ORIGINAL RESEARCH

Basiliximab induction therapy in kidney

transplantation: Benefits for long term allograft
function after 10 years?
Martina Koch
Thomas Becker
Rainer Lueck
Michael Neipp
Juergen Klempnauer
Bjoern Nashan
Klinik fuer Allgemein-, Viszeral- und
Transplantationschirurgie,
Medizinische Hochschule Hannover,
Hannover, Germany

Abstract: The interleukin-2 receptor antagonist basiliximab has proven in large clinical trials
to be safe and effective to reduce acute rejections in the rst year after renal transplantation.
Since acute rejections are a risk factor for chronic graft loss, their effective reduction might
have a positive effect on long term allograft survival. So far data is spares to prove this hypothesis and 10-year follow up on basiliximab induction therapy is not available. In our center,
41 patients were enrolled in the multicenter trial CHIB201 in 1995/96 comparing basiliximab
vs no induction therapy after renal transplantation. We retrospectively analyzed the outcome
of these patients after 10 years. The main reason for patient death with functioning graft were
infectious complications (basiliximab: 3/20, placebo 1/19), 21% of all patients developed
cancer without an obvious correlation to specic immunosuppression. Death censored 10-year
graft survival was equivalent in both groups: 65% in the basiliximab and 68% in the placebo
group with a mean s-creatinine-clearance of 60 and 44 ml/min. In this small study patient and
graft survival was equivalent 10 years after transplantation comparing basiliximab induction
therapy and placebo.
Keywords: basiliximab, induction therapy, long term graft survival, renal transplantation

Introduction

Correspondence: Martina Koch

Klinik fr Hepatobilire Chirurgie und
Transplantationschirurgie,
Universitaetsklinik Hamburg-Eppendorf,
Martinistr 52, 20246 Hannover, Germany
Tel +49 40 42803 6136
Fax +49 40 42803 3431
Email martina.koch@uke.uni.hamburg.de

Basiliximab (Simulect) is a chimeric monoclonal antibody directed against the alpha

chain of the interleukin-2 receptor (IL-2R) and competitively inhibits IL-2 dependent
T-cell activation in acute allograft rejection.1 Basiliximab induction therapy has
proven in large clinical trials to be effective to reduce the rate of acute rejections and
to allow sparing of calcinurin inhibitors (CNI) and steroides in the early postoperative period after renal transplantation (RTx) with similar tolerability to placebo.24
Most studies focus on acute rejection rates and one year allograft survival, but less
is known about the impact of induction therapy with IL-2R antagonists on long term
allograft survival.
Since it is known that acute rejections are a risk factor for chronic transplant
dysfunction,57 an effective induction therapy might have a benecial long-term effect
on renal function.
Other than induction therapies with antithymocyte globulin (ATG) or anti-CD3
monoclonal antibody (OKT3)8,9 no signicant increase in malignancies or infections
was related with the application of basiliximab in the rst years after RTx,4,10 but long
term evaluations are sparse.
In this study we address the question if antibody induction therapy with basiliximab
compared to no induction therapy leads to better long term renal allograft function
and/or patient survival after 10 years. We retrospectively analyzed patients enrolled
in a multicenter phase III trial (CHIB 201)3 at Hanover Medical School, Germany in

Biologics: Targets & Therapy 2009:3 5156

2009 Koch et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
which permits unrestricted noncommercial use, provided the original work is properly cited.

51

Koch et al

received OKT3 in a dose of 5 mg/day for 78 days. No routine

biopsies were performed.

1995/1996. Patients were treated either with basiliximab

or placebo in combination with cyclosporine A (CyA) and
steroides after rst cadaveric renal transplantation and were
followed over a 10-year period. The results of this study
were compared with published long-term data available for
other IL-2R antagonists.

Long term evaluation

Patients were followed for 10 years by using clinical
examination and laboratory tests done in our outpatient
facility at least once a year. If visits in our centre were not
possible records provided by the patients local nephrologists
were used for long-term follow up.
Follow up was terminated at the time patients returned
to dialysis or died.
Creatinine clearances were calculated using the
CockcroftGault formula:11 (140 age) (weight/(72
creatinine (mol/l)/88.4)) for male and multiplied with 0.85
for female patients.

Methods
Study design and patients demographics
We retrospectively analyzed the outcome of 41 recipients
of primary cadaveric renal allografts enrolled in the
CHIB 201 study at Hanover Medical School, Germany in
1995/1996. The primary objective of the CHIB 201 study
was to analyze the rate of acute rejections in the rst six
months after kidney transplantation in combination with
standard immunosuppressive therapy consisting of CyA
and corticosteroids.
Twenty one patients received 20 mg of basiliximab on
days 0 and 4 post-transplantation and 20 patients received
placebo. Induction therapy was combined with standard
immunosuppressive therapy consisting of CyA and corticosteroids. There were no relevant differences between the
placebo and the basiliximab group regarding demographic
data and medical condition at time of transplantation.
Gender, age, and reason for transplantation are shown in
Table 1.

Statistics
Statistical signicance of differences in renal function was
calculated using Students t-test (Microsoft Excel, Microsoft
Corp., Redmond, WA) and patient and graft survival was
analyzed by KaplanMeier estimates using Wilcoxon signedrank tests. P 0.05 was given as signicant.

Results
Patient and graft survival after 10 years
As in the multicenter trial3 in the subgroup of patients
analyzed here acute rejections in the rst six month posttransplantation were signicant higher in the placebo group
(55% vs 29%). No steroid resistant rejections occurred in the
basiliximab group, while in the placebo group ve patients
were treated with OKT3.
In both groups one patient was lost for follow up within
the rst year after transplantation and was excluded from
the long term analysis.
In the basiliximab group three patients (3/20) died with
functioning graft within 10 years after transplantation resulting

Immunosuppression
Initial immunosuppression consists of low doses of CyA and
corticosteroids with or without basiliximab induction therapy.
The mean CyA trough levels have been 130150 ng/ml
in both groups within the rst three months in our center.
In case of acute rejection treatment was performed with
bolus injections of 500 mg methylprednisolone given
intravenously for three days without a change in baseline
immunosuppression. If this was without success patients

Table1 Gender, age and reason for transplantation in the placebo and the basiliximab group
Basiliximab group

Placebo group

Male/female

10/10

13/6

Age at time of transplantation (years)

46 12

47 14

Glomerulonephritis

IgA nephritis

Cystic kidney degeneration

Interstitial nephritis/pyelonephritis

Others/unknown

Reasons for transplantation:

52

Biologics: Targets & Therapy 2009:3

10-year results of basiliximab in renal transplantation

in a patient survival of 85%. Reasons for death were: sarcoma

(three years post-RTx, age 68), Pneumococcus pneumonia
(four years post-RTx, age 59) and sepsis (Pneumocystis
carinii pneumonia, seven years post-transplantation in the
age of 44 years).
Seven patients lost their grafts in the basiliximab group,
due to the following reasons: two vascular complications
immediately after transplantation, ve patients returned to
dialysis due to long term renal failure. Reasons were (biopsy
conrmed): in three patients recurrent renal disease (2 IgA
nephropathy, 1 light chain amyloidosis) ve, six and seven
years after transplantation and chronic rejection and/or
CNI-toxicity in two patients after 10 years. 10/20 patients
(50%) had a functioning graft after 10 years (Figure 1).
Death-censored graft survival in the basiliximab group was
65% after 10 years.
In the placebo group, patient survival was 95% after
10 years; one (1/19) patient died from sepsis three years
after transplantation with functioning graft with 52 years.
In the placebo group six graft losses occurred: One due
to anemic infarction 20 days after transplantation, three
patients lost their graft due to chronic rejection (5, 6, and
9 years after RTx) and one patient due to hypertensive damage and CNI toxicity after 6 years. Considering one patient
dying with functioning graft 12/19 patients (63%) had a
functioning graft 10 years after transplantation (Figure 1).
Death-censored graft survival in the placebo group was
68% after 10 years.
For both groups, 22 of 39 kidneys were functioning
10 years after transplantation, this is a graft survival of 56%
for all patients, death-censored 67%.

Renal function after 10 years

In the basiliximab group, 10 patients with a functioning graft
have S-creatinine values between 93 and 158 mol/l and a
mean creatinine-clearance of 60 ml/min. In six patients renal
function was improved or stable (clearance 10 ml/min)
from year 1 to year 10 after transplantation, in four patients
renal function was decreasing (Figure 2a).
In the placebo group 12 patients with functioning grafts
had S-creatinine values between 78 and 332 mol/l and
a mean clearance of 44 ml/min. Six grafts displayed an
improved or stable function (clearance 10ml/min compared
to year one) over ten years and in six patients renal function
declined (Figure 2b).

Immunosuppression
In the basiliximab group, no OKT3 treatment was needed
for acute steroid-resistant rejection, while ve patients in the
placebo group received OKT3.
Ten years after transplantation, 9/10 patients with functioning graft in the basiliximab group were on CyA-based
immunosuppression, five of them in combination with
either mycophenolate mofetil (MMF) or azathioprine
(AZA). One patient takes rapamycine due to the diagnosis
of melanoma.
In the placebo group 9/12 patients are treated with
CyA-based immunosuppression, three of them in combination
with MMF or AZA. Two patients are on tacrolimus-based
immunosuppression and one patient with kaposi-sarcoma
takes AZA and steroids only.
Four of ve placebo-patients treated with OKT3 had
functioning grafts after 10 years.

1
0.9

Basiliximab
Placebo

0.8

Graft survival

0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0

365

730

1095

1460

1825

2190

2555

2920

3285

3650

Days after transplantation

Figure 1 Ten-year graft survival in the basiliximab and the placebo group. There was no significant difference in graft survival between both groups.

Biologics: Targets & Therapy 2009:3

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Koch et al

100

120

Clearance ml/min

Clearance ml/min

120

80
60
40
20
0

100

80
60
40
20
0

1 year

10 years

1 year

10 years

Figure 2 Changes in creatinine-clearance from year one to year ten after transplantation in patients with functioning graft at the end of the observation period. A) basiliximab
group, B) placebo group.

Malignancies
In the basiliximab group, six malignancies were reported
in ve patients: One patient died from sarcoma three years
post-RTx, a second was nephrectomized due to renal cell
carcinoma in his own kidney four years post-transplantation,
a third patient developed spinocellular carcinoma of the upper
lip after eight years, a forth patient developed a T1 melanoma
and a basalioma after nine years and a female patient was
diagnosed with lung and liver metastasis of a carcinoma of
the vagina after 10 years.
In the placebo group, three malignancies occurred. One
patient developed kaposi sarcoma 18 months post-transplantation, and is now doing well 10 years post-RTx, a second
patient developed spinocellular carcinoma of the lower lip
after ve years, and a third patient suffered from bladder
carcinoma in the eighth year after transplantation.
In both groups, three nonmelanoma skin cancers and six
other cancers including melanoma were found in 8/39 (21%)
patients. Seven of eight patients are alive with functioning
grafts after 10 years.

Discussion
The IL-2 receptor antagonist (IL-2RA) basiliximab has proven
to be effective in reducing acute rejection episodes in large
double blind multi center trials without signicant side effects.2,3
Due to these promising results, basiliximab is now commonly
used, but sparse analysis on its long-term effects exist.
A report on the murine IL-2RA BT563 vs placebo after
renal transplantation shows a comparable 10-year patient and
graft survival without increase in malignancies12 and a study
comparing induction therapy with the rat IL-2R antagonist
Lo-tact-1 and ATG demonstrated no difference in patient and
graft survival after 10 years, but a tendency to less chronic
rejection in the Lo-tact group.13

54

No 10-year follow-up data on basiliximab is available at the

moment. A ve year analysis by Kyllnen and colleagues compares basiliximabinduction with ATG-induction and standard
immunosuppression without induction primarily to analyze
effects on delayed graft function, showing no difference
between both induction groups for patient and graft survival,
but a superior ve year graft survival for the basiliximab group
compared to induction-free immunosuppression.14
Taken together, the results of these studies do not clearly
demonstrate a long-term benet for IL-2R antagonists compared to other induction therapies or to no induction regarding
patient or graft survival.
The CHIB 201 study, we used for retrospective analysis, was designed to compare basiliximab induction versus
no induction therapy in combination with a low dose dual
basic immunosuppression consisting only of CyA and corticosteroids. The study demonstrated an excellent reduction
of acute rejections for all patients3 and the patients included
in this sub-analysis despite of relatively low CyA levels in
our centre. The number of patients requiring urbason bolus
therapy for acute rejection within six months was reduced
in the basiliximab group and more important no OKT3 or
other antibody therapy was needed in the basiliximab group
for treatment of steroid resistant rejection.
With regard to the common suggestion of acute rejections
as a risk factor for chronic graft dysfunction, our hope was
to improve long term allograft survival in patients free of
acute rejections, but as in the studies mentioned above, we
found comparable patient survival of 85%/95% and deathcensored graft survival of 65%/68% in the basiliximab and
placebo group. Neither patient nor graft survival was signicantly different. This result may underline the fact that
acute rejections are only one risk factor in the multifactorial
process of chronic graft loss.

Biologics: Targets & Therapy 2009:3

10-year results of basiliximab in renal transplantation

By taking a closer look at each patient, it is remarkable

that in patients of the placebo group diagnosis of early acute
rejection seems not to be necessarily correlated with worse
long term graft function. All four patients after successful
OKT3 treatment due to steroid-resistant rejection have
functioning grafts after 10 years.
Kidney function in patients receiving basiliximab tended
to be better after 10 years, but in both groups ve chronic
grafts losses occurred. They comprise of recurrence of primary disease as well as chronic rejection and/or CNI toxicity
in both groups, again showing the multifactorial ethiology
of chronic allograft dysfunction.
Other than in registry data, main reasons for patients
death in this study were not cardiovascular events, but
infectious complications years after transplantation in both
groups.
Malignancies become a challenge after transplantation
since time of immunosuppression increases due to improved
patient survival, as well as rising numbers of retransplanted
and young patients. The incidence of most types of cancers is
increased after transplantation and the number of malignancies found in our study is in accordance with reported rats
of non melanoma skin and other cancers.1517 An association of malignancies and immunosuppression in general is
clearly proven, but a correlation with dened drugs is more
difcult. In this study the sarcoma was found in a patient on
tacrolimus based triple immunosuppression, while the other
patients with malignomas in the basiliximab group were on
dual therapy. One patient after OKT3 treatment in the placebo
group developed cancer (urothel carcinoma). The patient
diagnosed with a kaposi sarcoma was a placebo patient,
who received an acute rejection treatment with steroids and
was switched to tacrolimus based immunosuppression for
the same reason within the rst month post-RTx. After 10
years of immunosuppression, at least 1/3 of patients suffered from cancer including skin cancers, but luckily only
one patient died.
In summary we achieved a comparable patient and graft
survival 10 years after renal transplantation with and without
basiliximab induction therapy. While graft function in the
basiliximab group tended to be better, the number of graft
losses due to chronic damage including recurrence of primary
disease was equal in both groups. Our results are consistent
with reports available for other IL-2R antagonists and are not
able to prove an improved long term graft or patient survival
after basiliximab induction therapy. Since these are the only
10-year results available comparing basiliximab induction
therapy with placebo and the number of patients analyzed

Biologics: Targets & Therapy 2009:3

is small, the conclusions from this study must be drawn

carefully. Although basiliximab induction therapy is commonly used today, it seems worth to rethink the indication
of induction therapies and to focus on further investigation
on the effects of different immunosuppression on long term
allograft survival.

Acknowledgments
MK collected and analyzed data and wrote the paper. TB, RL,
MN, JK, BN performed and designed study. The multicenter
CHIB 201 trial was sponsored by Novartis Pharma, Basel,
Switzerland. The long term evaluation was not supported.
All authors received travel grants and/or lecture fees from
Novartis.

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