Rejection after simultaneous pancreas-kidney transplantation.
ABSTRACT Simultaneous pancreas-kidney (SPK) transplantation is an accepted therapy for type 1 diabetic patients with end-stage renal disease. This study analyses the occurrence of rejection episodes in patients undergoing SPK.
The study population was obtained from 205 patients enrolled in the Euro-SPK 001 study and randomized to receive tacrolimus- (n = 103) or cyclosporin microemulsion (ME)-based (n = 102) immunosuppressive therapy. All patients received concomitant antibody induction therapy, mycophenolate mofetil and short-term corticosteroids.
After 3 years of follow-up, rejection episodes occurred in 41 patients receiving tacrolimus and in 51 patients receiving cyclosporin-ME. The majority of first rejection episodes in both groups occurred during the first 6 months (93 and 90%, respectively) and in most cases were treated with corticosteroids alone (88 vs 90%). Actuarial rejection-free kidney and/or pancreas graft survival was similar for tacrolimus (54%) and cyclosporin-ME (44%). Human leukocyte antigen (HLA) compatibility (P = 0.003) and graft vessel extension (P = 0.000001) had a significant influence on rejection-free graft survival. Also, rejection influenced pancreas graft survival (P = 0.01), and pancreas graft loss due to rejection influenced patient survival (P = 0.02). In the intent-to-treat analysis of early rejection, significantly fewer tacrolimus- than cyclosporin-ME-treated patients had (i) more than one rejection episode (11 out of 40 vs 24 out of 47; P = 0.03); (ii) first moderate to severe rejection (one out of 40 vs 12 out of 47; P = 0.004); and (iii) refractory rejection (two out of 40 vs 10 out of 47; P = 0.03). Pancreas survival was lower in late rejectors (53%) than non-rejectors (86%; P = 0.002). Also, serum creatinine was highest in late rejectors.
Tacrolimus-based immunosuppressive therapy demonstrates significant advantages over cyclosporin-ME in terms of the severity of acute rejection in SPK transplant patients.
- [Show abstract] [Hide abstract]
ABSTRACT: The effect of acute allograft rejection (AR) on long-term pancreas allograft function is unclear. We retrospectively studied 227 consecutive pancreas transplants performed at our institution between January 1, 998 and December 31, 2009 including: 56 simultaneous pancreas and kidney (SPK), 69 pancreas transplantation alone (PTA); and 102 pancreas after kidney (PAK) transplants. With a median follow-up of 6.1 (IQR 3-9) years, 57 patients developed 79 episodes of AR, and 19 experienced more than one episode. The cumulative incidence for AR was 14.7%, 19.7%, 26.6% and 29.1% at 1, 2, 5 and 10 years. PTA transplant (hazards ratio [HR] = 2.28, p = 0.001) and donor age (per 10 years) (HR = 1.34, p = 0.006) were associated with higher risk for AR. The first AR episode after 3 months post PT was associated with increased risk for complete loss (CL) (HR 3.79, p < 0.001), and the first AR episode occurring during 3- to 12-month and 12- to 24-month periods after PT were associated with significantly increased risk for at least partial loss (PL) (HR 2.84, p = 0.014; and HR 6.25, p < 0.001, respectively). We conclude that AR is associated with increased risk for CL and at least PL. The time that the first AR is observed may influence subsequent graft failure.American Journal of Transplantation 02/2013; · 6.19 Impact Factor
Article: Therapie des Diabetes mellitus[Show abstract] [Hide abstract]
ABSTRACT: Eine langfristige Normalisierung des Zuckerstoffwechsels zur Vermeidung diabetischer Sekundrfolgen ist bei Patienten mit Diabetes mellitus derzeit nur mit -Zell-Ersatz in Form der Transplantation des Gesamtpankreas oder der Langerhans-Inseln mglich. Bei Patienten mit Typ-1-Diabetes und terminaler Niereninsuffizienz ist eine absolute Indikation zur simultanen Pankreas-Nieren-Transplantation gegeben. Die 1-Jahres-berlebensraten betragen dabei fr Patienten 94–100%, fr Nieren 89–92%, fr Pankreas 85–87%. Die hohe Erfolgsrate mit langfristiger Normalisierung des Glukosestoffwechsels fhrt zu einer Stabilisierung oder Verbesserung der Sekundrkomplikationen, zu einer deutlichen Steigerung der Lebensqualitt und zu einer signifikanten Senkung der Mortalitt im Vergleich zu nur nierentransplantierten Patienten. Die Indikationen von Insel- oder Pankreastransplantation sind vergleichbar. Die operative Prozedur ist bei der Inseltransplantation fr den Patienten wesentlich weniger belastend, die Inselisolierung aber methodisch schwierig und aufwndig. Die 1-Jahres-berlebensraten fr Patienten liegen bei 98%, die der Inseln bei 82%, die der Insulinunabhngigkeit bei 42%. Leider sinken die Funktionsraten innerhalb von 5Jahren auf etwa 10%. Die Stammzelltherapie beim Diabetes mellitus wre die definitive Lsung des Problems des physiologischen Insulinersatzes nicht nur fr Patienten mit Typ-1-Diabetes. Sie befindet sich aber noch in einer relativ frhen Entwicklungsphase.The long-term normalization of glucose metabolism – a prerequisite for the prevention of secondary complications in patients with diabetes mellitus – is only possible by transplantation of a whole pancreas or a reasonable number of islets. An absolute indication for pancreas grafting is given in type 1 diabetic patients with end-stage renal disease. The 1-year survival after simultaneous kidney/pancreas transplantation is, according to the international registry, 94–100% for patients, 89–92% for kidneys and 85–87% for the pancreas. The high success rate with long lasting normalization of glucose metabolism leads to a stabilization and/or amelioration of secondary complications, to an increase in quality of life and, most importantly, to a significant reduction in mortality when compared to diabetic kidney recipients. The indications for islet transplantation are similar to those for pancreatic grafting. Islet grafting is only a minor surgical procedure, but islet isolation is difficult. The 1-year survival for the recipients is 98%, for the islets 82% and for insulin-independency 42%. There is a significant decline of islet function to 10% 5years after transplantation. Stem cell therapy would provide a definitive treatment solution not only for patients with type 1 diabetes. So far, this therapeutic option is still at an early stage of development.Der Internist 04/2006; 47(5):489-501. · 0.33 Impact Factor
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ABSTRACT: Purpose: A review of recent literature was performed to identify trends and evaluate outcomes with respect to immunosuppression in pancreas transplantation (PTX). Current status. In the past decade, the majority of PTXs were performed with depleting antibody induction, particularly in the setting of either calcineurin inhibitor minimization, corticosteroid withdrawal or both. Maintenance immunosuppression consisted of predominantly tacrolimus (TAC)/mycophenolatemofetil, TAC/mycophenolic acid or TAC/sirolimus with or without corticosteroids. Depending on PTX category, donor and recipient risk factors, case mix and immunosuppressive regimen, the 1-year incidence of acute rejection has decreased to 5-20%. Current 1-year rates of immunological pancreas graft loss range between 1.8 and 6%. Summary: Depleting antibody induction and either TAC/mycophenolatemofetil or TAC/sirolimus maintenance therapy with early steroid withdrawal have become the mainstay of immunosuppression in PTX. However, the development of non-nephrotoxic, nondiabetogenic, and nongastrointestinal toxic regimens is highly desirable to improve quality of life in all solid organ transplant recipients.Expert Review of Clinical Immunology 11/2013; · 2.89 Impact Factor
Nephrol Dial Transplant (2005) 20 [Suppl 2]: ii11–ii17
Rejection after simultaneous pancreas–kidney transplantation
Helmut Arbogast1, Jacques Malaise3, Wolf-Dieter Illner1, Anwar Tarabichi1, Christoph Dieterle2,
Ru ¨ diger Landgraf2, Walter Land1and the Euro-SPK Study Group
1Department of Surgery,2Department of Medicine, Diabetology Center, University of Munich, Munich,
Germany and3Department of Kidney and Pancreas Transplantation and Organ Procurement,
Cliniques Universitaires St Luc, Universite ´ Catholique de Louvain, Brussels, Belgium
transplantation is an accepted therapy for type 1
diabetic patients with end-stage renal disease. This
study analyses the occurrence of rejection episodes in
patients undergoing SPK.
Methods. The study population was obtained from
205 patients enrolled in the Euro-SPK 001 study and
randomized to receive tacrolimus- (n¼103) or cyclo-
sporin microemulsion (ME)-based (n¼102) immuno-
suppressive therapy. All patients received concomitant
antibody induction therapy, mycophenolate mofetil
and short-term corticosteroids.
Results. After 3 years of follow-up, rejection episodes
occurred in 41 patients receiving tacrolimus and in
51 patients receiving cyclosporin-ME. The majority of
first rejection episodes in both groups occurred during
the first 6 months (93 and 90%, respectively) and
in most cases were treated with corticosteroids alone
(88 vs 90%). Actuarial rejection-free kidney and/or
pancreas graft survival was similar for tacrolimus
(54%) and cyclosporin-ME (44%). Human leukocyte
antigen (HLA) compatibility (P¼0.003) and graft
vessel extension (P¼0.000001) had a significant
influence on rejection-free graft survival. Also, rejec-
tion influenced pancreas graft survival (P¼0.01), and
pancreas graft loss due to rejection influenced patient
survival (P¼0.02). In the intent-to-treat analysis of
early rejection, significantly fewer tacrolimus- than
cyclosporin-ME-treated patients had (i) more than
one rejection episode (11 out of 40 vs 24 out of 47;
P¼0.03); (ii) first moderate to severe rejection (one out
of 40 vs 12 out of 47; P¼0.004); and (iii) refractory
rejection (two out of 40 vs 10 out of 47; P¼0.03).
Pancreas survival was lower in late rejectors (53%)
than non-rejectors (86%; P¼0.002). Also, serum
creatinine was highest in late rejectors.
therapy demonstrates significant advantages over
cyclosporin-ME in terms of the severity of acute
rejection in SPK transplant patients.
Keywords: cyclosporin microemulsion;
A pancreatic transplant is often performed at the same
time as a kidney transplant [simultaneous pancreas–
kidney (SPK) transplant] in uraemic patients with
type 1 diabetes.
The present analysis of the Euro-SPK 001 study was
undertaken to compare and analyse the occurrence,
frequency and the severity of rejection episodes in
patients receiving tacrolimus- or cyclosporin-micro-
emulsion (ME)-based immunosuppressive regimens for
up to 3 years after SPK transplantation.
Patients and methods
The overall objectives, methods and design of the Euro-SPK
001 study have been described in full previously  and also
elsewhere in this supplement (Saudek et al.). A brief synopsis
is provided below.
A total of 205 SPK transplant patients with end-stage
type 1 diabetic nephropathy were recruited into the study
from 10 centres in Europe and one centre in Israel. All
patients received quadruple immunosuppressive therapy
Correspondence and offprint requests to: Dr Jacques Malaise,
Organ Procurement, Cliniques Universitaires St Luc, Universite ´
Catholique de Louvain, avenue Hippocrate, 10/2207, B-1200
Dr Helmut Arbogast, Transplant Centre, Department of Surgery,
University of Munich, Grosshadern, Marchioninistr. 15, D-81377
Munich, Germany. Email: email@example.com
? The Author . Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
For Permissions, please email: firstname.lastname@example.org
by guest on May 18, 2011
based on either tacrolimus (n¼103) or cyclosporin-ME
(n¼102), given with mycophenolate mofetil (MMF), pred-
nisone and rabbit anti-thymocyte globulin (rATG) induc-
tion therapy . Corticosteroid therapy was progressively
withdrawn from all patients between 3 and 6 months post-
transplant. A graft vessel extension (GVE) was used in
cases where the donor vein or artery was too short to be
anastomosed directly to the recipient’s vessel.
The primary end-point of the study was the incidence of
biopsy-proven acute rejection at months 6 and 12 post-
transplant. A biopsy was taken in all cases of suspected
kidney or pancreas graft rejection. Local histopathologists
undertook biopsy analyses, and rejection was graded accord-
ing to the Banff 97 criteria  for the kidney and the
Drachenberg scale  for the pancreas. The selection
(corticosteroids, monoclonal or polyclonal antibodies) and
dosage of anti-rejection therapy were based on routine
practice at each individual centre. Responses to the treatment
were classified as corticosteroid-sensitive, corticosteroid-
resistant, antibody-sensitive, antibody-resistant or refractory
The intention was to perform a kidney or pancreatic biopsy
in all cases prior to initiating anti-rejection therapy. However,
in some cases, this was not adhered to. For the purpose of
analysis, such cases were considered to be clinical rejections.
Acute tubular necrosis
Acute tubular necrosis (ATN) was defined as a non-
functional kidney for a maximum of 1 month post-transplant,
requiring at least one episode of dialysis during the first
post-transplant week and not associated with a rejection
Delayed kidney graft function
If the creatinine level did not decrease from 50% within the
first 7 post-operative days, it was considered to be a delayed
graft function (DGF). This poor function of the trans-
planted graft required a late dialysis or no dialysis at all.
?2and Fisher’s exact tests were used to compare categorical
variables, and the Mann–Whitney U-test was used to
compare continuous variables. For univariate analyses,
survival rates were obtained using the Kaplan–Meier
method and differences between groups were compared by
using the log-rank test. The Cox regression analysis was
used for multivariate analyses. P<0.05 was considered stati-
stically significant. Mean values were expressed with SDs.
In total, 205 patients (127 male and 78 female) between
18 and 55 years of age were enrolled in the study; 103
were assigned pre-operatively to receive tacrolimus
and 102 to receive cyclosporin-ME. The two treatment
groups were comparable at baseline with respect to age,
gender and sensitization
(PRA) <5%]. Significantly more patients assigned to
treatment with tacrolimus (91%) than with cyclo-
sporin-ME (81%) were dialysis dependent prior to
transplantation (P<0.05). However, the two groups
were comparable with respect to surgical technique,
type of exocrine drainage of the pancreas, type of
venous drainage and the use of GVE.
In-study patients: first clinical or
biopsy-proven acute rejection episodes
After 3 years of follow-up, 41 patients in the tacrolimus
group and 51 in the cyclosporin-ME group experienced
at least one rejection episode while in the study. As
shown in Table 1, the first rejection episode occurred
during the first 6 months for 38 out of 41 (93%) patients
in the tacrolimus group and for 46 out of 51 (90%)
patients in the cyclosporin-ME group.
The 41 patients in the tacrolimus group had
confirmed first acute rejection episodes in 24 kidney
biopsies, in two pancreas biopsies and in one SPK
Table 1. Overview of first acute rejection episodes and time of onset
Acute rejection TacrolimusCyclosporin-ME
In study (n¼41)Out of study (n¼4) In study (n¼51)Out of study (n¼6)
<6 6–1212–24 <66–1212–24 <6 6–12 12–2424–36<6 6–1212–24
The table shows the number of acute rejection episodes and time of onset in months that occurred in tacrolimus- and cyclosporin
microemulsion-treated in-study and out-of-study patients.
ii12 H. Arbogast et al.
by guest on May 18, 2011
biopsy. The other 14 patients had clinically proven
episodes of kidney rejection. Of the 51 patients in
the cyclosporin-ME group who had first acute rejec-
rejection, two were biopsy-confirmed pancreas rejec-
tion, 13 were clinically confirmed kidney rejection
and two were clinically confirmed pancreas rejection
In the majority of patients, the first rejection
episodes were treated with corticosteroids (88% in
the tacrolimus group and 90% in the cyclosporin-ME
group). However, some cases were treated directly
with OKT3 (7 vs 8%, respectively) or ATG (5 vs 0%).
In addition, there was one case of pancreas graft loss
due to untreated rejection in the cyclosporin-ME
In-study patients: all clinical and
biopsy-proven acute rejection episodes
As shown in Table 2, 41 patients experienced 59
rejection episodes in the
presented with one episode of rejection; six patients
had two episodes; three had three episodes; and two
had four episodes. In the cyclosporin-ME group, there
were 73 episodes of rejection in 51 patients: 34 patients
had one episode; 13 had two episodes; three had three
episodes; and one had four episodes. There was no
statistically significant difference between tacrolimus
(11 patients) and cyclosporin-ME (17 patients) in terms
of the incidence of recurrent (more than one) rejection.
The frequency of clinical and biopsy-proven acute
rejection while in the study was 1.44 episodes per
patient with tacrolimus and 1.43 episodes per patient
with cyclosporin-ME (Table 2).
Rejection episodes were treated mainly with cortico-
steroids (81% in the tacrolimus group and 75% in the
cyclosporin-ME group). Some patients were treated
with OKT3 (15 vs 19%, respectively) or ATG (3 vs
0%). One case of antibody treatment was not speci-
fied and one pancreas was lost before treatment in
the cyclosporin-ME group. Two patients in the
cyclosporin-ME group received only temporary insulin
during pancreatic rejection.
In-study patients: first biopsy-proven
acute rejection episodes
Twenty-seven patients receiving tacrolimus and 36
patients receiving cyclosporin-ME had a primary
biopsy-proven acute rejection, whereas four patients
treated with tacrolimus and three receiving cyclosporin-
ME had their first biopsy-proven acute rejection after a
The severity of the first biopsy-proven episode was
borderline or mild for 30 out of 31 patients receiving
tacrolimus. This included two episodes occurring at
6–12 months and one episode occurring after 1 year.
Only one episode in this group was graded as moderate
to severe. In contrast, severity was borderline or mild
for 28 out of 39 cases in the cyclosporin-ME group
(including one episode occurring at 6–12 months and
one occurring at 2–3 years) and moderate or severe for
11 episodes (including one occurring after 1 year).
There were no statistical differences between the two
groups regarding the first biopsy-proven acute rejection
episode at 6 and 12 months (28 and 30 tacrolimus-
treated patients compared with 36 and 37 cyclosporin-
ME-treated patients). However, the number of patients
with a first moderate or severe acute rejection episode
was significantly higher with cyclosporin-ME (11 out
of 39 patients) than with tacrolimus (one out of 31
In-study patients: all biopsy-proven
acute rejection episodes
During the first 3 years post-transplant, 15 out of 38
biopsy-proven acute rejection episodes were classified
as borderline in the tacrolimus group compared with
17 out of 56 in the cyclosporin-ME group. In addition,
22 episodes in the tacrolimus group were classified
as mild and one as moderate. In the cyclosporin-ME
group, 22 episodes were classified as mild, 13 as
moderate and four as severe. As with first biopsy-
proven acute rejection, the occurrence of all moderate
to severe biopsy-proven acute rejection was signifi-
cantly lower with tacrolimus than with cyclosporin-ME
(one out of 38 vs 17 out of 56, respectively; P¼0.001).
Graft survival (intent-to-treat)
At 3 years post-transplant, five patients in each group
experienced chronic kidney rejection. An additional
patient in the tacrolimus group and two others in the
cyclosporin-ME group had chronic pancreas rejection
and received insulin.
Table 2. Summary of all acute rejection episodes occurring while
patients were in the study
Clinically proven rejections
Episodes per patient
Rejection after SPK transplantationii13
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The actuarial rejection-free kidney and/or pancreas
graft survival rate was similar in the two treatment
groups, with respective values for tacrolimus at
6 months 1, 2 and 3 years of 61, 57, 54 and 54%. The
corresponding values for the cyclosporin-ME group
were 50, 47, 45 and 44%.
Univariate and multivariate analyses indicated that
human leukocyte antigen (HLA) compatibility (both
P¼0.003) and the requirement for a venous or arterial
GVE for the pancreas (univariate, P¼0.000001; and
multivariate, P¼0.0005) had a significant effect on
rejection-free kidney and/or pancreas graft survival
in the entire study population (Figures 1 and 2). In
addition, rejection was found to influence pancreas
graft survival (P¼0.01), and pancreas graft loss due
to rejection appeared to influence patient survival
Intent-to-treat analysis at 3 years’ follow-up
To analyse the impact of acute rejection on follow-up,
the data were divided into three subgroups.
(i)Those patients with no episodes of rejection during
the 3-year post-transplant follow-up (tacrolimus,
n¼58; cyclosporin-ME, n¼45). This subgroup
included three patients in each group who had
died, lost both organs or were lost to follow-up
before 3 years without having any rejection
(ii) Those patients with an early (occurring during the
first 3 months post-transplant) first rejection epi-
sode (tacrolimus, n¼40; cyclosporin-ME, n¼47).
(iii) Those patientsexperiencing
>3 months post-transplant) first rejection episodes
(tacrolimus, n¼5; cyclosporin-ME, n¼10).
Although the difference in total number of first early
rejection episodes in each treatment group was not
statistically significant, there were significantly fewer
moderate or severe rejections in the tacrolimus group
than in the cyclosporin-ME group (one out of 40 vs 12
out of 47, respectively; P¼0.004) (Table 3). Also, there
were significantly fewer refractory rejection episodes
associated with tacrolimus than with cyclosporin-ME
(two out of 40 vs 10 out of 47; P¼0.03). Interestingly,
the occurrence of refractory rejection was more
frequent among late rejectors (six out of 15, 40%)
than among early rejectors (12 out of 87, 14%;
A summary of all rejection episodes by subgroup is
shown in Table 4. Among tacrolimus-treated patients
with early rejection, 11 out of 40 (28%) experienced
more than one episode during the first 3 years post-
transplant compared with 24 out of 47 (51%) in the
episodes occurred in four patients >3 months post-
transplant in the tacrolimus group compared with
10 episodes in eight patients receiving cyclosporin-ME.
No difference regarding rejection after 1 year post-
transplant could be observed: four episodes in three
patients treated with tacrolimus and three episodes in
three patients treated with cyclosporin-ME.
Among patients with early rejection, corticosteroid
withdrawal resulted in three rejection episodes in a
patient receiving tacrolimus and one rejection episode
in the cyclosporin-ME group. In the group of late
rejectors, there were two rejection episodes result-
ing from corticosteroid withdrawal in the tacrolimus
group and three in the cyclosporin-ME group. In
addition, there were five episodes of rejection in the
tacrolimus group and 10 in the cyclosporin-ME group
among patients still receiving corticosteroids.
Pre-transplant factors had no influence on the
occurrence of rejection episodes after transplantation:
no differences were found between the three rejection
subgroups regarding requirement for dialysis, duration
Fig. 1. Influence of HLA compatibility on rejection-free kidney
and/or pancreas graft survival. Rejection-free graft survival was
significantly higher for 0–3 HLA mismatches (MM) vs 4–6 HLA
MM (P¼0.003 univariate analysis; Kaplan–Meier/log-rank test).
o¼rejection; þ¼no rejection.
Fig. 2. Influence of graft vessel extension (GVE) on rejection-free
kidney and/or pancreas graft survival. Rejection-free graft survival
was significantly higher for no GVE vs GVE (P¼0.000001
univariate analysis; Kaplan–Meier/log-rank test). o¼rejection;
ii14 H. Arbogast et al.
by guest on May 18, 2011
of dialysis, duration of the diabetes, maximum PRA,
requirement for transfusion, pregnancy prior to trans-
plant or total and DR HLA mismatches. Likewise, no
differences were found between the subgroups with
respect to the type of venous or exocrine drainage of
the pancreas or the pancreatic and kidney ischaemic
The only surgery-related factor that had an influence
on the occurrence of rejection episodes after trans-
plantation was GVE. The number of patients who
had a venous or arterial GVE for the pancreatic vas-
cular anastomosis was significantly lower among non-
rejectors (40%) than among early rejectors (75%;
Post-transplant factors did not influence the occur-
rence of rejection episodes after transplantation. No
differences were found between subgroups regarding
the number of patients who had ATN or DGF.
Graft survival, patient survival
and study withdrawal
As shown in Table 4, when the first rejection episode
occurred >3 months post-transplant, it resulted in
a significantly higher rate of graft loss (40%) than
when it occurred before 3 months (10%; P¼0.003).
There appeared to be no differences between the
three subgroups regarding patient and kidney survival
(Table 5). In contrast, pancreas survival was signi-
ficantly higher in non-rejectors (86%) than in late
rejectors (53%; P¼0.002). In addition, significantly
fewer non-rejectors were withdrawn from the study
during the first 3 years post-transplant (29%) than
or laterejectors (67%;
At 6 months, fasting glucose was significantly higher
among early rejectors (96±18mg/dl) than among non-
rejectors (94±36mg/dl; P¼0.03). However, there
were no differences in fasting blood glucose between
the subgroups at 3 years. Based on WHO criteria for
diabetes classification , there were more patients
with impaired glucose function (glycaemia >110mg/dl)
at 3 years among the late rejectors (38%) than among
the early (7%; P<0.05) and non-rejector (7%;
Table 3. Summary of early and late first acute rejection episodes: intent-to-treat analysis
First rejection episode
Tac (n¼40) Cyc-ME (n¼47)Total (n¼87)Tac (n¼5) Cyc-ME (n¼10) Total (n¼15)
Tac¼tacrolimus; Cyc-ME¼cyclosporin microemulsion; SPK¼simultaneous pancreas–kidney.
aP<0.01 Tac vs Cyc-ME;bP<0.05 Tac vs Cyc-ME;cP<0.05 early vs late first acute rejection episode.
Table 4. Summary of all early and late acute rejection episodes: intent-to-treat analysis
First rejection episode
Tac (n¼40)Cyc-ME (n¼47)Total (n¼87) Tac (n¼5)Cyc-ME (n¼10)Total (n¼15)
No. of episodes
Patients with >1 episode [n (%)]
Graft losses/rejection [n (%)]
Tac¼tacrolimus; Cyc-ME¼cyclosporin microemulsion.
aP<0.05 Tac vs Cyc-ME;bP<0.01 early vs late first acute rejection episode.
Rejection after SPK transplantationii15
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Serum creatinine at 6 months was significantly higher
in the early (1.5±0.5mg/dl; P¼0.03) and late rejector
subgroups (1.9±1.0mg/dl; P¼0.04) than in non-
rejectors (1.3±0.3mg/dl). At 3 years post-transplant,
serum creatinine remained significantly higher in the
late rejectors (2.3±0.7mg/dl) than in non-rejectors
(1.4±0.3mg/dl; P<0.0001) and also in comparison
with early rejectors (1.6±0.9mg/dl; P¼0.0002). The
number of patients with elevations in serum creati-
nine of >0.25mg/dl between 6 months and 3 years
post-transplant was higher among late rejectors (75%)
than among early rejectors (19%, P¼0.0003) and non-
rejectors (29%, P¼0.003).
Long-term allograft function in SPK transplantation
has been shown to be dependent on the occurrence
of acute rejection episodes [5–10]. The severity and the
number of such episodes significantly impact the half-
life of the kidney transplant. Several publications have
confirmed the superiority of immunosuppressive regi-
mens containing MMF in reducing the number of acute
rejection episodes in patients undergoing SPK trans-
plantation [11–13]. Some authors report a decrease
in kidney dysfunction and reduced severity of rejec-
tion episodes when tacrolimus is used as a primary
immunosuppressant in comparison with cyclosporin
[7,14–16]. However, most of these studies are too small
to provide conclusive evidence.
The data presented here, obtained from a relatively
large cohort of 205 patients recruited in the Euro-SPK
001 study, confirm the findings of these smaller studies.
After 3 years of follow-up, our analysis shows that
clinical and biopsy-proven rejection tends to occur
more frequently among patients receiving immuno-
suppression with cyclosporin-ME than in those treated
with tacrolimus. However, the difference did not reach
significance at a 95% confidence level. Likewise, the
number of patients with recurrent rejection episodes
was similar in the two treatment groups.
A high proportion of biopsy-proven rejection epi-
sodes were classified as being of borderline to mild
severity, and the majority of all rejection episodes were
successfully treated by corticosteroid therapy alone
and did not require antibody treatment. These findings
are in accordance with the literature, which shows
that only a minority of rejection episodes in SPK
transplantation require treatment with antisera [8,17].
Analysis of first biopsy-proven rejection episodes
indicated a similar incidence in both treatment groups.
However, in accordance with previous findings, there
was a significantly lower incidence of first moderate
to severe rejection episodes with tacrolimus than with
cyclosporin-ME [14,16,18]. These findings were con-
firmed by the data on all biopsy-proven moderate to
severe rejection episodes.
The onset of the first rejection episode is known to
be an important prognostic factor. In our study,
a poor outcome was associated with late rejection
episodes, mainly affecting pancreatic graft survival.
This decreased from 86% in immunologically sound
patients to 53% in patients with late rejection
episodes, although there was no change in kidney and
patient survival. This not only underlines the necessity
for a sufficient immunosuppressive induction treat-
ment, but also the importance of frequent follow-up
and sufficient maintenance treatment .
There appeared to be a higher incidence of acute
rejection episodes within our population than in pre-
viously reported US studies [14,15,18,20], even though
the proportion of patients of African origin in our
study was virtually non-existent. However, relatively
poor HLA matching in the European trial could have
an influence on this phenomenon.
Additionally, pancreatic biopsies are not as com-
monly performed in Europe as in some US centres, so
a significant number of rejection episodes in our study
were based on clinical diagnosis alone. However, the
most likely reason for the higher rejection rates in the
Euro-SPK 001 study is the inclusion of all borderline-
classified rejection episodes into the count. This
explanation is supported further by the significantly
higher percentage of corticosteroid-resistant rejection
episodes reported by most US studies. In these centres,
the rejection rate is typically between 7 and 25%, and
82–100% of rejections are classified as corticosteroid
Surprisingly, in our study, the higher diabetogenic
potency of tacrolimus, which has been described in the
literature [22,23], did not result in significant differences
Table 5. Survival at 3 years: intent-to-treat analysis
No rejectionEarly rejection episode Late rejection episode
Patient survival [n (%)]
Kidney survival [n (%)]
Pancreas survival [n (%)]
Study withdrawal [n (%)]
Tac¼tacrolimus; Cyc-ME cyclosporin microemulsion.
aP<0.05 Tac vs Cyc-ME;bP<0.01 no rejection vs late first acute rejection;cP<0.01 no rejection vs early first acute rejection;dP<0.001 no
rejection vs early first acute rejection.
ii16H. Arbogast et al.
by guest on May 18, 2011
between treatment groups in terms of fasting blood
glucose levels. Impaired glucose function, however, was
more probable in the case of late rejection episodes.
Late rejection also had a significant negative influence
on kidney function. However, the relatively short
3-year follow-up period may be insufficient in terms
of demonstrating a significant effect of late rejection
on kidney survival [24,25].
Besides the predicted influence of HLA incompat-
ibility on rejection, one of the striking results of
this multicentre study was the high probability of a
rejection episode in cases where GVE was performed.
Since none of the centres propagated venous exten-
sions, most patients in the GVE group received an
arterial Y-graft. This resulted in a >50% relative risk
increase of rejection, which was highly significant.
Whether this phenomenon is due to a longer ischaemic
time during back table preparations in the case of
GVE or is due to other factors cannot be answered
by the underlying data. However, based on our find-
ings, we recommend omitting GVE in both vascular
anastomoses of the pancreas, whenever possible.
In pancreas transplantation, one of the main
concerns remains the optimization of immunosup-
pressive treatment, since rejection is still one of the
parameters significantly influencing pancreas graft
survival, and pancreas loss through rejection has
a significant influence on patient survival. The find-
ings from this study suggest that tacrolimus-based
immunosuppressive therapy shows advantages over
cyclosporin-ME in terms of preventing severe acute
rejection in SPK recipients.
Funding source. See Appendix 2.
The Euro-SPK Study Group; see Appendix 1.
Conflict of interest statement. None declared.
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Rejection after SPK transplantationii17
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