Rev. Nefrol. Dial. Traspl. 2024;44(3):127-132
Mycophenolate
mofetil vs Enteric-coated mycophenolate sodium in de-novo kidney transplant
recipients (summary of the side effects within first three months): single
center experience
Micofenolato mofetilo vs Micofenolato de sodio con
cubierta entérica en receptores de trasplante renal de novo (resumen de efectos
secundarios en los primeros 3 meses): experiencia de un solo centro
Mustafa Hakan Sozen1, Aydin Dalgic1, Ramazan Kozan2 , Ahmet Ziya Anadol2
1) Department of General
Surgery, Gazi University Faculty of Medicine, Ankara, Türkiye.
Transplantation Center, Gazi University, Ankara, Türkiye.
2) Department of General
Surgery, Gazi University Faculty of Medicine, Ankara, Türkiye.
RESUMEN
Objetivo: Este estudio
compara y evalúa los efectos secundarios gastrointestinales, de la médula ósea
y hepatotóxicos de MMF y EC-MPS en los primeros 3 meses después de un
trasplante renal de novo. Material y Métodos: Retrospectivamente, se analizaron datos de 100 receptores de
trasplante renal, entre enero de 2016 y diciembre de 2021, en el Centro de
Trasplantes de la Universidad de Gazi. Los pacientes se dividieron en dos
grupos: MMF (grupo A, n=68) y EC-MPS (grupo B, n=32). Se evaluaron los efectos
secundarios dentro de los primeros tres meses después del trasplante,
incluyendo efectos secundarios gastrointestinales (dispepsia, distensión
abdominal, diarrea), complicaciones de la médula ósea y hepatotoxicidad. El
análisis estadístico se realizó utilizando el software SPSS. Resultados: En el grupo A, no se observaron efectos secundarios de MMF en el 38% de los
receptores durante los primeros 3 meses postoperatorios. El 62% de los
receptores tuvieron los siguientes efectos secundarios: gastrointestinal en el
22%, médula ósea en el 24% y hepatotoxicidad en el 16%. En el grupo B, no se
observaron efectos secundarios de EC-MPS en el 43% de los receptores durante
los primeros 3 meses postoperatorios. El 57% de los receptores experimentaron
los siguientes efectos secundarios: médula ósea en el 28%, gastrointestinal en
el 25%, y hepatotoxicidad en el 4%. El manejo implicó ajustes en la medicación,
con la cesación de los efectos secundarios en la mayoría de los casos. Conclusiones: En conclusión, este estudio resalta los perfiles de seguridad favorables en
general de MMF y EC-MPS en el período post-trasplante temprano. Sin embargo,
subraya la ventaja potencial de EC-MPS sobre MMF en términos de
hepatotoxicidad, con EC-MPS demostrando una incidencia más baja de
hepatotoxicidad en comparación con MMF.
Palabras Clave: trasplante renal;
micofenolato mofetilo; micofenolato sódico con recubrimiento entérico;
inmunosupresión; efectos secundarios.
ABSTRACT
Aim: This study assesses and compares GI, bone marrow (BM), and
hepatotoxicity side effects of MMF and EC-MPS in the first 3 months after de-novo kidney
transplantation. Material andMethods: Retrospective data from 100 kidney
transplant recipients were analyzed between January 2016 and December 2021 at
Gazi University Transplantation Center. Patients were divided into two groups: MMF (group A, n=68) and EC-MPS (group B,
n=32). Side effects within the first three
months post-transplantation were assessed, including gastrointestinal side
effects (dyspepsia, bloating, diarrhea), bone marrow complications, and
hepatotoxicity. Statistical analysis was performed using SPSS software. Results: In group A, we have not seen any side
effects of MMF in 38% of recipients during the postoperative
first three months. Sixty-two percent of recipients had the following side
effects: gastrointestinal 22%, bone marrow 24%, and hepatotoxicity 16%. In
group B, we have not seen any side effects of EC-MPS in 43% of recipients
during the postoperative first three months. Fifty-seven percent of recipients
experienced the following side effects: BM in 28%, GI in 25%, and
hepatotoxicity in 4%. Management involved medication adjustments, with side
effects ceasing in most cases. Conclusions: In conclusion, this study highlights
the overall favorable safety profiles of MMF and EC-MPS in the early
post-transplant period. However, it underscores the potential advantage of
EC-MPS over MMF in hepatotoxicity, with EC-MPS demonstrating a lower incidence
of hepatotoxicity than MMF.
Keywords: kidney transplantation; mycophenolate
mofetil; enteric-coated mycophenolate sodium; immunosuppression; side effects.
INTRODUCTION
The success of organ transplantation is
due, in part, to the availability of potent and more selective
immunosuppression agents. More than 80% of kidney transplant recipients are
discharged on a maintenance immunosuppression regimen that includes a
mycophenolic acid (MPA)--based compound. Two formulations of MPA are currently
available in the United States. Mycophenolate mofetil (MMF; CellCept,
Roche Laboratories, Inc., Nutley, NJ), a morpholino ester prodrug of MPA, was
approved to prevent acute allograft rejection in kidney transplant patients in
1995. The use of MMF is associated with improved graft and patient survival and
reduced early and late acute allograft rejection (1). Enteric-coated
mycophenolate sodium (EC-MPS; Myfortic; Novartis
Pharmaceuticals Corp., East Hanover, NJ) is a delayed-release formulation of
MPA approved in the United States in 2004 (2).
The Mycophenolate (MPA) formulations are
the most frequently used immunosuppressive drugs in solid organ
transplantation. Enteric-coated mycophenolate sodium (EC-MPS) is a new
formulation of mycophenolic acid that delivers the active moiety MPA, the same
active moiety delivered by mycophenolate mofetil (MMF).
Similar safety and efficacy outcomes
were observed in two pivotal phase III trials comparing EC-MPS and MMF: one in
de novo renal transplant patients and one in stable maintenance renal
transplant patients (3). However, dose-dependent adverse
gastrointestinal effects (GI) are common with MPA-based therapy. Reducing or
interrupting MMF dosing for GI side effects has been associated with increased
risk of graft loss and healthcare costs (3,4).
Here, we retrospectively analyzed data
from patient charts at Gazi University Transplantation Center to assess and
compare the GI, bone marrow (BM), and hepatotoxicity side effects of MMF and
EC-MPS in the first three months after de novo kidney transplantation.
MATERIAL AND METHODS
Data were retrospectively collected from
patients’ charts who received their first kidney transplantation at Gazi
University Transplantation Center between January 2016 and December 2021. A
total of 103 kidney transplant operations were performed, with 21 out of 103 recipients
being pediatric and 82 out of 103 recipients being adults, enrolling one
hundred of 103 recipients for this study. There were 68 de novo MMF (group A)
and 32 EC-MPS (group B) patients in each group. In group A, the mean age was
32,4 ±14,6 years old. Twenty-nine of the recipients were female, and 39 were
male. Transplantations were performed with kidneys from 34 deceased donors and
34 with living donors. In group B, the mean age was 29,1 ±13,5 years old.
Fourteen of the recipients were female, and 18 were male. Transplantations were
performed with kidneys from 18 deceased donors and with 14 living donors.
The immunosuppressive protocol consisted
of a calcineurin-based triple regimen and Basiliximab induction (only for deceased donors, second or more transplantation, and high
PRA). All recipients received a single preoperative dose of either MMF 1000 mg
or EC-MPS 720 mg in living transplantation. After transplantation from D0, all
patients received either MMF 1000 mg BID or EC-MPS 720 mg BID.
All procedures carried out in this study
complied with the ethical standards of the institutional and/or national
research committee and the principles outlined in the 1964 Helsinki Declaration
and its subsequent revisions or equivalent ethical standards. This study was
approved by the Local Ethical Committee of Gazi University (reference No.
2024-294).
All data retrospectively were analyzed
from patient charts at Gazi University Transplantation Center to assess and
compare common gastrointestinal (diarrhea, dyspepsia, and floating), bone
marrow (pancytopenia, leukopenia, anemia), and hepatic side effects (at least a two-fold elevation of aspartate aminotransferase
(AST) and alanin aminotransferase (ALT) levels) of
MMF and EC-MPS in the first three months after de-novo kidney transplantation.
All the statistical analysis was
performed with SPSS software, version 20 (SPSS Inc., Chicago, IL, USA). Data
were expressed as median and range. Relevant variables were analyzed using
descriptive statistics.
RESULTS
In group A, we have not seen any side
effects of MMF in 38% (n=26) recipients during the postoperative first three
months. Sixty-two percent of recipients had the following side effects:
gastrointestinal 22%, bone marrow 24%, and hepatotoxicity 16%. Most GI side effects
are diarrhea (n=13), and dyspepsia (n=2). The majority of BM
side effects are leukopenia (n=13), pancytopenia (n=2), and anemia (n=1) (Figure 1) (Table 1). Side effects have ceased by stopping MMF in 13 patients,
reducing the drug in 13 patients, and converting them in 9 patients.
Figure
1:
Group A: Overall, GI and BM side
effects (%)
Table
1:
MMF vs EC-MPS comparison of side effects [n (%)]
Toxicity
|
MMF (n=68)
|
EC-MPS (n=32)
|
Gastrointestinal:
|
15 (22%)
|
9 (28%)
|
Diarrhea
|
13
|
6
|
Dyspepsia
|
2
|
2
|
Bloating
|
-
|
1
|
Bone Marrow:
|
16
(24%)
|
8
(25%)
|
Leukopenia
|
13
|
7
|
Anemia
|
2
|
-
|
Pancytopenia
|
1
|
1
|
Hepato
|
11
(16%)
|
1
(4%)
|
None-Overall
|
26
(38%)
|
14
(43%)
|
In
group B, we have not seen any side effects of EC-MPS in 43% (n=14) of
recipients in the first three postoperative months. Fifty-seven percent of
recipients experienced the following side effects: BM in 28%, GI in 25%, and
hepatotoxicity in 4% (Table 1). Among the GI side effects, there were cases of
diarrhea (n=6), dyspepsia (n=2), and floating (n=1). For bone marrow,
leukopenia was observed in seven cases, while pancytopenia was observed in one
case (Figure 2).
The
side effects stopped after stopping EC-MPS in 5 patients, reducing the dose in
8 patients, and converting them in 5 patients.
Figure 2: Group B: Overall, GI and BM side effects (%)
We have not seen any statistical differences between the two groups concerning side effects (p> 0,5) (Figure 3).
Also, we have not seen any graft loss
due to biopsy-proven acute rejection who received MMF or EC-MPS within three
months after de-novo kidney transplantation.
Figure 3: MMF vs EC-MPS comparison
of side effects (%)
DISCUSSION
The presented study offers valuable
insights into the short-term side effects of MMF and EC-MPS in kidney
transplant recipients during the initial three months post-transplantation. The findings
contribute to the existing literature on immunosuppressive strategies and shed
light on the safety profiles of these two commonly used medications (1-5).
In the study, most patients in both
groups did not experience any side effects, highlighting the overall
tolerability of MMF and EC-MPS. These results are positive, as minimizing
adverse events is crucial for patient well-being and adherence to immunosuppressive
regimens, which are essential for graft survival (3).
The observed side effects, when present,
varied between the two groups. In the MMF group (group A), gastrointestinal
disturbances, such as diarrhea and dyspepsia, were notable, along with bone marrow
and hepatotoxicity issues. On the other hand, the EC-MPS group (group B)
exhibited a more balanced distribution of side effects, with bone marrow
complications, particularly leukopenia, being prominent.
The side effects management involved
discontinuation, dose reduction, or conversion of medications, highlighting the
importance of close monitoring and tailored interventions (34.6%). Those issues
underscore the dynamic nature of immunosuppressive therapy, requiring ongoing
assessment and adjustment to optimize patient outcomes (4,5).
Notably, there were no statistically
significant differences in side effects between the two groups within the first
three months after de novo kidney transplantation. This similarity suggests
that, in the short term, both MMF and EC-MPS are equally well-tolerated by
kidney transplant recipients. Such information is valuable for clinicians when
choosing immunosuppressive agents based on individual patient characteristics.
However, it is essential to acknowledge
the limitations of this study. Firstly, the relatively short follow-up period
of three months may not capture long-term side effects or the impact on graft
survival (3-5). A more extended follow-up would provide a more
comprehensive understanding of MMF and EC-MPS safety profiles. Secondly, while
reasonable, the study's sample size might limit the
generalizability of the findings to broader populations. More extensive multicenter studies could validate and
extend these results. Additionally, the study did not delve into
patient-specific factors that might influence the likelihood of side effects,
such as pre-existing comorbidities or genetic variations.
In conclusion, this study highlights the
overall favorable safety profiles of MMF and EC-MPS in the early post-transplant
period. However, it underscores the potential advantage of EC-MPS over MMF in
hepatotoxicity, with EC-MPS demonstrating a lower incidence of hepatotoxicity
than MMF. These findings contribute valuable insights into selecting
immunosuppressive regimens in kidney transplantation, particularly in
minimizing adverse effects and optimizing patient outcomes.
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