Increased Early Rejection Rate after Conversion

Gary W Barone1, Beverley L Ketel1, Sameh R Abul-Ezz2, Meredith L Lightfoot1
1Department of Surgery and 2Department of Medicine, University of Arkansas for Medical
Sciences. Little Rock, AR, USA
ABSTRACT
Context A successful immunosuppression
regimen for combined kidney and pancreas
transplants is tacrolimus, mycophenolate
mofetil, and prednisone. However, not all
patients tolerate these immunosuppressants
especially tacrolimus.
Objective To evaluate the efficacy of
cyclosporine as a rescue agent for tacrolimus
toxicity in combined kidney and pancreas
transplants.
Design Retrospective.
Setting Single center.
Patients Thirty-five combined kidney and
pancreas transplants were performed between
July 1994 and January 1999. All patients were
insulin dependent diabetics with end-stage
renal disease. Twenty-eight (mean age: 36
years and 57% female) were available with at
least 12 month follow-up.
Interventions Conversion to cyclosporine
following renal (biopsy proven) or pancreatic
dysfunction.
Main outcome mearsures Toxicity, rejection
rate, and patient/transplant organ survival.
Results Nineteen transplant recipients (68%)
were continuously maintained on tacrolimus
while nine (32%) required conversion to
cyclosporine 75±20 days post-transplant.
Reasons
for
conversion
included:
hyperglycemia (n=2), hemolytic-uremic
syndrome (n=1), and severe tacrolimus
nephrotoxicity (n=6). By 12 months post-
transplant, the 19 patients maintained on
tacrolimus had 5 rejections (26%). Three of
the 9 patients (33%) converted to
cyclosporine had an acute rejection prior to
conversion. Seven of these 9 patients (78%;
P=0.017 vs.
patients maintained on
tacrolimus) had rejections an average of 25±4
days post-conversion. Four of the 7 patients
had no previous rejections prior to
conversion. In spite of increased rejections,
the 1- and 2-year patient/graft survivals were
unchanged by converting.
Conclusions Converting to cyclosporine from
tacrolimus was associated with an increased
risk of acute rejection especially within the
first 30 days post conversion.
INTRODUCTION
Combined kidney and pancreas transplants
(CKPT) are considered to be the treatment of
choice in selected patients with insulin
dependent diabetes mellitus and end-stage
renal disease requiring a renal transplant [1].
Tacrolimus (TAC), a newer formulation of
cyclosporine (CSA), and mycophenolate
mofetil (MMF) were all approved for clinical
transplantation in the mid 1990's. More
recently, sirolimus has been added to the

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50
transplant immunosuppression formulary.
Improved patient and graft survival and
decreased episodes of acute transplant
rejection in CKPT have been reported with
the combined use of these newer agents [2, 3,
4, 5, 6, 7]. A combination of TAC, MMF,
prednisone, and most often antibody
induction immunotherapy has become the
preferred immunosuppression regimen for
patients receiving CKPT. However once
started, not all CKPT patients tolerate this
combination of immunosuppressive agents
especially TAC. Kaufman et al. [7] observed
that 78% of their CKPT tolerated the
combination of TAC/MMF long-term
whereas 22% required switching to alternative
medications. When intolerance to TAC
occurred, CSA has often been chosen as an
alternative immunosuppressant. The long-
term efficacy and tolerability of CSA as a
rescue agent has not been well documented in
many series of CKPT [2, 3, 7]. In this current
study, the tolerability of TAC was assessed in
CKPT, and the outcome of CKPT recipients
who were switched to CSA from TAC was
reviewed.
METHODS
Patients
Thirty-five CKPT were performed at the
University of Arkansas for Medical Sciences
between July 1994 and January 1999 and
were retrospectively reviewed. Twenty-eight
patients were available with at least a 12-
month follow-up. Demographics of these
CKP recipient patients are shown in Table 1.
The venous drainage for all pancreas
transplants was systemic with the portal vein
anastomosed to the right external iliac vein.
Immunosuppression
All CKPT received Nashville/Rabbit Anti-
thymocyte (Applied Medical Research, Inc.
Nashville, TN, USA) induction therapy on
investigational protocol daily for 7-14 days
post-transplantation. The first dose was given
the day of transplant. Dosage was adjusted
according to absolute CD3 lymphocyte counts
(target: less than 150 lymphocytes/mL). Oral
TAC (Prograf. Fujisawa USA. Deerfield, IL,
USA) was started on post-transplant day 1 via
a nasogastric tube at 0.1 mg/kg twice daily
maintaining 12 hour trough levels of 10-15
ng/mL (IMx System: Tacrolimus II. Abbott
Laboratories. Abbott Park, IL, USA). CSA
(Neoral. Novartis Pharmaceuticals. Basel,
Switzerland), after conversion from TAC, was
started at 5 mg/kg twice daily with target 12
hour trough levels of 300-350 ng/mL
(TDxFlx System: Cyclosporine Monoclonal.
Whole Blood Abbott Laboratories. Abbott
Park, IL, USA). All patients received a total
of 1 g intravenous methylprednisolone in
divided doses peri-operatively followed by an
oral prednisone taper. Prednisone dose at one
year was 5-10 mg/day. Ten patients received
oral azathioprine (AZA) (Imuran. Glaxo
Wellcome Research. Triangle Park, NC,
USA) at a 2 mg/kg total daily dose while the
remaining patients received oral MMF
(Cellcept. Roche Pharmaceuticals. Nutley,
NJ, USA) at 1,000 mg twice daily.
ETHICS
The induction therapy was administered in
accordance with the ethical standards of the
1964 Declaration of Helsinki after receiving
written informed consent.
STATISTICS
Data are reported as mean values ± standard
deviation (SD) and ranges. Survival rates and
creatinine values were compared between
Table 1. Patient demographics (n=28).
Age
36±2 years
Gender
- Female
16 (57.1%)
- Male
12 (42.9%)
Race
- Caucasian
24 (85.7%)
- African American
4 (14.3%)
HLA Match
1.6±0.3 Antigens

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51
patients continuously receiving TAC and
those converted to CSA by means of the
Fisher’s exact and the Mann-Whitney
Wilcoxon tests, respectively. Data were
analyzed by running the SPSS/PC+ package
on a personal computer. A two-tailed P value
of 0.05 was chosen to define the statistical
significance.
RESULTS
Tolerability of TAC Immunosuppression
Nineteen CKPT recipients (68%) were
continuously maintained on TAC whereas
nine recipients (32%) required conversion to
CSA. Conversion occurred at an average of
75±20 days (range 14-188 days) post-
transplant. Renal transplant biopsies were
performed in all recipients at the time of
conversion. Recipients were converted to
CSA because of hyperglycemia (n=2),
hemolytic-uremic syndrome (n=1), and severe
TAC-induced nephrotoxicity refractory to
TAC dose reductions (n=6). Patients with
TAC-induced toxicity had TAC levels slightly
elevated ranging from 13 to 17 ng/mL.
Rejection
A total of 5 rejections occurred in the 19
patients maintained continuously on TAC
resulting in an overall incidence of rejection
at 12 months of 26%. All cases of rejection
were confirmed by renal transplant biopsy.
All rejection episodes were successfully
reversed. Two patients were on MMF while 3
were on AZA. These 3 patients converted to
MMF post-rejection. Four rejections occurred
within 30 days post-transplant while the other
rejection occurred at four months post-
transplant in a patient who suffered a
protracted episode of emesis with resultant
low TAC levels. Therefore, no acute rejection
episodes occurred after 4 months. Three of
the 4 early rejection episodes required
antibody treatment.
Three of the nine patients (33%) who were
converted to CSA had acute rejection
episodes prior to conversion to CSA. These
rejections occurred early in the post-transplant
course (average 28±5 days post-transplant),
and all were successfully reversed.
Importantly, 7 patients (78%; P=0.017 vs.
patients maintained on tacrolimus) had
rejection episodes after conversion from TAC
to CSA with 4 on MMF and 3 on AZA (these
3 patients converted to MMF post-rejection).
These rejections occurred early with an
average of 25±4 days after conversion. All the
3 patients who had had acute rejection
episodes prior to conversion to CSA had also
rejection episodes after conversion; therefore,
4 patients (57%) had had no previous
rejection episodes prior to CSA conversion.
Two of the 7 patients who had rejection
episodes, eventually lost renal transplant
function and returned to dialysis.
Two patients had no rejection episodes either
before or after conversion.
The overall incidence of rejection in the CSA
converted CKPT at 12 months was 78%.
Patient and Graft Survival
Patient, kidney, and pancreas allograft
survival rates are shown in Table 2. In
patients continuously maintained on TAC the
1- and 2-year patient survival rates were
100% and 95%, respectively. One patient died
of intestinal infarction 15 months post-
transplant with normal allograft function.
Table 2. Patient and allograft survival of patients continuously receiving tacrolimus and of patients converted to
cyclosporine-based immunosuppression.
Patients continuously
receiving tacrolimus
Patients converted
to cyclosporine
P value
(n=19)
(n=9)
1 year
2 year
1 year
2 year
1 year
2 year
Patient survival
19 (100%)
18 (95%)
9 (100%)
9 (100%)
1.000
1.000
Kidney survival
19 (100%)
17 (89%)
8 (89%)
7 (78%)
0.321
0.574
Pancreas survival
17 (89%)
16 (84%)
8 (89%)
8 (89%)
1.000
1.000

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52
Patient survival was 100% at 2-years in the 9
patients converted to CSA. The 1- and 2-year
kidney allograft survival rates were 100% and
89% respectively, in the TAC group and 89%
and 78%, respectively, in the CSA conversion
patients.
A total of four kidneys were lost, two from
each group. In the group receiving TAC, one
kidney was lost at 15 months because of
patient death; and one kidney failed at 22
months due to polyoma virus infection. In the
patients converted to CSA, one kidney failed
at 3 months because of irreversible rejection;
and a second kidney failed at 14 months from
chronic allograft nephropathy. The creatinine
in the remaining 7 CSA converted renal
transplants at 2 years averaged slightly high at
1.9±0.14 mg/dL (normal range: from 0.4 to
1.0 mg/dL) which was not significantly
different from the 1.7±0.17 mg/dL in the
group maintained on TAC (P=0.120).
Pancreas allograft survival was defined as
normal fasting glucose and normal HgbA1C
without exogenous insulin administration.
The 1- and 2-year pancreas allograft survival
was 89% and 84% respectively in the TAC
group, and 89% at both time points in the 9
patients converted to CSA. Three pancreas
allografts were lost in the group receiving
TAC. Two were due to irreversible rejection
in the first 6 months post-transplant, and one
was due to patient death at 15 months. One
pancreas allograft was lost in patients
converted to CSA in a recipient who had
severe vascular rejection after plasmapheresis
treatment for recurrent hemolytic uremic
syndrome. The only one pancreas transplant
converted from TAC for hyperglycemia had
the HgbA1C decrease from 6.8 to 6.2%
(normal range: from 4.4 to 6.4%) post
conversion to CSA.
CONCLUSION
The combination of TAC, MMF, and
prednisone for immunosuppression in CKPT
recipients has proven to be very efficacious
with excellent patient and graft survival and
associated with a low incidence of acute
cellular rejection episodes [2, 3, 4, 5, 6, 7].
However, some CKPT recipients do not
necessarily
tolerate
all
these
immunosuppressive agents especially TAC.
The best alternative immunosuppressive
regimens for CKPT patients intolerant to
TAC has not been clearly defined. In our
series, 32% of our CKPT patients required
discontinuation of TAC because of drug-
related toxicity during the first six months
post-transplant. CSA was chosen as an
alternative calcineurin inhibitor in these
patients. Seven of nine patients experienced
an episode of acute rejection within one
month of CSA conversion (average 25±4
days). However, 1- and 2-year patient and
graft survival were not significantly different
in the patients converted from TAC to CSA
compared to the group of patients maintained
continuously on full dose TAC. While our
numbers are small, 60% of the patients on
AZA suffered rejections compared to 33% in
the MMF group.
Several other reports [2, 3] and one especially
by Kaufman et al. [7] support our findings.
Stegall et al. [2] did report a 16.7%
conversion rate (3 patients in 18 CKPT) from
TAC to CSA between 3 to 6 months post-
transplant. Conversions were performed not
for renal toxicity but for systemic and
infections indications. They did not report any
specific follow-up in these patients. Peddi et
al. [3] noted that 37% of their series of CKPT
on TAC developed TAC nephrotoxicity, but
all initially responded to reduction in TAC
doses. In the series by Kaufman et al. [7],
TAC intolerability was observed in 18% of
their CKPT recipients. Similarly, conversion
to CSA was associated with an increased 12
month post-transplant rejection rate of 56%
compared to 20% for the CKPT who
remained on TAC. As in our series, 1- and 2-
year patient and graft survival was not
affected by the conversion.
We conclude that the substitution of CSA for
TAC may be associated with an increased risk
of acute rejection especially within the first 30
days post conversion. Therefore, patients
should be closely monitored during this time
period. Two-year results are not worse in
CKPT converted from TAC to CSA but

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53
longer-term outcomes of allograft function
may be adversely affected. Patients who
experience acute transplant rejection episodes
have lower graft survival than those who
remain free of rejection [2]. Because CSA
conversion appears to be associated with an
increased rate of rejection, the recent
introduction of sirolimus may provide another
choice. Besides changing to CSA in CKPT
recipients who do not tolerate full-dose TAC
especially
with
associated
TAC
nephrotoxicity, sirolimus with or without low
dose TAC may be a better option. However,
this combination needs further investigation
in CKPT.
Received July 16th, 2001 – Accepted
November 14th, 2001
Key words Drug Toxicity; Graft Rejection;
Immunosuppressive Agents
Abbreviations AZA: azathioprine; CKPT:
combined kidney and pancreas transplants;
CSA: cyclosporine; MMF: mycophenolate
mofetil; TAC: tacrolimus
Presented at the 8th Congress of International
Pancreas and Islet Transplantation
Association. Innsbruck, Austria. June 12-15,
2001.
Correspondence
Gary W Barone
Department of Surgery
University of Arkansas for Medical Sciences
Slot 520-4
4301 West Markham
Little Rock
Arkansas 72205
USA
Phone: +1-501.686.6644
Fax: +1-501.686.5725
E-mail address: baronegary@uams.edu
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