Tacrolimus Extended Release could be an Alternative to the use of Cyclosporine after Allogeneic HSCT in case of Renal Impairment due to Cyclosporine : A Prospective pilot study from two centers in France

1Hematology Department, Centre Hospitalier Régional Universitaire de Nancy, Hôpitaux de Brabois, Université de Lorraine, Vandoeuvre-lès-Nancy, France 2Biostatistics, Hematology Research Department, Hospices civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France 3Laboratory of biochemistry, Biology Department, Centre Hospitalier Lyon Sud, Pierre-Bénite, France 4Pharmaceutical Department, Centre Hospitalier Lyon Sud, Pierre-Bénite, France 5Hematology Department, Hospices civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France Received date: 08 Aug 2017; Accepted date: 07 Sep 2017; Published date: 15 Sep 2017.


Introduction
After allogeneic hematopoietic stem cell transplantation (HSCT), we are often confronted with acute renal failure (ARF) and sometimes this complication is severe.The median time of onset of ARF after allogeneic HSCT was between 7 and 40 days according to several previous studies [1][2][3][4][5].Pre-existing kidney dysfunction, arterial hypertension, conditioning with total body irradiation (TBI), sepsis, acute graft-versus-host disease (aGvHD) and microangiopathic syndromes as sinusoidal occlusion syndrome may be associated with renal impairment.Acute renal failure may also occur in the absence of these conditions due to nephrotoxicity of many drugs, such as amphotericin B or cyclosporine (CsA) which are the most frequent [1,[4][5].
Calcineurin inhibitors had adverse effect on the renal afferent arteriole with vasoconstriction associated with an imbalance between

Abstract
Tacrolimus is a calcineurin inhibitor regularly used in allogeneic hematopoietic stem cell transplantation for prevention of graft-versus-host disease.Recently, several transplantation centers showed advantageous effects for patients with tacrolimus extended-release compared to cyclosporine regarding renal function after organ transplantation.Based on these observations, we propose in this study to switch cyclosporine for tacrolimus extended-release in case of renal failure due to cyclosporine for allogeneic hematopoietic stem cell transplantation recipients.Thirty consecutive patients were included between March 2012 and March 2016 from two centers in France (Lyon and Nancy) with renal impairment due to cyclosporine (serum creatinine>90 µmol/L).We evaluated the residual tacrolimus level after conversion, the serum creatinine, the eGFR (CKD-EPI) and the potassium level with both cyclosporine and tacrolimus extended-release.The median time to which tacrolimus replaced cyclosporine was 40 days (range, 3-1286) and the median of serum creatinine for switching was 110 µmol/L (range, 94-262).Regarding creatinine, the median level was 105 µmol/L (range, 51-262) with cyclosporine and 84 µmol/L (range, 50-129) with tacrolimus extended-release (p<0.01) and for potassium level 4.2 mmol/L (range, 3.2-5.2) with cyclosporine and 4.0 (range, 3-5.1) with tacrolimus extended-release (p<0.001).After 30 days of switching, all patients had creatinine clearance >50 ml/min.In conclusion, the replacement of CsA by tacrolimus extendedrelease resulted in an improvement in renal function.We suggested that the use of tacrolimus extended-release in case of renal impairment due to cyclosporine is safe for allogeneic hematopoietic stem cell transplantation recipients.
Keywords: Allogeneic hematopoietic stem cell transplantation recipients; Graft-versus-host disease; Cyclosporine; Acute renal failure; Creatinine clearance; Tacrolimus extended-release oral formulation vasoconstrictor (endothelin and thromboxane) and vasodilator agents (prostaglandin E2, prostacyclin and nitric oxide).Concomitantly the inhibition of the calcineurin-NFAT signaling leads to COX-2 inhibition associated with renal vasoconstriction and a decrease of glomerular filtration rate (GFR).Adequate monitoring of serum creatinine and the serum residual value of CsA or tacrolimus is crucial for detecting nephrotoxicity induced by these drugs; an increase in concomitant serum creatinine and residual level of CsA or tacrolimus will allow to be stopped or adjusted the dose of CsA or tacrolimus [6][7][8].The renal toxicity of calcineurin inhibitors is the most common cause of ARF after allogeneic HSCT.
Tacrolimus is now available in two oral formulations: standard-release (Prograf™, twice-daily tacrolimus) and extended-release (Advagraf™, once-daily tacrolimus).Tacrolimus extended-release (Tacrolimus ER) has been developed with the aim to obtain a stable and progressive absorption through intestinal tract over the day.
In previous studies in kidney and liver transplantation, the extendedrelease tacrolimus has been compared with the standard-release formulation to shown bioequivalent drug exposure, efficacy and safety [9][10][11][12][13][14].Moreover, several transplantation centers showed in recent studies advantageous effects of tacrolimus in comparison with CsA regarding renal function in patients after renal and heart transplantation.[15][16].
Based on these observations, we realised a prospective study in which CsA (Neoral Sandimmun, Novartis Pharma) is replaced by tacrolimus ER (Advagraf, Astellas Pharma) in case of renal impairment secondary to CsA nephrotoxicity.Discontinuation of nephrotoxic drugs and correction of dehydration were realised before the switch of molecule.Renal relapse of malignant disease was excluded and other cause of renal failure was excluded to.

Patients, Method
We enrolled 30 consecutive patients in a pilot study between March 2012 and March 2016 from two centers in France (Lyon and Nancy) with renal impairment due to CsA.Renal impairment was defined by a serum creatinine>90 µmol/L.All patients received an allogeneic HSCT for hematologic malignant disease after myeloablative or reduced intensity conditioning (RIC).The prophylaxis of acute GvHD was provided by a combination of CsA and methotrexate or mycophenolate mofetil.The minimum age for inclusion was 17 years.To be included, patients should have normal renal function defined by serum creatinine<90 µmol/L and estimated GFR (eGFR) with CKD-EPI equation>60 ml/min prior to transplantation.The demographic and characteristics of patients are presented in table 1.After exclusion of other cause of renal failure, correction of dehydration and discontinuation of CsA, the conversion was carried out and the dose was established on an mg:mg basis 1:100 from CsA total daily dose to a total daily dose of tacrolimus.The discontinuation of CsA is followed by taking tacrolimus ER the next day at noon.In this cohort, 27 patients received oral formulation of tacrolimus ER (Advagraf) and 3 received Prograf initially iv. and then converted to tacrolimus ER oral form.The dose was readjusted to obtain a tacrolimus blood trough level between 5 and 15 µg/L.We evaluated the tacrolimus blood trough level changes after conversion, serum creatinine, potassium, one time a week from one week after switching to discontinuation.Renal function was analysed by serum creatinine levels and estimated glomerular filtration rate (eGFR) assessed by CKD-EPI equation.The stage of acute kidney injury (AKI) has been established according to definition by Acute Kidney Injury Network [17].This study was conducted according to the 2008 ethical Declaration of Helsinki and the ethics committees of each center approved this study.

Statistics
The exact tests of Wilcoxon Mann-Whitney and Kruskal Wallis (nonparametric tests) were performed for the physiological parameters analysis.The p values are calculated with the Mann-Whitney tests.

Results
The characteristics of patients and transplantation are summarized in table 1.
All patients received allogeneic HSCT for malignant blood disease; the median age in this cohort was 54 years (range, 17-67).Before the switch, 22 patients (73%) had CsA for GvHD prophylaxis and 8 patients (27%) for acute GvHD treatment in association with prednisone.

Discussion
There is currently no recommendation in allogeneic HSCT if a patient has acute renal failure secondary to CsA.Each center has its own strategy after discontinuation of CsA, most of the time, CsA is replaced by corticosteroids and CsA is resumed after normalization of renal function if possible otherwise the corticosteroids are being prosecuted.To our knowledge, this study with tacrolimus ER is the first in allogeneic HSCT.Our principal objective was to measure the serum creatinine level and the eGFR after the change for tacrolimus ER in case of decreased renal function due to CsA.Only patients with acute renal failure secondary to CsA toxicity were considered in this study.For the majority of patients (53%), the stage of renal insufficiency was 1 but 2 patients had a severe renal failure a score of 3 according to acute kidney injury network [17].We found for creatinine a median level of 105 µmol/L (range, 51-262) with cyclosporine and 84 µmol/L (range, 50-129) with tacrolimus (p<0.01).The median of serum creatinine level was 88 µmol/L (range, 59-130), 84 µmol/L (range, 54-129) and 84 µmol/L (range, 54-129) at D+5, D+15 and D+30 after the change for tacrolimus ER.After 30 days of switching, all patients had creatinine clearance >50 ml/min.The serum creatinine level and the eGFR are significantly improved after the change for tacrolimus ER.These results confirm previous studies in organ transplantation concerning renal protection with tacrolimus ER especially in heart transplantation.Two studies reported that CsA was associated with decreased renal function mostly in the first 6 months after heart transplantation when high CsA drug levels are imperative to prevent acute rejection of the graft; at this time a superior rejection profile of the tacrolimus based immunosuppressive regimen had been demonstrated with respect to renal function [15,18].
Concerning, the potassium level, we found an improvement in the potassium level which was often high with CsA.This observation has already been made in the past and several studies are showed that decreased numbers of mineral corticoid receptors lead to hyperkaliemia with aldosterone resistance in patients treated with CsA [6].
In healthy volunteers, acute reduction in GFR is attenuated with tacrolimus and tacrolimus ER compared with CsA and moreover tacrolimus has a lower nephrotoxicity than CsA in studies and animals and humans [6,19].
In organ transplantation, the choice between Tacrolimus (Prograf or Advagraf) and CsA is based on the experience and preference of the physician as well as the toxicity profile of the molecule according to the patient.There are several multi-centers studies and retrospective analysis in favour of tacrolimus over CsA concerning renal function in liver, heart and renal transplantation.Tacrolimus was associated with significantly lower serum creatinine levels compared to Csa and better graft survival in long term after renal transplantation.In case of renal graft dysfunction, a switch from CsA to tacrolimus was associated with a significant improvement in renal function [16,[20][21][22][23].In liver transplantation, several centers reported improved kidney function, improved lipid profile and better blood pressure [24].
In allogeneic HSCT, calcineurin inhibitors (CNIs) are habitually combined with methotrexate in myeloablative allogeneic HSCT and are usually used with mycophenolate mofetil (MMF) after reduced intensity conditioning (RIC) for GvHD prophylaxis.Cyclosporine has been used for 1983 in the prevention and treatment of GvHD after allogeneic HSCT.Concerning CsA, this molecule can cause ARF, but it is known that levels of residual values are not always correlated with the occurrence of ARF [25].Tacrolimus has been used since the early 1990s in organ transplantation and has an advantage particularly in the prophylaxis of GvHD in unrelated allogeneic HSCT.It can also be used in case of development of GvHD with CsA prophylaxis.[26][27].
The immunosuppression secondary to CsA or tacrolimus results from inhibition of calcineurin, a calcium-and calmodulin-dependent phosphatase (protein phosphatase 3).Two different molecules are binded intracellularly by CsA and tacrolimus: cyclophylin and FKBP12 respectively.The phosphatase activity of calcineurin is inhibited by competitive binding of cyclosporine-cyclophylin and tacrolimus-FKBP12 complexes.By this mechanism, the transcription of IL-2 is inhibited and the nuclear factor of activated T cells (NFAT) which regulates IL-2 transcription is impaired.The T cell activation is therefore no effective [28][29][30].In this way, these molecules allow the prevention of acute GvHD immediately after allogeneic HSCT.In our study the cumulative incidence of grade II-IV aGvHD was 53% (95%CI, 25-64) at +90 days and the cumulative incidence of cGvHD was 26.5% (95%CI, 7.75-45) at 1 year, 32.14%(95% CI, 11.6-52) after 2 years and 32.14% (95% CI, 11.6-52) after 3 years.These results are expected but the small number of patients limits the conclusions.
The main interest of this study is to demonstrate the feasibility of this molecule change in case of renal failure due to CsA without excessive incidence of GvHD or side effects.In this way, the pursuit of a calcineurin inhibitor is possible and corticosteroids should not be used, which is

Figure 3 :
Figure 3: The residual value of tacrolimus ER was in therapeutic range (5-15 µg/l) after five and twenty days of introduction

Table 1 :
Characteristics of patients and transplantation

Table 2 :
Details for each patient in the study: age, gender (M/F), stage of acute kidney injury (AKI), creatinine (µmol/L) level and eGFR (CKD-EPI) ml/min/1, 73 m2 at Day -30, at Day +30, at Day +45, at Day of switching if different than Day+30 or Day+45 and at thirty days after the conversion for tacrolimus ER Abbreviations: eGFR=estimated glomerular filtration rate; AKI=acute kidney injury