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NDT Advance Access originally published online on May 25, 2007
Nephrology Dialysis Transplantation 2007 22(8):2354-2358; doi:10.1093/ndt/gfm313
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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

The impact of FTY720 (fingolimod) on vasodilatory function and arterial elasticity in renal transplant patients

Timm H. Westhoff1, Sven Schmidt1, Petra Glander2, Lutz Liefeld2, Sebastian Martini2, Gerd Offermann1, Hans H. Neumayer2, Walter Zidek1, Markus van der Giet1,* and Klemens Budde2,*

1Centrum 10 – Nephrology, Charité – Campus Benjamin Franklin and 2Department of Nephrology, Charité – Campus Mitte, Berlin, Germany

Correspondence and offprint requests to: Dr Timm H. Westhoff, Medizinische Klinik IV – Nephrology, Charité – Campus Benjamin Franklin, Hindenburgamm 30, 12200 Berlin, Germany. Email: timm.westhoff{at}charite.de



   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 
Background. FTY720 has recently demonstrated a similar efficacy in prevention of acute graft rejection compared with mycophenolate mofetil (MMF) in a large phase III trial of de novo renal transplant recipients. Creatinine clearance, however, was significantly lower in FTY720-treated patients. In the present study, we examined the impact of FTY720 on vascular function in a subgroup of patients of this trial.

Methods. Eighteen patients (12 FTY720, 6 MMF) agreed to be enrolled for an analysis of vascular function. Vascular measurements were performed 1.5 years post-transplant and were repeated 3 months after conversion of the patients from FTY720 to MMF. Arterial stiffness was assessed as augmentation index (AI75); endothelium-dependent and -independent vasodilation were measured sonographically as flow-mediated dilation (FMD) and as vasodilation after application of glyceroltrinitrate (GTN).

Results. Conversion from 2.5 mg FTY720 to MMF led to a significant improvement of FMD (5.40 ± 1.84 vs 7.77 ± 3.36%, P 0.02). AI75 and GTN tended to be higher after conversion without reaching significance (83 ± 20.43 vs 78.69 ± 15.39%, P 0.06; 13.76 ± 4.52 vs 17.39 ± 3.76%, P 0.07). In the MMF group, AI75, FMD and GTN did not significantly change during the observation period.

Conclusion. The present study constitutes the first analysis of the impact of FTY720 on vascular function in humans and reveals an improvement of arterial vasodilatory function after discontinuation of FTY720 in de novo renal transplant recipients on cyclosporine.

Keywords: FTY720; renal transplantation; endothelial function; arterial elasticity



   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 
The novel immunomodulator FTY720 has proven to be effective in animal models of transplantation and autoimmune disorders [1]. In phase I and II clinical trials, FTY720 was well tolerated and revealed no significant side-effects, except for transient and asymptomatic bradycardia [2,3]. In phase II trials, FTY720 in combination with cyclosporine (CsA) showed a similar efficacy as standard immunosuppressive regimens of CsA and mycophenolate mofetil (MMF) in preventing acute allograft rejection in de novo renal transplantation [2–4]. Due to these promising results, two large phase III trials were initiated in order to compare the efficacy of FTY720-containing immunosuppressive regimens to conventional regimens. In the first of two large phase III trials (668 patients), FTY720 in combination with regular doses of CsA demonstrated a similar efficacy of prevention of acute renal graft rejection as CsA and MMF, but failed to reveal a significant benefit [5]. Furthermore, this study revealed that FTY720 therapy was associated with impairment of renal function and macula oedema leading to a pause of the clinical programme for the development of FTY720 in renal transplantation [5]. To date, the reasons for the lower creatinine clearance in patients treated with FTY720 remain elusive.

FTY720 is structurally similar to sphingosine 1-phosphate (S1P), an endogenous lysophospholipid that mediates various signalling pathways via S1P receptors [6]. Unlike conventional immunosuppressants, the efficacy of FTY720 in transplantation is not mediated by an impairment of activation, proliferation or effector functions of lymphocytes, but a retainment of lymphocytes in lymphatic organs [1]. Besides the effects on lymphocyte migration, there is increasing evidence for cardiovascular effects of FTY [7]. Interestingly, S1P-receptors were first identified as receptors involved in endothelial differentiation. FTY720 exerts profound effects on endothelial cell function and permeability [8,9]. Recently, we have shown that FTY720 potently induces S1P3-receptor mediated vasodilation in mouse aortae by activation of the Akt/eNOS/NO pathway [10]. FTY reduces atherosclerotic wall changes in apolipoprotein E-deficient mice and S1P stimulates the functional capacity of endothelial progenitor cells [11,12]. These data suggested that FTY720 might have beneficial effects in transplant recipients beyond immunosuppression. To date, however, there are no data on the effects of FTY720 on endothelial function in humans.

In the present study, we describe the impact of FTY720 on endothelial function and arterial elasticity in de novo renal transplant recipients.



   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Acknowledgements
 References
 
Protocol
The present work depicts a subgroup of patients of the first phase III trial of FTY720 in de novo renal transplantation [5]. The study was a multi-centre, three-arm, randomized study conducted between April 2003 and April 2005 in 62 transplant centres in Europe, Asia and Australia. Patients were randomized 1 : 1 : 1 to receive FTY720 5.0 mg o.d. plus reduced-dose CsA (RDC, starting dose 3–4 mg/kDa/day) (Group 1), FTY720 2.5 mg o.d. plus full-dose CsA (FDC, starting dose 8–10 mg/kg/day) (Group 2), or MMF 1 g b.i.d. plus FDC (Group 3) as published before [5]. In October 2004, on the recommendation of the data safety monitoring board, all patients receiving FTY720 5.0 mg plus RDC (Group 1) were converted to FTY720 2.5 mg plus regular doses of CsA due to increased risk of acute rejection in the reduced CsA group. Due to cessation of the clinical FTY720 transplant programme, all patients on FTY720 were converted to 2 g MMF between October and November 2005. Informed consent for participation in the study was obtained from all patients before inclusion in the study. The study was approved by the Institutional Review Board/Independent Ethics Committee/Research Ethics Board (IRB/IEC/REB). Approval for assessment of vascular function was obtained from the local ethical committee of the Charité, Berlin, Germany.

The vascular measurements were performed at the last day of FTY720 treatment (baseline) and were repeated 3 months later (follow-up). Patients, who were randomized to MMF in the original trial served as controls.

Assessment of arterial elasticity by augmentation index
Haemodynamic measurements were conducted in a quiet clinical research laboratory at a constant ambient temperature of 20–22°C between 12 and 2 p.m., at least 3 h and on average 4–6 h after ingestion of CyA Neoral. Since CyA levels might acutely influence arterial elasticity, all the measurements were performed at this defined span of time in order to assure comparability of results. All measurements were performed by the same person. Patients were resting in a supine position for 15 min before the measurement procedure was started. AI, systolic blood pressure, diastolic blood pressure and heart rate were measured by the HEM-9000AI device (Omron Healthcare). Blood pressure was measured oscillometrically on the non-fistula arm. Augmentation index (AI) was assessed by computerized radial artery pulse wave analysis. The HEM-9000AI device makes use of a multi-sensor array technology to detect pulse waves by applanation tonometry. The AI was calculated as the difference between the first and second systolic peak of the pulsewave. Since AI depends on heart rate, the device offers a software tool correction AI to a heart rate of 75/min (AI75).

Three measurements were performed and mean values for blood pressure and AI were used for statistical evaluation.

Assessment of endothelial function by flow-mediated dilation
Endothelial function was assessed in the brachial artery, as published previously [13,14]. By means of high-resolution ultrasound, diameter changes in response to reactive hyperaemia (FMD) and glyceroltrinitrate (GTN), were measured, according to standard protocols [15]. Accuracy and reproducibility of the method had been documented previously. Flow-mediated vasodilation in response to FMD represents endothelium-dependent vasoreactivity, whereas GTN indicates smooth muscle cell function and is independent of endothelial function.

The brachial artery was examined by two-dimensional ultrasound images, with a 10-MHz linear array transducer and a standard 128XP/10c-system (Acuson, Mountain View, California). Artery diameters were measured by a computerized edge detection programme (Cardiovascular Imaging Software, Information-Integrity, Boston, Massachusetts); the images were acquired ECG-triggered at end-diastole throughout the study. A resting scan was recorded for 2 min. A pneumatic tourniquet, placed distal of the elbow of the subject, was then inflated to a pressure of 300 mmHg for 3 min. The release immediately induces increased blood flow in the subject's forearm for a few seconds, which represents the stimulus for endothelium-dependent vasodilation. A break of 10 min with the patient continuously staying in a supine position was required before the scan for endothelium-independent vasodilation was started. After a resting scan of 2 min, 400 µg GTN was administered sublingually; the scan was completed 5 min after application. The same experienced person performed all of the scans. The computer-assisted calculation of vessel diameters was conducted in a blind fashion, as published previously [13]. FMD represents the percentage of diameter increase caused by shear stress compared with baseline. The NO-independent dilation represents the percentage of diameter increase induced by GTN compared with baseline.

Statistical analysis
Results are presented as mean ± standard deviation (SD). Blood pressure, AI, AI75, FMD and GTN-induced vasodilation at baseline and follow-up using the Wilcoxon test for paired samples in each group. P <0.05 was regarded to be statistically significant.



   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Acknowledgements
 References
 
Eighteen patients (6 female, 12 male) out of the originally enrolled 25 patients in our institution agreed to be enrolled in an analysis of vascular function. Mean age was 46.0 ± 10.4 years. Baseline measurements took place 1.50 ± 0.38 years post-transplant in the FTY720 group and 1.54 ± 0.43 years post-transplant in the MMF group. Patient characteristics including gender, age, concomitant diseases and cause of renal failure are summarized in Table 1. All of the patients suffered from arterial hypertension and were on antihypertensive medication. The median number of antihypertensive drugs per patient apart from diuretics was two in the FTY720 group (range 1–4) and two in the MMF group (range 1–3). Choice of antihypertensive agents was comparable in both groups and was not changed during the study.


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  		Table 1. Patient characteristics

 
Seven patients were randomized to Group 1, 5 patients to Group 2, and 6 patients to Group 3. Thus, after conversion of Group 1 in October 2004, 12 patients were on 2.5 mg FTY720 and 6 patients on 2 g MMF, all with regular CsA doses. Baseline values of FMD, GTN and AI75 were normally distributed as shown, e.g. by the Kolmogorov–Smirnov test. Signal detection of arterial pulse wave analysis did not allow estimation of AI75 in one patient of the MMF group. All the other haemodynamic measurements worked out properly.

Haemodynamic measurements showed no alteration of AI75 in the MMF group within the 3 months (Table 2, Figure 1). In the FTY group, arterial stiffness tended to be slightly lower 3 months after the switch from FTY to MMF as reflected by a decrease of AI75 without reaching significance (P 0.06, Table 2, Figure 1). Endothelium-independent vasodilation (GTN) revealed no significant change from baseline to follow-up in the MMF group, but tended to be increased in the FTY720 group after conversion to MMF without reaching significance (P 0.06). FMD significantly improved from baseline to follow-up in the FTY720 group (P 0.02, Table 2, Figure 1), whereas it remained unchanged in MMF patients (P > 0.05, Table 2, Figure 1). Change of FMD from baseline to follow-up in Group 1 (RDC + FTY720) and Group 2 (FDC + FTY720) did not significantly differ (1.97 ± 3.13 vs 2.94 ± 2.83 percentage points, P > 0.05).


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  		Table 2. Endothelium-dependent (FMD) and endothelium-independent (GTN) vasodilation, augmentation index (AI), augmentation index corrected for a heart rate of 75/min (AI75), systolic blood pressure (RRsys), diastolic blood pressure (RRdias), cyclosporine trough levels (CsA) and creatinine in the FTY720 and the MMF group at baseline and follow-up after 3 months

 

Figure 1
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  		Fig. 1. (A, B) Endothelium-dependent vasodilation (FMD) and (C, D) arterial stiffness (augmentation index, AI75) in the FTY720 group (baseline measurement before and follow-up 3 months after discontinuation of FTY720) and MMF group (MMF at baseline and follow-up).

 


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Acknowledgements
 References
 
Recently, it was shown that FTY720 induces S1P3-receptor mediated endothelium-dependent vasodilation in mouse aortae [10]. The present data of de novo renal transplant recipients, however, reveal no significant benefit of vasodilatory function in patients having received FTY720 instead of MMF as part of a triple immunosuppressive therapy with CsA. Since there are several potential confounders that might have an impact on baseline arterial function such as antihypertensive medication, age, diabetes, hyperlipidaemia and underlying renal disease, we performed a longitudinal observation and repeated vascular measurement procedures 3 months after discontinuation of FTY720 and conversion to MMF. After this, time flow-mediated dilation significantly improved compared with the values during FTY720 treatment.

The study is limited by the fact that—due to the three-arm design of the study—the MMF group is smaller than the FTY720 group. Furthermore, baseline diastolic blood pressure values and CsA trough levels differ in the FTY720 and MMF group. Therefore, we refrained from a direct statistical comparison between the two groups. These limitations, however, have no impact on the longitudinal intra-individual observations. Although the overall sample size is small, it is sufficient to reveal a significant improvement of vasodilatory function after conversion from FTY720 to MMF.

Why does vasodilatory function improve after withdrawal of FTY720? In the in-vitro studies of mouse aortae, FTY720 doses of 1 nmol/l to 10 µmol/l were used and vasodilatory responses of mouse aortae started at levels of 10 nmol/l [10], whereas, in dose-finding trials in renal transplant recipients, doses of 0.25–2.5 mg/day resulted in plasma concentrations of 1.0–8.8 ng/l (2.9–25.6 pmol/l) [16]. Thus, the in-vitro concentrations are markedly higher than the in-vivo concentrations (factor 390–3448), which might contribute to the observed differences. The differential cardiovascular effects of FTY720 are diverse and strictly depend on the tissue-specific arrangement of S1P-receptor subtypes. S1P is released by endothelial cells and by platelets during platelet activation and can be found in significant amounts in serum as part of lipoproteins [17]. In-vitro data suggest that FTY720 might assist in preserving the endothelial integrity of the vasculature [18]. In endothelial cells, we and others have demonstrated that S1P activates Akt and eNOS resulting in vasodilation [19,20]. There is increasing evidence that the FTY-induced vasodilation is mediated by the S1P3 receptor [10]. On the other hand, S1P has vasoconstrictive effects on basal arterial tone in isolated arteries, which are supposed to be mediated by the S1P2 and S1P3 receptors [20–23]. These vasoconstrictive effects are based on both an increase of intracellular calcium release and a sensitization of vascular smooth muscle cells to the contractile effect of intracellular calcium [23]. Thus, both the subtype of the S1P receptor and the specific action of FTY on this receptor (activation or internalization) predict the vascular effects of FTY in a specific tissue. Besides the significant improvement of flow-mediated dilation after conversion from FTY720 to MMF, our data show a trend to an increased arterial elasticity and an increased endothelium-independent vasodilation (GTN) after conversion. Thus—in accordance with the data on the vasoconstrictive properties of S1P-receptors—the observed improvement of vasodilatory function might not only be based on a change of NO liberation, but on a change of smooth muscle cell function as well. It may be speculated whether the vasotoxic effects of CsA on the endothelium prevented the expected beneficial effect of FTY720 on eNOS activity leading to a predominance of the direct vasoconstrictive effect on vascular smooth muscle cells.

Arterial vasodilatory function—mediated by endothelium-dependent and endothelium-independent mechanisms—is a crucial pre-requisite for intact glomerular function. With regard to the lower creatinine clearance in FTY720-treated patients in the first phase III trial of de novo renal transplant recipients, our present findings should encourage further research. The pause of the clinical programme on the use of FTY720 in renal transplant recipients makes an expansion of the present investigation impossible. The upcoming use of FTY720 in patients with multiple sclerosis should be used for large-scale studies on the impact of FTY720 on endothelial function.

The present study constitutes the first analysis of the impact of FTY720 on vascular function in humans and reveals an improvement of vasodilatory function after conversion of FTY720 to MMF in de novo renal transplant recipients.



   Acknowledgements
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
References
 
We thank Mrs Daniela Todd for her excellent organization of the study and Mrs Christl Harsch for her kind technical assistance.

Conflict of interest statement. K.B., H.H.N. and M. van der G. received research grants from Novartis.



   Notes
 
*Authors contributed equally to the work. Back



   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 

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Received for publication: 23. 3.07
Accepted in revised form: 26. 4.07


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