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NDT Advance Access originally published online on October 23, 2007
Nephrology Dialysis Transplantation 2008 23(1):369-373; doi:10.1093/ndt/gfm620
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org


Ezetimibe treatment in hypercholesterolaemic kidney transplant patients is safe and effective and reduces the decline of renal allograft function: a pilot study

Tobias R. Türk1, Eva Voropaeva1, Matthias Kohnle1, Jens Nürnberger1, Thomas Philipp1, Andreas Kribben1, Uwe Heemann2 and Oliver Witzke1

1Department of Nephrology and Hypertension, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45122 Essen and 2Department of Nephrology, Klinikum rechts der Isar der Technischen Universität, Ismaninger Straße 22, 81675 München, Germany

Correspondence to: Oliver Witzke, Priv.-Doz. Dr med, Department of Nephrology & Hypertension, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, D-45122 Essen, Germany. Email: oliver.witzke{at}uk-essen.de



   Abstract
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 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Ezetimibe has shown efficacy in the therapy of hypercholesterolemia in renal transplant patients. This is the first study investigating the effect of ezetimibe on renal function in kidney transplant recipients.

Methods. Fifty-six patients with statin-resistant hypercholesterolemia (total cholesterol >200 mg/dl) after renal transplantation received additional ezetimibe therapy (10 mg/day) for 12 months. A group receiving statin therapy (n = 28) served as controls in this prospective study.

Results. Total cholesterol and LDL cholesterol concentrations decreased significantly in the ezetimibe-treated patients but remained stable in the control group (delta total cholesterol: –24 ± 49 mg/dl vs 19 ± 49 mg/dl, P < 0.01; delta LDL: –30 ± 39 mg/dl vs – 3 ± 31 mg/dl, P < 0.01). Mean creatinine clearance remained stable in ezetimibe-treated patients but decreased significantly in control group (delta Cockcroft–Gault: 0.9 ± 7.3 ml/min vs – 4.8 ± 12.8 ml/min, P = 0.025; delta Modification of Diet in Renal Disease: –0.4 ± 6.2 ml/min/1.73 m2 vs 4.7 ± 8.8 ml/min/1.73 m2, P = 0.033).

Conclusions. The data of our prospective case–control study suggest that ezetimibe appears to ameliorate the decline of renal function after renal transplantation.

Keywords: allograft function; ezetimibe; hypercholesterolemia; renal transplantation



   Introduction
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 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
There is increasing evidence that statin therapy has a positive influence on allograft outcome of kidney transplant recipients. Cholesterol has been shown to be an independent predictor of renal transplant long-term outcomes and survival of transplant recipients. The positive effect of statin therapy not only may be mediated by lowering cholesterol levels but there may also be other pleiotropic effects on proliferation of cells (including fibroblasts, vascular smooth muscle cells and mesangial cells), modification of cells of mesenchymal origin, immunomodulatory effects and restoration of endothelium-derived nitric oxide production [1–4].

Ezetimibe has shown efficacy in the therapy of hypercholesterolemia in transplant patients in several short-term uncontrolled studies with small patient cohorts [5–8]. To our knowledge, there has been no published study to date investigating the influence of ezetimibe on renal function. In our prospective study, we investigated, for the first time, the long-term effect of ezetimibe therapy in a larger number of kidney transplant patients. The primary study endpoint was lowering of cholesterol levels. The secondary endpoint was change of renal allograft function.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Study population
Eighty-four renal transplant patients with hypercholesterolemia on high-dose statin therapy were included in this prospective study. Inclusion criteria were renal transplantation at least 6 months prior to enrolment, uncontrolled hypercholesterolemia with respect to the criteria of the American Heart Association (AHA) and the National Cholesterol Education Program (NCEP), despite high statin therapy [9–11], stable statin therapy for at least 3 months before inclusion in the study and informed consent of the patient. Criteria of the AHA and NCEP were chosen because to date there is no evidence base or established knowledge for targets for lipids in renal transplant recipients. Exclusion criteria were uncontrolled malignant or infectious disease, active liver disease (aspartate aminotransferase or alanine aminotransferase >2x the upper norm), signs of rhabdomyolysis [creatinine kinase (CK) <2x the upper norm], therapy with fibrates or cholestyramine and pregnancy.

The patients were distributed on a 2:1 basis to the groups depending on the day of presentation in our outpatient clinics. Eligible patients presenting on Tuesday and Wednesday in our outpatient department were included in group one and treated with ezetimibe. Appointments were made by the patients without influence of investigators and medical staff. Eligible patients presenting on Thursdays were included in group two and had no change of therapy. Our outpatient department receives mostly emergency transplant patients on Mondays and Fridays, who were not included in the study. Fifty-six received ezetimibe therapy (10 mg/day) and continued their current statin therapy [48 patients were on fluvastatin (dose range 20–80 mg/day), 6 patients were on pravastatin (dose range 20–40 mg/day) and 2 patients were on simvastatin (both 80 mg/day)]. In the second group, 28 patients continued their statin therapy without change of the agent or the daily doses [19 patients were on fluvastatin (dose range 20–80 mg/day) and 9 patients were on pravastatin (dose range 20–40 mg/day)] and served as the control group. All patients were followed for 12 months. There were no significant differences between the baseline data of the two groups (Table 1). All patients but two patients in the ezetimibe group and one patient in the control group received kidneys from deceased donors. The three patients received a living donation. None of the patients had panel-reactive antibodies (PRA) prior to transplantation. Creatinine clearance was estimated by the Cockcroft–Gault formula [12] and the abbreviated modification of diet in renal disease (MDRD) equation [13]. The underlying kidney disease was glomerulonephritis (n = 19), interstitial nephritis (n = 17), cystic kidney disease (n = 9), unknown (n = 6), vasculitis (n = 3), amyloidosis (n = 1) and alport syndrome (n = 1) in the ezetimibe-treated patients. The cause of renal failure was glomerulonephritis (n = 14), unknown (n = 5), interstitial nephritis (n = 5), cystic kidney disease (n = 2), vasculitis (n = 1) and alport syndrome (n = 1) in the control group.


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  		Table 1. Patient demographics

 
Immunosuppression
In the ezetimibe-treated group, 51 patients received prednisone (dose range 2.5–10 mg/day), 33 patients received cyclosporine (mean trough level 122 ± 36 ng/ml), 15 patients received tacrolimus (mean trough level 6.5 ± 1.5 ng/ml), 17 patients received mycophenolate mofetil (dose range 250–500 mg bid), 2 patients received mycophenolic sodium (dose 360 mg bid), 3 patients received sirolimus and 7 patients received azathioprine. Thirty-six patients were on a dual immunosuppressive regimen, 19 patients were on a triple immunosuppressive regimen and 1 patient received monotherapy with azathioprine. Eight patients were on a calcineurin inhibitor (CNI)-free immunosuppressive regimen (prednisone and mycophenolate mofetil, three; prednisone and azathioprine, two; prednisone and sirolimus, two; prednisone, sirolimus and mycophenolate mofetil, one).

In the control group, all patients received prednisone (dose range 2.5–10 mg/day), 15 patients received cyclosporine (mean trough level 118 ± 42 ng/ml), 12 patients received tacrolimus (mean trough level 7.7 ± 2.8 ng/ml), 10 patients received mycophenolate mofetil (dose range 250–500 mg bid) and 4 patients received azathioprine. Sixteen patients were on a dual immunosuppressive regimen and 10 patients were on a triple immunosuppressive regimen. Two patients received a CNI-free immunosuppressive regimen (prednisone, azathioprine and mycophenolate mofetil, one; prednisone and mycophenolate mofetil, one).

There was no significant change in the mean trough levels of tacrolimus or cyclosporine during the follow-up period in either treatment groups.

Statistical analysis
Data are expressed as mean ± SD unless mentioned otherwise. Means of ordinal data as baseline data or changes from baseline were compared using the non-paired Student's t-test. Frequency data were analysed using Chi-square test. Pearson's correlation was used for correlation analysis. A multiple regression was performed for multivariate analysis (dependent variable: delta creatinine clearance; independent variables: treatment group, immunosuppression with cyclosporine, immunosuppression with tacrolimus, acute rejections, donor age, PRA, HLA mismatches and time since transplantation). A two-tailed P-value <0.05 was considered to be significant.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
Total cholesterol and LDL cholesterol concentrations decreased significantly in the ezetimibe-treated patients but remained stable in the control group (delta total cholesterol: –24 ± 49 mg/dl vs 19 ± 49 mg/dl, P < 0.01; delta LDL: –30 ± 39 mg/dl vs – 3 ± 31 mg/dl, P < 0.01; Figure 1). No kidney transplant was lost; no patient deceased during follow-up. Two patients reported muscle pain after 4 and 12 months of ezetimibe treatment, without increase in level of CK or myoglobin. One patient reported dizziness 2 months after initiation of ezetimibe treatment. These three patients discontinued ezetimibe treatment.


Figure 1
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  		Fig. 1. Delta of total cholesterol and LDL cholesterol during the observation period. The differences between the deltas of the two groups after 12 months are significant.

 
Creatinine clearance remained stable in ezetimibe-treated patients but decreased significantly in the control group (Cockcroft–Gault: +0.9 ± 7.3 ml/min vs – 4.8 ± 12.8 ml/min, P = 0.025; MDRD: –0.4 ± 6.2 ml/min/1.73 m2 vs – 4.7 ± 8.8 ml/min/1.73 m2, P = 0.033; Figure 2). Excluding the 10 patients on CNI-free immunosuppression, the results were similar (Cockcroft–Gault: –0.4 ± 7.4 ml/min vs 5.1 ± 12.9 ml/min, P = 0.021; MDRD: –0.7 ± 6.5 ml/min vs 5.0 ± 9.0 ml/min, P = 0.019). In the 12 months before inclusion into the study, the delta of creatinine clearance was similar in the two groups (Cockcroft–Gault: –5.0 ± 10.3 ml/min in the ezetimibe group and –5.9 ± 11.5 ml/min in the control group, P = 0.743; MDRD: 3.5 ± 8.1 ml/min/1.73 m2 in the ezetimibe group and 2.9 ± 7.2 ml/min/1.73 m2 in the control group, P = 0.75).


Figure 2
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  		Fig. 2. Delta of the creatinine clearance (Cockcroft–Gault formula and MDRD equation) assuming the creatinine clearance level at the start of treatment/observation period as reference. The differences between the deltas of the two groups after 12 months are significant.

 
In the multivariate analysis, no other independent factor than treatment with ezetimibe emerged as significantly influencing the delta creatinine clearance (Table 2).


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  		Table 2. P-values of the independent variables of the multivariate analysis (PRA). Only treatment with ezetimibe showed a significant influence on the delta of the creatinine clearance after 12 months

 
Mean values of creatinine clearance in ezetimibe-treated patients were as follows: 50.6 ± 17.0 ml/min at baseline and 51.6 ± 18.1 ml/min after 12 months, P = 0.34 (Cockcroft–Gault); 40.3 ± 14.7 ml/min/1.73 m2 at baseline and 39.8 ± 14.4 ml/min/1.73 m2 after 12 months, P = 0.52 (MDRD). Means of creatinine clearance in the control group were: 53.9 ± 17.7 ml/min at baseline and 49.1 ± 20.2 ml/min after 12 months, P = 0.056 (Cockcroft–Gault); 41.7 ± 10.9 ml/min/1.73 m2 at baseline and 37.1 ± 14.0 ml/min/1.73 m2 after 12 months, P = 0.009 (MDRD).

There was a significant negative correlation between mean cholesterol levels over the 12 months and the creatinine clearance after 12 months in the control group (–0.6514, P = 0.0002) but not in the ezetimibe-treated group (–0.0567, P = 0.6897).

There was no rejection episode in either group during the study period. There was no significant change in the mean trough levels of tacrolimus or cyclosporine during the follow-up period. Mean cyclosporine trough levels were 122 ± 36 ng/ml at baseline and 116 ± 26 ng/ml after 12 months in the ezetimibe group and 118 ± 42 ng/ml at baseline and 124 ± 70 ng/ml after 12 months in the control group. Mean tacrolimus trough levels were 6.5 ± 1.5 ng/ml at baseline and 7.4 ± 2.0 ng/ml after 12 months in the ezetimibe group and 7.7 ± 2.8 ng/ml at baseline and 6.7 ± 1.3 ng/ml after 12 months in the control group.

Blood pressure in ezetimibe-treated patients was 141(±18)/83(±10) mmHg at baseline and 138(±17)/82(±8) mmHg after 12 months. Blood pressure in the control group was 140(±19)/80(±9) mmHg at baseline and 151(±22)/87(±13) mmHg after 12 months. This last mean blood pressure was significantly (P < 0.05) higher than the mean blood pressure of the control group at baseline and the blood pressure of the ezetimibe-treated group at 12 months as well. Pulse pressure was similar in both groups (58 ± 15 mmHg in the ezetimibe group and 60 ± 18 mmHg in the control group) and did not change significantly during the study (56 ± 15 mmHg in the ezetimibe group and 64 ± 21 mmHg in the control group). At inclusion, patients were treated with 2.5 ± 1.0 antihypertensive drugs (range 0–4; median 2.5) in the treatment group. Control group patients were treated with 2.4 ± 1.3 antihypertensive drugs (range 0–5; median 2) at this time point. After 12 months, ezetimibe-treated patients received 2.5 ± 1.1 antihypertensive agents (range 0–4; median 3) and control patients were given 2.4 ± 1.2 antihypertensive drugs (range 0–4; median 2.0). Proteinuria was present in 17 patients treated with ezetimibe (30.4%) at inclusion and in 16 patients (28.6%) at the end of the study. In the control group, three patients (10.7%) showed proteinuria at inclusion and four patients (14.3%) had proteinuria after 12 months.



   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
This is the first controlled prospective study to investigate the safety and the effect of additional ezetimibe treatment in renal transplant recipients under statin treatment, with persistently high cholesterol levels. The primary study endpoint was reduction of total cholesterol and LDL cholesterol levels. Our data show that ezetimibe treatment in renal transplant patients is effective and nearly without side effects.

Regarding the secondary endpoint, change of renal function, our data show a better preservation of renal function after 12 months of additional treatment with ezetimibe in renal transplant recipients with hypercholesterolemia compared with the control group continuing high-dose statin therapy. There is a significant negative correlation between the mean cholesterol level over the follow-up period and the function of the kidney transplant in the control group but not in the ezetimibe-treatment group.

Dimeny et al. [14] have already reported in 1993 on the impact of pretransplant hypercholesterolemia on graft loss due to acute and chronic rejection. Isoniemi et al. [15] reported in 1994 on a significant relationship between low–LDL cholesterol levels and graft outcome in renal allografts. Furthermore, Hamar et al. [16] have shown a negative effect of high cholesterol levels before and after kidney transplantation on graft survival. Roodnat et al. [17] identified cholesterol as an independent predictor of outcome of renal transplant function in a study including more than 650 patients. They were able to show a negative correlation between cholesterol and course of renal allograft function. Therefore, the cholesterol-lowering effect of ezetimibe is one possible explanation for its positive effect on renal function, as seen in our study.

Masterson et al. [1] reported in 77 renal transplant recipients a better first-year graft outcome in those treated with statin compared with those treated without statin. Ruiz et al. [3] showed an improvement in lipid profile and an increase in antioxidant capacity but no difference in renal function in kidney transplant recipients. Otherwise, Fellström et al. [18] could not show a difference regarding renal allograft function between the patients receiving fluvastatin therapy and the control group over a follow-up for 6 years in the Assessment of Lescol in Renal Transplantation (ALERT) study, a multicenter study including more than 2000 patients. These and other reports show benefits of statin therapy in renal transplant patients but not always a better preservation of renal function. There are some known effects of statins such as reduced proliferation of cells (including fibroblasts, vascular smooth muscle cells and mesangial cells), modification of cells of mesenchymal origin, immunomodulatory effects and restoration of endothelium-derived nitric oxide production. However, none of these effects could be identified to improve renal function in kidney transplants [3,19]. There are few studies indicating a direct positive effect of ezetimibe on endothelial function [20,21]. Although there is a need for further investigations on this effect, this mode of action might be another explanation of the positive effect of ezetimibe on renal function.

Our study has some limitations. First, patients were selected using a case–control method and renal function was not the primary endpoint of this study. Second, we did not perform kidney biopsies at the time of inclusion or after 12 months for histological correlation. However, despite these limitations of the chosen study design, it is remarkable that renal function remained stable in such a large group of kidney transplant recipients treated with ezetimibe.

In conclusion, our data indicate that ezetimibe appears to ameliorate the decline of renal function after renal transplantation. Further studies with renal function as primary endpoint are required to investigate the influence of ezetimibe on kidney transplants.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Masterson R, Hewitson T, Leikis M, Walker R, Cohney S, Becker G. Impact of statin treatment on 1-year functional and histologic renal allograft outcome. Transplantation (2005) 80:332–338.[CrossRef][Web of Science][Medline]
  2. Cosio FG, Pesavento TE, Pelletier RP, et al. Patient survival after renal transplantation: the effects of statins. Am J Kidney Dis (2002) 40:638–643.[CrossRef][Web of Science][Medline]
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  9. Kasiske B, Cosio FG, Beto J, et al. National Kidney Foundation Clinical practice guidelines for managing dyslipidemias in kidney transplant patients: a report from the Managing Dyslipidemias in Chronic Kidney Disease Work Group of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative. Am J Transplant (2004) 4:13–53.
  10. Pearson TA, Blair SN, Daniels SR, et al. AHA guidelines for primary prevention of cardiovascular disease and stroke: 2002 update: consensus panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vascular diseases. American Heart Association Science Advisory and Coordinating Committee. Circulation (2002) 106:388–391.[Free Full Text]
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Received for publication: 27. 4.07
Accepted in revised form: 16. 8.07


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