NDT Advance Access originally published online on April 21, 2009
Nephrology Dialysis Transplantation 2009 24(7):2026-2029; doi:10.1093/ndt/gfp179
© The Author [2009]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Transplantation in type 1 diabetes
Christian Morath and
Martin Zeier
Department of Nephrology, University of Heidelberg, Heidelberg, Germany
Correspondence and offprint requests to: Christian Morath; E-mail: christian.morath{at}med.uni-heidelberg.de
Keywords: diabetes; kidney; pancreas; transplantation
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Introduction
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In the clinical course, type 1 diabetic patients suffer from
several micro- and macrovascular complications and usually have
progressive renal impairment. For these patients, several transplant
strategies are available. These include kidney transplantation,
pancreas transplantation and clinical islet transplantation,
either alone, in a combined procedure or in a sequential approach
[
1,2]. Herein we give a short overview on transplantation strategies
in type 1 diabetes. We focus on new aspects in simultaneous
pancreas–kidney transplantation and the effects of normoglycaemia
(achieved by a functioning pancreas allograft) on diabetic complications
as well as patient and kidney graft survival.
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Transplantation strategies in type 1 diabetic patients
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In the USA, 78% of all pancreas transplants are simultaneous
pancreas–kidney transplants, 16% are pancreas after kidney
transplants and 7% are pancreas transplants alone. Outside the
USA, a clear majority of pancreas transplants are performed
as combined transplants (91%) as compared to pancreas after
kidney transplantation and pancreas transplantation alone (4%
each) (International Pancreas Transplant Registry; IPTR; http://www.iptr.umn.edu;
[
2]).
Simultaneous pancreas–kidney transplantation
In 2004, 1-, 3- and 5-year renal allograft survival rate after simultaneous pancreas–kidney transplantation was 92%, 85% and 77%, respectively. The 1-, 3- and 5-year pancreas allograft survival rate after simultaneous pancreas–kidney transplantation was 86%, 79% and 71%, and patient survival was 95%, 91% and 86%, respectively (IPTR; http://www.iptr.umn.edu; [2]).
Pancreas transplantation
Pancreas after kidney transplantation and pancreas transplantation alone represent <10% of the pancreas transplants performed in Europe (IPTR; http://www.iptr.umn.edu; [2]). Especially in pancreas transplantation alone, one has to consider that the benefit of this procedure (normoglycaemia without exogenous insulin) is outweighed by the need of immunosuppressive medication. In contrast, pancreas after kidney transplantation might be an alternative for the type 1 diabetic patient who has already received a kidney transplant and has good renal allograft function. Allograft survival in pancreas after kidney transplantation, however, is much lower than that in simultaneous pancreas–kidney transplantation (IPTR; http://www.iptr.umn.edu; [2]). This might be the consequence of an increased rate of immunological graft loss in pancreas after kidney transplantation.
Clinical islet transplantation
Clinical islet transplantation was long considered an experimental procedure until the so-called Edmonton protocol was published, showing excellent outcome with all seven patients being free of insulin 1 year after the procedure [3]. Unfortunately, the results were not confirmed by a multicentre study where only 53% of patients were free of insulin for 1 year (another 19% received a reduced insulin dose; www.immunetolerance.org). A recent report showed the negative effects of clinical islet transplantation in type 1 diabetic patients who otherwise would not require immunosuppression [4]. The positive effects of normoglycaemia in those patients were outweighed by the negative effects of immunosuppression with accelerated loss of kidney function and an increased excretion of albumin.
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Impact of glycaemic control on diabetic lesions
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Several studies impressively illustrated that intensified glycaemic
control in diabetic patients (without a renal allograft) can
retard the progression of diabetic lesions of different organ
systems [
5,6]. It had been shown in the Steno studies that multifactorial
intervention, e.g. tight glucose control in combination with
the use of renin–angiotensin system blockers, aspirin
and lipid-lowering agents, reduces cardiovascular deaths, the
progression to end-stage renal disease as well as microvascular
lesions in type 2 diabetic patients with microalbuminuria [
7,8].
There is also evidence that the transplantation of a vascularized
pancreas can halt the progression of diabetic micro- and macrovascular
lesions in patients with type 1 diabetes (Table
1). However,
it takes a long period of normoglycaemia until positive effects
become visible, which is impressively illustrated by the work
of Fioretto
et al. [
9,10]. In 13 patients with diabetic nephropathy
(of native kidneys), they found no regression of diabetic kidney
lesions 5 years after pancreas transplantation [
10]. After 10
years, 8 of the initial 13 patients were studied again. They
showed a significant improvement of renal pathology with either
regression or the complete absence of diabetic lesions [
9].
In patients with simultaneous pancreas–kidney transplantation
or pancreas after kidney transplantation, the development of
diabetic kidney lesions can even be prevented [
11].
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Impact of glycaemic control on renal allograft and patient survival
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Simultaneous pancreas–kidney transplantation is considered
to be the treatment of choice for patients with type 1 diabetes
and chronic kidney disease stage 4 or 5. After successful simultaneous
pancreas–kidney transplantation, a majority of patients
have normal or near-normal fasting blood glucose and normal
glycosylated haemoglobin levels as well as good kidney function.
This is accompanied by a substantial improvement in the quality
of life. However, there is still a lack of evidence to support
the superiority of simultaneous pancreas–kidney transplantation
compared to kidney transplantation alone (either from a living
or a deceased donor) in type 1 diabetic patients with chronic
kidney disease. There is indeed a survival benefit (with regard
to graft and patient survival) for patients who received a combined
transplant in contrast to those patients who received a single
kidney transplant. However, much of this benefit is attributable
to the selection of the allograft recipient as well as the donor
organ. Patients who underwent a combined procedure were often
younger and in better physical shape. They often had a shorter
waiting time and also a shorter time on dialysis. Furthermore,
donor organs in simultaneous pancreas–kidney transplantation
are usually of better quality. The donors are younger and the
cold ischaemia time is short (compared to recipients of deceased
donor kidneys). Several studies on this issue with varying results
have been published in the past (Table
2). In a recent analysis,
Waki and Terasaki studied type 1 diabetic patients who received
either a simultaneous pancreas–kidney transplant or the
contralateral kidney (kidney transplant alone) from the same
deceased donor [
12]. By this approach, the authors eliminated
donor effects, which might contribute to an improved outcome
in recipients of simultaneous pancreas–kidney transplants.
In this study, there was no significant difference in the outcome
of patients with a combined procedure compared to patients who
received a kidney transplant alone with a maximum follow-up
of 9 years. In contrast, other authors could prove a superior
patient and allograft survival in simultaneous pancreas–kidney
transplantation compared to deceased donor renal transplantation,
but not living donor transplantation (Table
2). Most of these
studies have a median follow-up of <5 years. Taking into
account that it takes >5–10 years to halt or reverse
diabetic lesions (as demonstrated by the work of Fioretto
et al. mentioned earlier), it becomes clear that a comparison of
simultaneous pancreas–kidney transplantation and kidney
transplantation alone should be performed with >5 years of
follow-up. Using the Collaborative Transplant Study (CTS) registry,
a recent analysis investigated graft and patient survival in
type 1 diabetic patients who received a simultaneous pancreas–kidney
transplant or a renal allograft (either from a living or a deceased
donor) with a follow-up of 10 and 18 years, for the periods
from 1984 to 1990 and 1991 to 2000, respectively [
13]. A clear
survival benefit for simultaneous pancreas–kidney transplantation
and living donor kidney transplantation compared to recipients
of a deceased donor allograft was visible. After 10 years, patient
survival in simultaneous pancreas–kidney transplantation
was even better than that in recipients of a living donor kidney
(HR = 0.55;
P < 0.005). In parallel, there was a lower rate
of cardiovascular deaths in recipients of a combined organ transplant
(37%) compared to living donor (49%) and deceased donor (46%)
kidney transplantation [
13]. This effect was mainly attributable
to improved glycaemic control in patients who received a simultaneous
pancreas–kidney transplant as compared to those patients
with kidney transplantation alone. It is a limitation of this
registry analysis, however, that no information is available
on glycaemic control in patients who received kidney transplantation
alone. One might speculate that with intensified treatment,
i.e. by the use of insulin pumps, the latter group (kidney transplantation
alone) would have done better.
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Summary
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Simultaneous pancreas–kidney transplantation is now a
routine procedure in transplantation. Surgical complication
rates are low, and with potent immunosuppressive medication,
long-term allograft and patient survival are excellent. From
data that were also derived from pancreas transplantation alone,
we know that longstanding normoglycaemia can halt or even reverse
diabetic lesions in various organs, i.e. heart or kidney. However,
data on long-term allograft and patient survival in type 1 diabetics
who received a combined transplant in contrast to patients who
received a kidney transplant alone (either from a living or
a deceased donor) are still scarce. Recent evidence suggests
that simultaneous pancreas–kidney transplantation is highly
superior to kidney transplantation alone from a deceased donor
with respect to allograft and patient survival, and this survival
benefit is already visible after only 5 years of follow-up [
13].
After 10 years of posttransplant follow-up, patient survival
in simultaneous pancreas–kidney transplantation is even
superior to that in type 1 diabetic patients who received a
kidney transplant (alone) from a living donor. These data clearly
argue in favour of simultaneous pancreas–kidney transplantation
in type 1 diabetic patients with kidney failure. Therefore,
every type 1 diabetic patient with chronic kidney disease stage
4 or 5 should be evaluated for a combined transplant, and this
procedure should ideally be performed in a pre-emptive fashion
before the patient goes to dialysis. One might speculate that
intensified glycaemic control, i.e. targeting a glycosylated
haemoglobin value below 6.5% by the use of insulin, might have
comparable positive effects in patients who received a kidney
transplant alone in type 1 diabetes and this may also apply
to patients with type 2 diabetes or posttransplantation diabetes
mellitus after kidney transplantation. However, it is often
difficult to reach those target levels and adverse events such
as hypoglycaemia and even an increased rate of deaths have been
reported [
14,15].
Conflict of interest statement. None declared.
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Received for publication: 9. 7.08
Accepted in revised form: 24. 3.09
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Introduction
Transplantation strategies in...