefrologia, Dialisi e Trapianto, Azienda Ospedaliera Universitaria S. Martino, Lgo R. Benzi 10, 16132, Genova, Italy. E-mail: [email protected] © 2007 by the National Kidney Foundation, Inc. 0272-6386/07/5001-0016$32.00/0 doi:10.1053/j.ajkd.2007.04.013

American Journal of Kidney Diseases, Vol 50, No 1 (July), 2007: pp 133-142

133

134

Paoletti et al

were planned immediately after renal transplantation, when LVH is mainly the result of previous ESRD.5,6 No data are available about the longterm effect of ACE inhibitors on LVH persisting after and despite successful transplantation. The aim of our study therefore is to assess the effectiveness of ACE inhibitors in regressing LVH persisting after renal transplantation during an 18-month observation period. The impact of the interaction of such therapy with the calcineurin inhibitors cyclosporine or tacrolimus in affecting LVH outcome also was evaluated because results from previous studies never were reported for this issue. METHODS The protocol of this study conformed to the guidelines of the ethical committee of our institution. Informed consent was obtained from each patient enrolled in the study.

Patients Subjects considered eligible for our trial were consecutive patients without diabetes receiving a single-kidney transplant from a deceased donor at our institution during a 3-year period starting January 1, 2001. As part of an earlier trial aimed at evaluating long-term immunosuppressive effects of cyclosporine compared with tacrolimus, patients previously had been randomly assigned to receive either cyclosporine or tacrolimus, together with mycophenolate mofetil and prednisone. Subjects receiving a preemptive second transplant or a transplant from a living donor were excluded. Patients were considered eligible for the present trial if they had stable graft function (creatinine ⬍ 2.5 mg/dL [⬍221 ␮mol/L]) and urinary protein excretion rate not exceeding 1 g/24 h within 3 to 6 months of transplantation. Exclusion criteria were heart failure or severe valvular disease, previous therapy with drugs acting on the reninangiotensin system (RAS), episodes of acute rejection in the previous 3 months, and hemodynamically significant renal artery stenosis. Subjects meeting the inclusion criteria underwent echocardiographic examination to determine left ventricular mass index (LVMi). Screening of patients using echocardiography 3 to 6 months after renal transplantation was an a priori decision because we were interested in assessing the behavior of LVH persisting despite successful transplantation, not of LVH resulting from previous ESRD in patients on dialysis therapy. Of 104 patients evaluated by means of echocardiography, 74 had an LVMi greater than 49.2 g/m2.7 or greater than 46.7 g/m2.7, values considered the upper limits for defining normal LVMi in men and women, respectively.9 These patients underwent randomization to either ACE-inhibitor or no therapy. Subjects were randomly assigned 1:1. At the start of the 18-month follow-up period, our cohort consisted of 37 patients administered ACE inhibitors (19 patients, cyclosporine; 18 patients, tacrolimus) and 37 controls (20 patients, cyclosporine; 17 patients, tacrolimus).

Figure 1 shows patient flow through the earlier trial and the present study.

Methods Antihypertensive drugs, if any, were progressively withdrawn, and after a 2-week washout period during which no patient experienced a hypertensive emergency, the ACEinhibitor group started treatment with lisinopril at an initial dose of 5 mg/d, whereas controls received no treatment. ACE-inhibitor therapy was titrated weekly for the first month and subsequently monthly on the basis of average systolic BP (SBP) and ranged from a minimum of 2.5 to a maximum of 20 mg/d. Antihypertensive therapy using medications not acting on the RAS was permitted in both groups to achieve BPs of 130/80 mm Hg or less, which is the optimal target for renal patients according to criteria issued by the Kidney Disease Outcomes Quality Initiative guidelines for chronic kidney disease.10 BP was measured weekly using a mercury sphygmomanometer with the cuff adapted to the circumference of the arm contralateral to the arteriovenous fistula, with subjects resting for at least 15 minutes. SBP was recorded at Korotkoff phase I, and diastolic BP (DBP) was recorded at Korotkoff phase V. Pulse pressure (PP) was calculated as SBP ⫺ DBP. Antihypertensive medications were titrated monthly according to BP values. Immunosuppressive medications were titrated monthly. For either cyclosporine or tacrolimus, titration was calibrated according to trough levels with the objective of maintaining values between 100 and 300 mg/mL for cyclosporine and between 5 and 15 ng/mL for tacrolimus. Echocardiography was performed at baseline and after 18 months. Echotracings were collected using a 2-dimensional guided M-mode echocardiograph according to recommendations of the American Society of Echocardiography11 and read in a blinded fashion by a single experienced cardiologist (P.C.). Measurements included end-systolic (ESD) and end-diastolic diameters (EDD) of the left ventricle, enddiastolic interventricular septum thickness (IVSd), and enddiastolic thickness of the left ventricular posterior wall (PWd). Left ventricular mass (LVM) was calculated from these measurements according to the formula: LVM ⫽ 0.80 ⫻ 1.04 ⫻ ([IVSd ⫹ PWd ⫹ EDD]3 ⫺ EDD3) ⫹ 0.6 g,12 then indexed for height2.7, which was reported as the most reliable indexation for renal patients.13 Relative wall thickness (RWT) was calculated as 2PW/EDD ratio, and a value of 0.44 was taken as a cutoff limit to define concentric (RWT ⬎ 0.44) or eccentric LVH (RWT ⱕ 0.44).14 Percentage of fractional shortening of the left ventricle was calculated as EDD ⫺ EDS/EDD ⫻ 100. Serum from each patient was tested at least monthly for hemoglobin (Hb), urea nitrogen, uric acid, lipids, calcium, phosphorus, and either cyclosporine or tacrolimus trough levels and quarterly for intact immunoreactive parathyroid hormone (iPTH).

Statistical Analysis Data were analyzed according to intention-to-treat analysis, with the restriction that a second echocardiogram was available. Data are presented as mean ⫾ SD. For continuous variables, unpaired Student t-test or analysis of variance was used for between-group comparisons, when appropriate,

ACE Inhibitor and LVH Regression in Renal Transplantation

135

Figure 1. Screening, enrollment, and randomization and patients eligible for intention-to-treat analysis. The top of the figure shows flow through the earlier trial. Abbreviations: ACE, angiotensin-converting enzyme; CyA, cyclosporine; LVMi, left ventricular mass index, DGF, delayed graft function.

whereas paired t-test was used for intragroup comparisons. Fisher exact test or chi-square test was used to assess differences in the prevalence of noncontinuous variables in the 2 groups, when appropriate. Intragroup comparisons for BP values at any given time were made by means of analysis of variance for repeated measures. Linear regression analysis was used to assess the significance of associations between changes in LVMi and both baseline variables and their changes during the 18-month period. The following variables were analyzed: SBP, DBP, PP, Hb, creatinine, daily urinary protein excretion, lipids, uric acid, and iPTH. Stepwise multiple regression analysis was performed analyzing the same variables to determine independent predictors of LVMi variability. A general linear model was used to analyze effects of categorical variables in the final model. A post hoc multiple regression analysis was used to assess simultaneously the association of ACE inhibitors and anticalcineurins with ⌬LVMi and test for their interaction effect.

RESULTS

Thirty-six patients on ACE-inhibitor therapy and 34 controls completed the 18-month fol-

low-up period and were considered in the final intention-to-treat analysis. Four patients, 1 in the ACE-inhibitor group and 3 in the control group, were excluded because they had not undergone a second echocardiographic study because of worsening renal graft function (3 patients) or severe infectious disease (1 patient; Fig 1). Table 1 lists demographic and clinical data for the 36 patients randomly assigned to ACE-inhibitor therapy, 34 controls, and 56 patients randomly assigned to either cyclosporine or tacrolimus treatment in the earlier trial, but who did not undergo further randomization in the present trial. No significant differences in baseline data were shown among the 3 groups by means of analysis of variance (Table 1). Nor were significant differences identified between the ACEinhibitor group and controls as regards baseline echocardiographic data (Table 2).

136

Paoletti et al

Table 1. Baseline Demographic and Clinical Data for 36 Renal Transplant Recipients Randomly Assigned to ACE Inhibitors, 34 Controls, and 56 Patients Not Included

No. of patients Age (y) Sex (men/women) Cause of chronic kidney disease (G/HPT/PKD/TI/other) Dialytic age (mo) Randomized to CyA/tacrolimus Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Pulse pressure (mm Hg) Serum creatinine (mg/dL) Hemoglobin (g/dL) Cholesterol (mg/dL) Triglycerides (mg/dL) Uric acid (mg/dL) iPTH (pg/mL) Urinary protein excretion (g/24 h) Height (m) Weight (kg) Body surface area (m2)

ACE Inhibitor

Controls

Subjects Not Included

P

36 52 (30-68) 26/10

34 53 (34-64) 21/13

56 51 (28-67) 34/22

0.7 0.5

10/15/4/3/4 40 ⫾ 25 19/17 140 ⫾ 13 85 ⫾ 7 55 ⫾ 10 1.49 ⫾ 0.4 13.1 ⫾ 1.4 214 ⫾ 46 165 ⫾ 66 6.5 ⫾ 1.2 94 ⫾ 88 0.35 ⫾ 0.28 1.73 ⫾ 7.33 75.5 ⫾ 10.4 1.89 ⫾ 0.15

8/14/5/4/3 40 ⫾ 28 19/15 142 ⫾ 15 85 ⫾ 8 56 ⫾ 10 1.42 ⫾ 0.37 12.7 ⫾ 1.6 226 ⫾ 50 168 ⫾ 79 6.7 ⫾ 1.4 91 ⫾ 54 0.38 ⫾ 0.59 1.69 ⫾ 9.98 73.9 ⫾ 13.9 1.84 ⫾ 0.20

15/22/8/5/6 39 ⫾ 24 29/27 138 ⫾ 15 85 ⫾ 13 54 ⫾ 16 1.66 ⫾ 0.63 12.5 ⫾ 1.2 212 ⫾ 43 166 ⫾ 64 6.5 ⫾ 1.2 115 ⫾ 101 0.33 ⫾ 0.53 1.68 ⫾ 9.07 65.5 ⫾ 13.2 1.74 ⫾ 0.20

0.9 0.9 0.9 0.6 0.9 0.7 0.1 0.3 0.4 0.9 0.8 0.6 0.3 0.02 ⬍0.01 ⬍0.01

Note: For between-group comparison of continuous variables, analysis of variance was used. For noncontinuous variable comparison, chi-square test was used. To convert serum creatinine from mg/dL to ␮mol/L, multiply by 88.4; hemoglobin from g/dL to g/L, multiply by 10; cholesterol in mg/dL to mmol/L, multiply by 0.02586; triglycerides in mg/dL to mmol/L, multiply by 0.01129; uric acid in mg/dL to ␮mol/L, multiply by 59.48; iPTH in pg/mL to ng/L, multiply by 1. Abbreviations: ACE, angiotensin-converting enzyme; G, glomerulonephritis; HPT, hypertensive kidney disease; PKD, polycystic kidney disease; TI, chronic tubulointerstitial disease; iPTH, immunoreactive intact parathyroid hormone; CyA, cyclosporine.

During the observation period, no adverse cardiovascular event was recorded for patients in both the ACE-inhibitor and control group. Incidences of posttransplantation diabetes were 4 of 36 patients in the ACE-inhibitor group (11%) and 5 of 34 in controls (14%; P ⫽ 0.7, Fisher exact test). Although slightly greater in subjects on tacrolimus (15%) compared with cyclosporine (10%) therapy, the incidence was not significantly different for either immunosuppressive regimen (P ⫽ 0.5, Fisher exact test). Antihypertensive medications were increased in both groups while maintaining the proportion between different classes of drugs (Table 3). No significant changes were shown in the use and distribution of immunosuppressive drugs during the entire follow-up period in both groups (Table 3). In both groups, significant decreases in both SBP and DBP were observed during the 18month follow-up (Fig 2). No significant betweengroup differences were shown comparing the magnitude of decrease in either SBP (⫺1.7 ⫾ 3.3 mm Hg; 95% confidence interval [CI], ⫺4.8 to

8.2; P ⫽ 0.6) or DBP (0.3 ⫾ 2.2 mm Hg; 95% CI, ⫺4.8 to 4.1; P ⫽ 0.9). No difference in percentage of patients who did not achieve the desired target BP level of 130/80 mm Hg was observed in either group (17 of 36 patients, ACE-inhibitor group; 16 of 34 controls; P ⫽ 0.9, Fisher exact test). No significant between-group Table 2. Baseline Echocardiographic Data for 36 Renal Transplant Recipients Randomly Assigned to ACE Inhibitors and 34 Controls

EDD (mm) IVSd (mm) PWd (mm) RWT FS (%) LVMi (g/m2.7)

ACE Inhibitors

Controls

P

53.4 ⫾ 4.6 13.2 ⫾ 2.1 11.9 ⫾ 2.4 0.45 ⫾ 0.13 39 ⫾ 5 63.1 ⫾ 14.0

51.6 ⫾ 6.9 12.9 ⫾ 1.8 11.2 ⫾ 1.9 0.45 ⫾ 0.12 38 ⫾ 6 60.0 ⫾ 11.6

0.2 0.6 0.2 0.9 0.9 0.3

Abbreviations: ACE, angiotensin-converting enzyme; EDD, left ventricular end-diastolic diameter; IVSd, enddiastolic interventricular septum thickness; PWd, enddiastolic left ventricular posterior wall thickness; RWT, left ventricular relative wall thickness; FS, left ventricular fractional shortening; LVMi, left ventricular mass index.

Note: Values expressed as mean ⫾ SD or number of subjects. For within-group comparisons of continuous variables, paired t-test was used. For between-group comparisons of continuous variables, unpaired t-test was used. For noncontinuous variables comparison, chi-square test was used. Abbreviations: ACE, angiotensin-converting enzyme; CCB, calcium channel blockers; CyA, cyclosporine; MMF, mycophenolate mofetil; CI, confidence interval.

0.3 0.9 0.9 0.23 ⫾ 0.23 (⫺0.68-0.23) 0.01 0.8 0.9 2.03 ⫾ 0.97 24/26/3/15 19/15/21/30 1.62 ⫾ 1.04 17/18/4/15 19/15/23/30 2.36 ⫾ 0.9 17/21/2/9 19/17/22/32 No. of antihypertensive medications No. of subjects using CCBs/␤-blockers/diuretics/others No. of subjects using CyA/tacrolimus/MMF/steroids

1.72 ⫾ 0.97 22/21/2/17 19/17/23/32

⬍0.001 0.7 0.9

P Change (95% CI) 18 Months Baseline

P

Baseline

18 Months

P

ACE Inhibitor v Controls Controls ACE Inhibitor

Table 3. Antihypertensive and Immunosuppressive Medications During an 18-Month Observation Period in 36 Renal Transplant Recipients Randomly Assigned to ACE Inhibitors and 34 Controls

ACE Inhibitor and LVH Regression in Renal Transplantation

137

differences were observed regarding changes in PP, serum creatinine level, Hb level, serum cholesterol and triglyceride levels, iPTH level, and 24-hour urinary protein excretion rate (Table 4). Significant LVMi decrease (⌬LVMi) was shown in the ACE-inhibitor group at the end of the 18-month follow-up period (⫺9.1 ⫾ 13.3 g/m2.7; P ⬍ 0.001) as a consequence of a decrease in internal dimension of the left ventricle (⫺1.7 ⫾ 4.8 mm; P ⬍ 0.05) and thickness of both the IVSd (⫺0.8 ⫾ 2.3 mm; P ⬍ 0.05) and PWd (⫺1.2 ⫾ 3.1 mm; P ⫽ 0.03). Conversely, no significant changes in LVMi were shown in the control group (Fig 3). The magnitude of ⌬LVMi was significantly greater in the ACEinhibitor group than in controls (between-group difference, 10.1 ⫾ 16.3 g/m2.7; 95% CI, 4.2 to 16.1; P ⬍ 0.01; Table 5). Linear regression analysis showed no significant relationship between ⌬LVMi and either baseline values or variation over time in all continuous variables considered to be putative independent predictors of ⌬LVMi (such as SBP, DBP, Hb level, serum creatinine level, lipid level, iPTH level, and urinary protein excretion rate). This was the case whether considering the ACE-inhibitor group alone or all transplant recipients as a whole. Greater LVMi at baseline (␤ coefficient, 0.334; P ⬍ 0.01), ACE-inhibitor therapy (␤ coefficient, 10.433; P ⬍ 0.001), and cyclosporine therapy (␤ coefficient, 7.676; P ⬍ 0.01) emerged as the only significant independent predictors of ⌬LVMi in renal transplant recipients according to a multivariate regression model that also took account of variations in all continuous putative predictors of ⌬LVMi and which accounted for 41% of total LVMi variance in our sample. On the basis of this association, a post hoc model was constructed aimed at evaluating the interaction effect of ACE inhibitors with cyclosporine therapy in predicting LVH outcome. A significant interaction was shown by means of multiple regression analysis (P ⬍ 0.01). In the ACE-inhibitor group, a significant difference in ⌬LVMi was shown between subjects administered cyclosporine and those administered tacrolimus (P ⬍ 0.01), whereas no significant difference in ⌬LVMi was shown comparing cyclosporine- and tacrolimustreated patients in the control group (P ⫽ 0.4; Table 6).

138

Paoletti et al

Figure 2. Systolic (SBP) and diastolic (DBP) blood pressure (BP) behavior during 18 months in 36 renal transplant recipients randomly assigned to angiotensin-converting enzyme (ACE) inhibitor therapy and 34 controls. SBP ACE inhibitor, P ⬍ 0.01; SBP controls, P ⬍ 0.001; DBP ACE inhibitor, P ⬍ 0.001; DBP controls, P ⬍ 0.001 (analysis of variance for repeated measures).

DISCUSSION

The 2 principal and new findings of this study are: (1) ACE inhibitors are effective in reversing LVH persisting despite successful renal transplantation, probably through mechanisms that are at least partially independent of hemodynamic effects on BP; and (2) this effectiveness is limited to patients undergoing cyclosporine therapy. In a previous study, ACE inhibitors were effective in decreasing the LVMi of hypertensive transplant recipients by inducing a BP decrease because the LVMi did not change in control subjects for whom BP remained higher.5 The effectiveness of

BP decrease was shown in another study in which significant ⌬LVMi was obtained by decreasing BP regardless of the class of antihypertensive medications used.6 Our patients also showed significant decreases in both SBP and DBP, potentially accounting for the lack of LVH worsening we observed. However, at variance with previous reports,6 LVH significantly regressed only in patients randomly assigned to ACE-inhibitor therapy, and no relationship was evident between degree of BP decrease and magnitude of ⌬LVMi. It is noteworthy that baseline BP was almost adequately controlled in all subjects, both treated and controls, and it is possible

Table 4. Change in Clinical Parameters From Baseline to 18 Months in 36 Renal Transplant Recipients Randomly Assigned to ACE Inhibitors and 34 Controls

Weight (kg) Body surface area (m2) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Pulse pressure (mm Hg) Serum creatinine (mg/dL) Hemoglobin (g/dL) Urinary protein excretion (g/24 h) Cholesterol (mg/dL) Triglycerides (mg/dL) Uric acid (mg/dL) iPTH (pg/mL)

ACE Inhibitors

Controls

P

⫺0.3 ⫾ 3.8 ⫺0.01 ⫾ 0.04 ⫺5 ⫾ 14 ⫺4 ⫾ 10 ⫺0.4 ⫾ 12 ⫺0.05 ⫾ 0.39 ⫺0.3 ⫾ 1.2 ⫺0.14 ⫾ 0.28 ⫺6 ⫾ 56 ⫺5 ⫾ 63 0.3 ⫾ 1.6 ⫺11 ⫾ 54

⫺0.8 ⫾ 6.3 ⫺0.01 ⫾ 0.07 ⫺7 ⫾ 13 ⫺4 ⫾ 8 ⫺3 ⫾ 11 0.02 ⫾ 0.36 0.3 ⫾ 1.4 ⫺0.11 ⫾ 0.44 4 ⫾ 63 21 ⫾ 68 ⫺0.2 ⫾ 1.5 18 ⫾ 46

0.3 0.4 0.6 0.9 0.4 0.7 0.1 0.8 0.6 0.2 0.3 0.2

Note: To convert serum creatinine from mg/dL to ␮mol/L, multiply by 88.4; hemoglobin from g/dL to g/L, multiply by 10; cholesterol in mg/dL to mmol/L, multiply by 0.02586; triglycerides in mg/dL to mmol/L, multiply by 0.01129; uric acid in mg/dL to ␮mol/L, multiply by 59.48; iPTH in pg/mL to ng/L, multiply by 1. Abbreviations: ACE, angiotensin-converting enzyme; iPTH, immunoreactive intact parathyroid hormone.

ACE Inhibitor and LVH Regression in Renal Transplantation

139

Figure 3. Change in left ventricular mass index (⌬LVMi) during an 18-month period in 36 renal transplant recipients randomly assigned to angiotensin-converting enzyme (ACE) inhibitor therapy and 34 controls. Difference from baseline to 18 months and 95% confidence intervals are shown. ACE inhibitor versus controls, P ⫽ 0.001.

that further BP decreases failed to produce an additional effect on the LVMi of our population. Taken together, these findings suggest that nonhemodynamic mechanisms independent of BP control may have had a role in the action of ACE inhibitors on the cardiac mass of our patients. Previous observations reported nonhemodynamic LVMi-decreasing effects of ACE inhibitors in dialysis patients undergoing long-term treatment with lisinopril.8 Thus, it is conceivable that the antiproliferative effect of ACE inhibitors also might be a major mechanism involved in the reversal of LVH for renal transplant recipients. Recently, a retrospective analysis was published

showing that renal transplant recipients treated with drugs acting on the RAS had a better survival rate than subjects not receiving this class of medication.15 Taking into account that the main cause of death was cardiovascular events, although no data were available regarding the cardiac hypertrophy of that cohort, we cannot rule out the possibility that a decrease in cardiovascular morbidity of those patients could be linked in some manner to a positive effect of ACE inhibitors on LVMi. The LVMi-decreasing effect of ACE inhibitors observed in our sample was restricted to patients randomly assigned to a cyclosporine-

Table 5. Change in Echocardiographic Data From Baseline to 18 Months and Between-Group Comparison of Change in 36 Renal Transplant Recipients Randomly Assigned to ACE Inhibitors and 34 Controls

EDD (mm) IVSd (mm) PWd (mm) RWT FS (%) LVMi (g/m2.7)

ACE Inhibitors

Controls

Effect (ACE Inhibitor v Controls)

⌬ (P)

⌬ (P)

⌬ (95% CI)

P

⫺1.7 ⫾ 4.8 (⬍0.05) ⫺0.8 ⫾ 2.3 (⬍0.05) ⫺1.2 ⫾ 3.1 (0.03) ⫺0.04 ⫾ 0.14 (0.2) 1.4 ⫾ 6.8 (0.4) ⫺9.1 ⫾ 13.3 (⬍0.01)

0.9 ⫾ 4.4 (0.2) ⫺0.2 ⫾ 2.1 (0.6) 0.1 ⫾ 1.8 (0.8) ⫺0.02 ⫾ 0.10 (0.3) ⫺0.4 ⫾ 5 (0.9) 1.0 ⫾ 11.5 (0.6)

2.55 ⫾ 1.1 (⫺0.34-4.75) 0.6 ⫾ 0.53 (⫺0.47-1.67) 1.31 ⫾ 0.62 (⫺0.07-2.56) 0.01 ⫾ 0.03 (⫺0.07-0.05) ⫺1.8 ⫾ 1.9 (⫺1.9-5.6) 10.1 ⫾ 16.3 (4.2-16.1)

0.02 0.3 0.04 0.7 0.3 ⬍0.01

Abbreviations: ACE, angiotensin-converting enzyme; ⌬, difference between final and baseline value; CI, confidence interval; EDD, left ventricular end-diastolic diameter; IVSd, end-diastolic interventricular septum thickness; PWd, enddiastolic left ventricular posterior wall thickness; RWT, left ventricular relative wall thickness; FS, left ventricular fractional shortening; LVMi, left ventricular mass index.

Note: Test for interaction of ACE inhibitors with cyclosporine: F ⫽ 7.103; P ⬍ 0.01, multiple regression analysis. Abbreviations: ACE, angiotensin-converting enzyme; ⌬, difference between final and baseline value; CI, confidence interval; LVMi, left ventricular mass index.

⫺3.8 ⫾ 4.2 (⫺4.7-12.2) P ⫽ 0.4 13.3 ⫾ 3.9 (5.4-21.2) P ⬍ 0.01 ⌬ (95% CI)

57.0 ⫾ 10.4 59.1 ⫾ 7.1 Tacrolimus

⫺2.1 ⫾ 10.0

60.0 ⫾ 14.3

63.4 ⫾ 16.3

3.4 ⫾ 14.8

15.1 ⫾ 3.5 (7.9-22.2) P ⬍ 0.001 5.5 ⫾ 4.6 (⫺3.9-14.9) P ⫽ 0.2 ⫺0.3 ⫾ 9.5 59.6 ⫾ 9.6 59.9 ⫾ 10.3 51.2 ⫾ 15.9 66.6 ⫾ 17.5 Cyclosorine

⫺15.4 ⫾ 13.0

⌬LVMi LVMi at 18 Months LVMi at 18 Months LVMi at Baseline

⌬LVMi

LVMi at Baseline

Controls ACE Inhibitors

Table 6. Interaction Effect of ACE Inhibitors With Anticalcineurins on LVMi in 70 Renal Transplant Recipients

⌬ (95% CI)

Paoletti et al Effect ACE Inhibitor v Controls

140

based immunosuppressive regimen, and no such effect was evident in subjects administered tacrolimus. We do not have an explanation for this discrepancy, which emerged from a post hoc analysis of our results. In an animal model, the calcineurin transcriptional pathway is likely to have a major role in the development of pressure-overload LVH.16 However, results from studies performed to ascertain the role of calcineurin inhibitors in preventing or attenuating this cardiac response are inconclusive.17,18 Moreover, in the sole study showing the effectiveness of FK506 (tacrolimus) in preventing the onset of LVH in hypertensive rats, administered doses of the drug were more than 10-fold those usually prescribed to transplant recipients in clinical practice.18 Cases of hypertrophic cardiomyopathy were reported in children administered FK506,19 although the prevalence of such cardiac disorders in 1,333 adult tacrolimus-treated kidney transplant recipients was no different from that reported in the general population.20 Cyclosporine was shown to stimulate both the circulating and local RAS.21 Angiotensin II seems to be involved in the development of myocardial hypertrophy, also through mechanisms independent of its hemodynamic effects.22,23 Thus, it is conceivable that ACE inhibitors may have an effective antagonistic role in the growth-promoting effect of angiotensin, and we cannot rule out the possibility that the effectiveness of ACE inhibitors in regressing LVH was limited to our cyclosporine-treated patients because of a local blockade as opposed to a systemic effect. Last, in a recent report, Covic et al24 showed that cyclosporine acutely improved large arterial compliance function, shown to be a major factor in the development of LVH in patients with ESRD.25,26 This effect could be additive to the similar result described for ACE inhibitors25-27; however, it is unlikely that such a mechanism had a role in our cohort because a reliable indirect index of the distensibility of large arteries, such as PP, did not change in our patients during ACE-inhibitor therapy. We acknowledge some limitations in our study. First, it is a single-center12 study and the sample size is small. Moreover, the interaction of ACE inhibitors with cyclosporine emerged from a post hoc analysis. Although such associations may prove spurious, our finding none-

ACE Inhibitor and LVH Regression in Renal Transplantation

theless appears relevant and worthy of further investigation. In conclusion, to our knowledge, this is the first trial to show that ACE inhibitors are effective in regressing the persistent LVH of renal transplant recipients only in cyclosporine-treated subjects and at least in part by means of nonhemodynamic mechanisms. Additional controlled trials of larger cohorts are needed to assess both the role of immunosuppressive therapy in possibly affecting LVH behavior and the general cardiovascular outcome of renal transplant recipients. In the meanwhile, we recommend that ACEinhibitor therapy be adopted early in posttransplantation management, at least for patients with proven LVH who are undergoing cyclosporine-based immunosuppressive therapy. ACKNOWLEDGEMENTS The authors thank Mark Northway for help in revision of the manuscript. Support: None. Financial Disclosure: None.

REFERENCES 1. Rigatto C, Parfrey P: Therapy insights: Management of cardiovascular disease in the renal transplant recipient. Nat Clin Pract Nephrol 2:514-526, 2006 2. Rigatto C, Foley RN, Jeffery J, et al: Electrocardiographic left ventricular hypertrophy in renal transplant recipients: Prognostic value and impact of blood pressure and anemia. J Am Soc Nephrol 14:462-468, 2003 3. Foley RN, Parfrey PS, Sarnak MJ: Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 32:S112-S119, 1998 (suppl 3) 4. Parfrey PS, Harnett JD, Foley RN, et al: Impact of renal transplantation on uremic cardiomyopathy. Transplantation 60:908-914, 1995 5. Hernandez D, Lacalzada J, Salido E, et al: Regression of left ventricular hypertrophy by lisinopril after renal transplantation: Role of ACE gene polymorphism. Kidney Int 58:889-897, 2000 6. Midtvedt K, Ihlen H, Hartmann A, et al: Reduction of left ventricular mass by lisinopril and nifedipine in hypertensive renal transplant recipients: A prospective randomized double-blind study. Transplantation 72:107-111, 2001 7. London GM, Pannier B, Guerin AP, et al: Cardiac hypertrophy, aortic compliance, peripheral resistance and wave reflection in end-stage renal disease. Comparative effects of ACE inhibition and calcium channel blockade. Circulation 90:2786-2796, 1994 8. Cannella G, Paoletti E, Delfino R, et al: Prolonged therapy with ACE inhibitors induces a regression of left ventricular hypertrophy of dialyzed uremic patients independently from hypotensive effects. Am J Kidney Dis 30:659664, 1997

141

9. Ferrara LA, Vaccaro O, Cardoni O, et al: Indexation criteria of left ventricular mass and predictive role of blood pressure and body composition. Am J Hypertens 18:12631265, 2005 10. National Kidney Foundation: K/DOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease. Am J Kidney Dis 43:S1-S290, 2004 (suppl 1) 11. Sahn DJ, De Maria A, Kisslo J, et al: Recommendations regarding quantitation in M-mode echocardiography: Results of a survey of echocardiographic measurements. Circulation 58:1072-1083, 1978 12. Devereux RB, Alonso DR, Lutas EM, et al: Echocardiographic assessment of left ventricular hypertrophy: Comparison to necroscopy findings. Am J Cardiol 57:450-458, 1986 13. Zoccali C, Benedetto FA, Mallamaci F, et al: Prognostic impact of the indexation of left ventricular mass in patients undergoing dialysis. J Am Soc Nephrol 12:27682774, 2001 14. Ganau A, Devereux RB, Roman MJ, et al: Patterns of left ventricular hypertrophy and geometric remodeling in essential hypertension. J Am Coll Cardiol 19:1550-1558, 1992 15. Heinze G, Mitterbauer C, Regele H, et al: Angiotensinconverting enzyme inhibitor or angiotensin II type 1 receptor antagonist therapy is associated with prolonged patient and graft survival after renal transplantation. J Am Soc Nephrol 17:889-899, 2006 16. Molkentin JD, Lu JR, Antos CR, et al: A calcineurindependent transcriptional pathway for cardiac hypertrophy. Cell 93:215-228, 1998 17. Zhang W, Kowal RC, Rusnak F, et al: Failure of calcineurin inhibitors to prevent pressure-overload left ventricular hypertrophy in rats. Circ Res 84:722-728, 1999 18. Sakata Y, Masuyama T, Yamamoto K, et al: Calcineurin inhibitor attenuates left ventricular hypertrophy, leading to prevention of heart failure in hypertensive rats. Circulation 102:2269-2275, 2000 19. Chang RK, Alzona M, Alejos J, et al: Marked left ventricular hypertrophy in children on tacrolimus (FK506) after orthotopic liver transplantation. Am J Cardiol 81:12771280, 1998 20. Coley KC, Verrico MM, McNamara DM, et al: Lack of tacrolimus-induced cardiomyopathy. Ann Pharmacother 35:985-989, 2001 21. Lee DBN: Cyclosporine and the renin-angiotensin axis. Kidney Int 52:248-260, 1997 22. Schmieder RE, Lagenfeld MRW, Friedrich A, et al: Angiotensin II related to sodium excretion modulates left ventricular structure in human essential hypertension. Circulation 94:1304-1309, 1996 23. Schmieder RE, Schlaich MP, Klingbeil AU, et al: Update on reversal of left ventricular hypertrophy in essential hypertension (a meta-analysis of all randomized double-blind studies until December 1996). Nephrol Dial Transplant 13:564-569, 1998 24. Covic A, Mardare N, Gusbeth-Tatomir P, et al: Acute effect of CyA A (Neoral) on large artery hemodynamics in renal transplant patients. Kidney Int 67:732737, 2005

142 25. London GM, Pannier B, Vicaut E, et al: Antihypertensive effects and arterial hemodynamic alterations during angiotensin converting enzyme inhibition. J Hypertens 14: 1139-1146, 1996 26. Paoletti E, Cassottana P, Bellino D, et al: Left ventricular geometry and adverse cardiovascular events

Paoletti et al in chronic hemodialysis patients on prolonged therapy with ACE inhibitors. Am J Kidney Dis 40:728-736, 2002 27. Shimamoto H, Shimamoto Y: Lisinopril reverses left ventricular hypertrophy through improved aortic compliance. Hypertension 28:457-463, 1996