ABSTRACT Since the introduction of pancreas transplantation more than 40 years ago, efforts to develop more minimally invasive techniques for endocrine replacement therapy have been in progress, yet this surgical procedure still remains the treatment of choice for diabetic patients with end-stage renal failure. Many improvements have been made in the surgical techniques and immunosuppressive regimens, both of which have contributed to an increasing number of indications for pancreas transplantation. This operation can be justified on the basis that patients replace daily injections of insulin with an improved quality of life but at the expense of a major surgical procedure and lifelong immunosuppression. The various indications, categories, and outcomes of patients having a pancreas transplant are discussed, particularly with reference to the effect on long-term diabetic complications.
- SourceAvailable from: António Castro Henriques[Show abstract] [Hide abstract]
ABSTRACT: Pancreas-kidney transplantation (PKT) may significantly improve quality of life (HRQOL) in type1 diabetic patients. We have assessed the changes felt by PKT patients, using the GIQLI and EuroQol-5D questionnaires. Patients were asked to compare how their HRQOL had changed from pretransplantation to the last visit. The 60 men and 66 women enrolled had a mean follow-up of 5 years; 84.1% with both grafts, 15.9% with one graft functioning. In all domains of EuroQol-5D scores improved after PKT, as well as the VAS-scale health state (from 38% to 84%, P<0.001; effect size 3.34). In GIQLI, physical function was felt better after PKT than before (14.83±3.86 vs 7.86±4.43, P<0,001; effect size 1.68); the same was observed for psychological status; social function; and GI complaints. Concerning the burden of medical treatment, the score significantly improved (from 1.31 to 3.63, P <0.001, effect size 2.02). The rate of unemployed patients decreased after PKT (from 50.8% to 36.5%, P<0.001). Multivariate analysis showed that having only 1 functioning graft was associated with worse HRQOL scores (B=-5.157, p=0.015). In conclusion, for all assessed domains, patients reported a significant improvement in HRQOL after PKT. Maintenance of the two grafts functioning predicted higher improvement of HRQOL scores.This article is protected by copyright. All rights reserved.Clinical Transplantation 01/2015; · 1.49 Impact Factor
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ABSTRACT: Ischemia-reperfusion injury is a primarily non-allospecific event leading to the depletion of the essential nitric oxide synthase cofactor and potent antioxidant tetrahydrobiopterin. Suboptimal concentrations of tetrahydrobiopterin result in a reduced biosynthesis of nitric oxide leading to vascular endothelial dysfunction. Tetrahydrobiopterin supplementation has been shown to protect from this pathological state in a plethora of cardiovascular diseases including transplant-related ischemia-reperfusion injury. Even though still controversially discussed, there is increasing evidence emerging from both human as well as animal studies that tetrahydrobiopterin-mediated actions rely on its nitric oxide synthase cofactor activity rather than on its antioxidative properties. Herein, we review the current literature regarding the role of tetrahydrobiopterin in ischemia-reperfusion injury including our experience acquired in a murine pancreas transplantation model.Pteridines. 01/2013; 24(1).
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ABSTRACT: Important trends are being observed in pancreas transplantation in the USA. We will describe recent trends in simultaneous pancreas kidney (SPK) transplantation related to immunosuppression, treatment of rejection, and transplantation for patients of advanced age and C-peptide positive diabetes. Rates of pancreas transplantation have declined, despite improved pancreatic graft outcomes. Regarding immunosuppression, trends in SPK transplantation include T-cell depletion induction therapy, waning mammalian target of rapamycin inhibitor use and steroid use in greater than 50% of pancreas transplant recipients with few patients undergoing late steroid weaning. Rejection of the pancreas may be discordant with the kidney after SPK and there is a greater appreciation of antibody-mediated rejection of the pancreas allograft. De-novo donor-specific antibody without graft dysfunction remains an active area of study, and the treatment for this condition is unclear. SPKs are being performed with greater frequency in type 2 diabetes mellitus patients and in patients of advanced age, with exemplary results. The current state of the art in SPK transplantation is yielding superb and improving results.Current opinion in organ transplantation. 02/2015; 20(1):94-102.
www.thelancet.com Vol 373 May 23, 2009
Steve A White, James A Shaw, David E R Sutherland
Since the introduction of pancreas transplantation more than 40 years ago, eff orts to develop more minimally invasive
techniques for endocrine replacement therapy have been in progress, yet this surgical procedure still remains the
treatment of choice for diabetic patients with end-stage renal failure. Many improvements have been made in the
surgical techniques and immunosuppressive regimens, both of which have contributed to an increasing number of
indications for pancreas transplantation. This operation can be justifi ed on the basis that patients replace daily
injections of insulin with an improved quality of life but at the expense of a major surgical procedure and lifelong
immunosuppression. The various indications, categories, and outcomes of patients having a pancreas transplant are
discussed, particularly with reference to the eff ect on long-term diabetic complications.
The fi rst case of a whole pancreas transplantation was
reported in 1966 at the University of Minnesota,
(Minneapolis, MN, USA)1 and a series of ten transplants
was reported in 1970.2 Pancreas transplantation is still the
gold standard endocrine replacement treatment even
though minimally invasive approaches, such as islet
transplantation, are being developed. The importance of
pancreas transplantation for patients with diabetes is
The goal of pancreas transplantation is to safely restore
normoglycaemia by the provision of suffi cient β cell
mass. Improved glucose control reduced the long-term
complications of insulin-dependent diabetes in the
Diabetes Control and Complications Trial. Similar results
were noted in patients with type 2 diabetes in the UK
Prospective Diabetes Study.3 Nevertheless, treatment
with intensifi ed insulin regimens can cause severe
hypoglycaemia. Although an intensifi ed insulin regimen
improves glycosolated haemoglobin con cen trations and
reduces the rate of long-term complications, it does not
prevent them. Treatment with new insulin analogues (eg,
glargine) are unlikely to improve long-term outcomes
because they do not mimic the minute-to-minute
physiological adjustment of insulin secretion.
Transplantation of a pancreas, unlike liver, lung, and
heart, is not a life-saving operation but it improves quality
of life4 because patients do not need to inject insulin on a
daily basis or regularly monitor glucose concentrations
with fi nger sticks, and hypoglycaemic unawareness is no
longer a problem. The long-term advantages of this
surgical procedure have to be balanced against the potential
morbidity and mortality associated with it, and the
side-eff ects from the long-term immunosuppression that
is needed to prevent allo immunity and autoimmune
recurrence.5 The risk of immunosuppression is particularly
relevant for recipients of pancreas transplant alone (PTA;
unlike patients with uraemic diabetes who are also given a
kidney transplant), since the only benefi t of immuno-
suppression in this category is insulin-free euglycaemia.
More than 23 000 pancreas transplants have been
reported to the International Pancreas Transplant
Registry.6 Most recipients have type 1 diabetes but 7·7%
have type 2 disease.6,7 A previous total pancreatectomy is
an often overlooked indication.8 A simultaneous pancreas
and kidney transplant (SPK), usually with both organs
from the same deceased donor, is the most common
transplant involving the pancreas, but it can also be done
with a pancreas from a deceased donor and a kidney
from a living donor,9 or both organs (segmental pancreas)
from a living donor (fi gure 1).10 About 2% of pancreas
transplants have been done with other organs,6 including
en-bloc transplantation with a liver or a lung (in patients
with cystic fi brosis).11 The other categories are pancreas
after kidney transplantation (PAK) and PTA. Since 1995,
the numbers of SPK have remained almost constant but
the numbers of solitary pancreas transplants (PAK and
PTA) have quadrupled (fi gure 1).6,12
Patients are eligible for a pancreas transplant if they
have or are at high risk of secondary complications of
diabetes (eg, nephropathy, retinopathy, neuropathy), have
disabling or life-threatening hypoglycaemic unaware-
ness, or are likely to develop these and are judged to be fi t
enough to survive the operation. β cell replacement
therapy has virtually no age limit and age is not a
contraindication to pancreas transplantation providing
the patient is healthy enough to survive surgery. The
rejection rate is lower in older than in younger recipients6
but those older than 50 years have an increased rate of
postoperative complications13 that should be taken into
account when the benefi ts and risks are assessed. 15% of
all recipients of pancreas transplants are older than
Lancet 2009; 373: 1808–17
Freeman Hospital, Newcastle
upon Tyne, Tyne and Wear, UK
(S A White MD); Diabetes
Centre, University of
Newcastle, Newcastle, UK
(J A Shaw MD); and Department
of Surgery, University of
Minnesota, Minneapolis, MN,
USA (Prof D E R Sutherland MD)
Mr Steve A White, Department of
Hepatobiliary and Organ
Transplant Surgery, Freeman
Hospital, High Heaton,
Newcastle upon Tyne NE7 7DN
Tyne and Wear, England
Search strategy and selection criteria
We did an English literature search of Medline, PubMed,
Embase, and the Cochrane Collaboration Library from
January, 1966, to January, 2009, for all relevant studies,
including retrospective, prospective, and cohort studies, case
reports, and randomised controlled trials. We used the search
terms “pancreas transplantation”, “pancreas transplant”,
“immunosuppresssion”, “renal failure”, and “diabetes
mellitus“. We used major randomised controlled trials that
were reported as summaries only if all data had been
presented at international symposia.
www.thelancet.com Vol 373 May 23, 2009 1809
50 years.6 Candidates at high risk of surgical complications
might be eligible for an islet transplant instead if they
meet various other criteria (eg, ratio of insulin IU to
bodyweight is low).
The category depends on patient comorbidity, renal
function, and availability of a living donor. For those
patients with hypoglycaemic unawareness, stable renal
function, and minimum proteinuria, a PTA is
appropriate. Patients with a glomerular fi ltration rate
(GFR) of 80–100 mL/min/1·73 m² are unlikely to need a
kidney transplant in the future. 30% of those given only
a PTA will eventually need a kidney transplant 9 years or
10 years later because of the detrimental cumulative
eff ects of immune suppression with calcineurin
inhibitors.14 Patients with a GFR of less than 80 mL/min
will be sensitive to these drugs and are likely to need a
kidney transplant in the future.15 PTA has a more rapid
deterioration in GFR than does treatment with an
intensifi ed insulin regimen, and is an independent risk
factor for renal failure in retrospective studies.16
Morphological resolution of diabetic lesions in native
kidneys after pancreas transplantation is not associated
with improvement in renal function because of treatment
with calcineurin inhibitors.17 Deterioration in GFR has
also been reported in recipients of islet cell transplants
given calcineurin inhibitors.18
Patients with a GFR of less than 50–60 mL/min/
1·73 m² will usually need a kidney transplant before,
with, or after a pancreas transplant. Serum creatinine
levels can increase slightly when a pancreas is transplanted
after a kidney transplant.19 However, in one study the
function of the renal allograft did not deteriorate after
PAK, and the long-term function of a kidney from a living
donor was better than in recipients of a kidney transplant
alone (KTA; from a living-related donor) who were not
given a subsequent pancreas transplant.20 Exposure of a
previously unexposed kidney to calcineurin inhibitors
increases creatinine con centrations after PTA, and GFR
can decline by up to 20% during the fi rst year.21 Therefore,
immuno suppressive regimens that do not include these
drugs still need to be developed for maintenance of renal
function.22,23 A living-donor operation should be done
before the need for dialysis arises if a kidney transplant is
needed after PTA. The benefi ts of PAK compared with
SPK include a reduced waiting time, and the option of
transplanting a kidney from a living donor with correction
of uraemia.24 In patients with uraemic diabetes, SPK from
a deceased donor does not seem to confer a survival
advantage compared with KTA from a living donor.25,26
Therefore, a pancreas transplanted after a kidney
transplant (from a living donor) might lead to a better
outcome than does SPK because of the high mortality
rate while waiting for two organs to transplant.12 The
timing of the PAK does not seem to aff ect the outcome;27
mean interval between transplants is about 20 months.6
An SPK is probably best for most candidates needing
a pancreas transplant. However, because of the world-
wide shortage of deceased donors, living-kidney
donation should be encouraged for all patients with
uraemic diabetes irrespective of whether they need a
pancreas. When the waiting time for SPK is long, a
pre-emptive kidney transplant from a living donor
should be followed by a pancreas transplant from a
deceased donor to avoid the high risk of mortality and
the need for dialysis.12 However, SPK is the most
cost-eff ective option.28 Recipients of a pre-emptive SPK
have better survival 8 years after transplantation when
compared with those transplanted while already on
dialysis.29,30 The main advantage of SPK is the increased
rate of success of the pancreas graft because concurrent
acute rejection in both organs can be recognised by an
increase in serum creatinine concentrations.
The rates of acute rejection with PAK are now similar
to those after SPK.6,18,31 Rejection rates are 4·3% and 4·0%,
respectively.6,32 Recipients of a PAK generally do well
because the uraemia has resolved and their general
health has improved.31 Simultaneous transplants are also
Time after transplant (months)
1990 19921994 1996
Pancreas graft survival (%)
Number of transplants
6 1218 2430
Figure 1: Pancreas transplant categories
(A) Pancreas transplants reported to the International Pancreas Transplant Registry. (B) Pancreas graft survival
from decreased donors. Primary pancreas transplants from deceased donors during Jan 1, 2000, to Dec 31, 2005.
PAK=pancreas after kidney transplantation. PTA=pancreas transplantation alone. SPK=simultaneous pancreas and
www.thelancet.com Vol 373 May 23, 2009
done when a pancreas becomes available from a deceased
donor at the time of a scheduled kidney transplant from
a live donor, or the living donor is on standby to give a
kidney when a deceased-donor pancreas is allocated to
the candidate. This simultaneous transplant combines
the highest kidney transplant success rate with the ability
to pre-empt the need for dialysis or have a short wait for
a kidney transplant, and still obtain a pancreas with just
one operation. A higher rate of immunological loss of the
pancreas graft after simultaneous pancreas and live-donor
kidney transplantation than after the transplantation of
both organs from a deceased donor was inferred in one
study (13·0% vs 5·7%).33
Only 0·5% of all transplanted pancreases are from
living donors;6 these transplants have been done in all
recipient categories.34–36 The best recipients are those with
high panel-reactive antibody concentrations who are
likely to have a long wait for a deceased donor but have a
crossmatch negative live donor whose β cell reserve is
excellent (as assessed by a three-fold increase in insulin
concentrations after stimulation with arginine and
glucose). Exclusion criteria for a pancreas transplant
from a live donor include diabetes in fi rst-degree relatives,
gestational diabetes, body-mass index greater than
27 kg/m², haemoglobin A1c (HbA1c) greater than 6%, and
age older than 50 years.
Cardiac morbidity and postoperative infection are the
most common problems in recipients of a pancreas
transplant. Coronary artery disease should be treated
early. 30% of asymptomatic patients with type 1 diabetes
with end-stage renal failure will have substantial coronary
stenosis on angiography.37 Various management algo-
rithms have been suggested to optimise investi gations—
eg, coronary angio graphy for those older than 45 years
because the probability of coronary artery disease is high.38
A minimum workup should include an ECG, cardiac
echocardiography, or a cardiopulmonary exercise test.
Most (95%) pancreas grafts are from deceased heart-
beating donors, and some are from highly selected non-
heart-beating donors39 or from living donors.34,35 Solid
organ donors are underused for pancreas transplants in
the UK40 and USA41 despite meeting suitable criteria.
Pancreas grafts from small donors (bodyweight 25–50 kg)
have low 1-year graft success rates (72%) due to high rates
of graft thrombosis (18%).42 People older than 55 years are
less likely to be used as donors for pancreas transplants
than are those younger than 55 years, but an analysis of
more than 700 SPK from 45-year-old donors showed
acceptable 5-year pancreas success rates of 71%.43
Hyperglycaemia in the donor at the time of organ
retrieval is common and not a contraindication for use
of the pancreas, but it is a minor risk factor for long-term
graft loss.44 Hyperamylasaemia can be of salivary origin
and is not a contraindication for pancreas donation,
providing the donor has no overt signs of pancreatitis or
damage due to trauma.45 Obesity in the donor is a
common reason for refusal of pancreas donation, and
those with a body-mass index greater than 35 kg/m² are
virtually never used as donors. Gross fatty infi ltration of
the pancreas is a risk factor but the degree that is
unacceptable is diffi cult to decide. An allocation policy
used in the USA and UK is to use pancreases from local
donors with a body-mass index greater than 30 kg/m² and
who are older than 50 years for recipients needing islet
Matched donor and recipient size is less important for
pancreas transplantation than it is for liver transplantation.
ABO incompatible (A₂ to O) transplants have been done
in recipients with a high panel-reactive antibody.47 HLA
matching is less important for SPK and PAK than it is for
PTA.19 About half of PTA or PAK are done with at least a
fi ve-antigen mismatch.6 With the exception of no
mismatch, patient survival rates do not diff er but two
HLA B mismatches are associated with an increased rate
of immunological graft loss.6 Pancreases have been
successfully transplanted in patients with previously
positive T cell and present positive B cell crossmatches.
Intravenous IgG and plasmapheresis can be used to try
and neutralise or eliminate antibody. A positive T cell
crossmatch is more of a risk factor for graft loss than is a
positive B cell crossmatch.48
The pancreas is reconstructed with a Y graft from the
donor iliac artery sutured onto the donor superior
mesenteric and splenic arteries (fi gure 2). It is usually
placed in the pelvis similar to a kidney transplant. The
arterial anastomosis is usually to the recipient’s
common iliac artery, whereas venous drainage can be to
the recipient’s portal vein, common iliac vein, or
inferior vena cava. Exocrine secretions can be drained
into either the bowel or the bladder.
Portal venous versus systemic venous drainage
Portal venous drainage is usually combined with enteric
drainage of exocrine secretions, and allows physiological
passage of insulin through the liver in which it undergoes
50% fi rst-pass metabolism. With systemic venous
drainage of the pancreas graft, the liver is bypassed on
fi rst passage, resulting in systemic hyperinsulinaemia.
De-novo hyper insulinaemia pre disposes to accelerated
atherosclerosis49,50 but there is no evidence to suggest that
hyperinsulinaemia induced by a pancreas transplant has
such an eff ect. Carbohydrate metabolism does not seem
to diff er in recipients having SPK compared with
non-diabetic recipients after KTA51 when similar immuno-
suppression is used. Systemic drainage increases the
concentrations of LDL and apolipo pro tein B whereas
www.thelancet.com Vol 373 May 23, 2009 1811
portal venous drainage reduces them, in addition to
lowering free cholesterol and VLDL concentrations.52 Any
theoretical disadvantage associated with hyper insulin-
aemia is likely to be outweighed by the benefi ts of
long-term normo glycaemia.
The management of pancreatic exocrine secretions has
always been diffi cult with many variations—including
duct ligation, cutaneous duodenostomy, or direct drainage
into the recipient’s bowel (enteric)—that have all been
used. In the 1980s, Sollinger and colleagues53 connected
the pancreas duct to the bladder; this technique was
modifi ed by Nghiem and Corry54 by doing a
duodenocystostomy and this modifi ed technique is still
in use. The main advantage of bladder drainage after PTA
and PAK is that early rejection can be indicated by a
decline in urinary amylase concentration that precedes
irreversible hyperglycaemia.55 Thrombosis rates are
similar for SPK, PTA, and PAK with grafts for bladder
drainage (5·0–7·2%) but are increased with grafts for
enteric drainage (5·5–11·6%).6 The likely explanation is
the increased rate of unrecognised rejection in grafts with
enteric drainage that manifests as graft thrombosis.56
One of the diffi culties associated with enteric drainage
is the management of an anastomotic leak, which often
needs further surgery if the patient becomes septic.
However, a leak after bladder drainage can usually be
managed with long-term urinary catheterisation.
Whether an enteric anastomosis is stapled or sewn by
hand makes no diff erence in reduction of the risk of a
leak.6 To help the management of a leak, some surgeons
prefer to use a Roux en Y to isolate the pancreatic graft.
Disadvantages of bladder drainage include acidosis (due
to loss of bicarbonate), dysuria, upper-urinary-tract
infections, haematuria, and dysplasia. Refl ux pancreatitis
(50%)57,58 can arise from urinary retention, and cystitis
from pancreatic enzymes activated by enterokinase
within the brush border of the graft duodenal mucosa.59
A patient with diabetes and a neuropathic bladder is not
necessarily precluded from a bladder-drained pancreatic
graft even in the presence of abnormal urodynamic
studies.60 Up to 25% of patients with bladder drainage
will need a conversion to enteric drainage within 10 years,
and precious grafts can be lost after the conversion.61
Bladder drainage was used for 85% of simultaneous
pancreas and kidney transplants until 1995 but its use
gradually declined to 20% by 2005.6 However, it is still
commonly used for solitary pancreas transplants.6
Neither bladder nor enteric drainage had any benefi cial
eff ects on patient survival and graft success in retro-
spective62 and prospective trials.63
Rejection and immunosuppression
Pancreas transplantation is associated with graft loss by
rejection as a result of alloimmunity or autoimmune
recurrence.5 Even transplants between identical twins
need immunosuppression to prevent autoimmune
recurrence.64 During the ciclosporin era, pancreas-graft
rejection rate was 78% (for PTA) with up to a third of
rejections recurring.10,65 Although a consensus has not
been reached about which is the best immuno suppres-
sion regimen, most surgeons agree that rejection can
be kept to a minimum.6 Rejection rates are about
5–25%, depending on the combination of immuno-
suppression that is used. Mycophenolate mofetil in
combination with tacrolimus or ciclosporin is more
eff ective in the prevention of rejection than is the
combination of ciclosporin and azathioprine (11% vs
77%).65,66 Acute rejection is an important risk factor for
long-term graft loss as a result of chronic rejection (10%
for solitary pancreas transplants and 4% for SPK).67
Tacrolimus plus mycophenolate mofetil and short-
course steroid with antibody induction is the most
commonly prescribed regimen, and therefore important
studies including tacrolimus and induction agents will
Unlike most other solid organ transplants, some form
of anti-T cell antibody induction is used for pancreas
transplants (80%).6,66 The most common T cell depleting
induction agent is thymoglobulin at total doses of
4–12 mg/kg, depending on the recipient category;
highest dose is used for PTA and lowest for SPK.
An interleukin-2-receptor antagonist—basiliximab or
daclizumab—and the T cell depleting antibody alemtu-
zumab (Campath, Genzyme, Cambridge, MA, USA)
can also be used as an alternative.
Induction treatment68 with T cell depleting antibodies
(eg, thymoglobulin)69,70 or interleukin-2-receptor anti-
bodies71,72 reduces the number and severity of biopsy-
proven rejection episodes but does not have any eff ect
on the survival rates of patients or success rates of
pancreas grafts.68,72 Induction with antibody improves
success of the kidney graft at 3 years (92% vs 82%), with
highest rates of rejection in African Americans.69,72
Comparison of two diff erent dosing regimens of
daclizumab in patients maintained on tacrolimus,
mycophenolate mofetil, and steroid also showed no
diff erence in the eff ect of treatment on graft success or
patient survival.71 Overall, rejection was 8% with the
Figure 2: Pancreas transplantation
(A) Prepared graft with a duodenal segment. (B) Y graft for anastomosis to the donor splenic artery (left) and
donor superior mesenteric artery (right).
www.thelancet.com Vol 373 May 23, 2009
two-dose short-course induction regimen versus 36%
with the non-induction treatment.71
Comparison of ciclosporin (Neoral, Novartis, Basel,
Switzerland) with tacrolimus in combination with
mycophenolate mofetil, and steroid plus induction with
antithymocyte globulin in the EuroSPK 001 trial
(n=205)73 showed a reduction in the rates of severe
rejection with much lower rates of pancreas graft loss at
3 years in the group given the tacrolimus combination
treatment (72·4% vs 89·2%).74 However, the rate of
technical failure due to graft thrombosis was
unexpectedly high in the Neoral group (9·8% vs 2·0%),
which might also explain the reduced rate of pancreas
graft survival rather than inadequate immuno-
suppression being the only cause.75 Conversely,
comparison of Neoral with tacrolimus showed no
diff erence in the loss of the pancreas graft in
portal-enterically drained grafts with induction with
First-year results from the EuroSPK 002 study77 (n=241)
suggested that the rates of acute rejection were similar
(about 40%) in patients treated with tacrolimus plus
sirolimus or tacrolimus plus mycophenolate mofetil in
addition to polyclonal antibody induction with a rapid
steroid taper. However, rates of pancreas-graft success
were higher in patients treated with tacrolimus plus
mycophenolate mofetil (86% vs 76%). Grade 2 and 3
rejection was highest in this group, but triglyceride and
cholesterol con centrations were higher at 1 year, and
more delayed wound healing, hernias, and lymphoceles
(21% vs 13%) were noted in the tacrolimus plus sirolimus
group.77 However, steroid-free regimens of tacrolimus
plus sirolimus resulted in poor renal-graft success at
5 years versus a steroid-free maintenance regimen of
tacrolimus plus mycophenolate mofetil (90% vs 70%,
Most steroid-free treatment regimens—to keep insulin
resistance and poor healing to a minimum—include
either antithymocyte globulin or alemtuzumab. A direct
retrospective comparison of alemtuzumab and anti-
thymocyte globulin as part of a steroid-free regimen
with tacrolimus and sirolimus maintenance suggests
similar rates of pancreas graft success with 20% of
patients having rejection in each group.79 Alemtuzumab
is cheaper and is associated with a lower rate of viral
infection than is antithymocyte globulin.79 Basiliximab
is not associated with increased survival in recipients of
KTA and SPK.80 Alemtuzumab has also been successfully
used with tacrolimus monotherapy, albeit with a slightly
increased rate of rejection at 30%.81 Whether
alemtuzumab is better than other induction agents is
not known because of the absence of good randomised
controlled trials. Despite the long-term lymphopenia
associated with alemtuzumab, allowing the use of
steroid-free and calcineurin-free or minimisation
protocols to improve long-term renal function has not
Outcome and eff ect on diabetic complications
Quality of life
The eff ects of pancreas transplantation on diabetic
complications and quality of life are often diffi cult to
interpret because complications are often too advanced
to reverse, and patients who have SPK are generally
younger and fi tter than are those with diabetes who are
given KTA. Also, conclusions can only be drawn from
those patients with functioning or failed grafts and not
from the 5% of patients who do not survive beyond the
fi rst year. Cessation of insulin injections and removal of
dietary constraints reduce the eff ects of and worry caused
by diabetes, and improve the overall quality of life for
recipients of SPK who have an uncomplicated post-
operative course;4,14,30 these eff ects are not seen when
patients are given KTA.83
Patients who are insulin independent have better
quality of life outcomes than those with grafts that do
not function.83,84 Diabetic patients with a successful
kidney transplant have an improved quality of life
irrespective of whether they have a pancreas transplant
or not.84,85 Patients have an improved quality of life after
a PTA despite surgery and immunosuppression versus
those with a failed graft at 2 years.12 However the main
problems relate to continued diabetes in failed pancreas
transplants, side-eff ects from immunosuppression in
successful pancreas transplants, and graft rejection
Transplantation of a pancreas lowers HbA1c levels to
within normal limits even after 10 years.86 In 54 patients
who had undergone pancreas transplants, the mean
HbA1c at 6 years was 6% versus 7% in those treated with
the intensifi ed insulin regimen only in the Diabetes
Control and Complications Trial.87,88 Pancreas trans-
plantation restores glucagon secretion (whereas islet
allo transplantation does not);89–91 improves the counter-
regulatory responses to hypoglycaemia92 but does not
completely eliminate them;93 returns hepatic glucose
production to normal;94 and improves lipid profi les95
and insulin-mediated protein kinetics.96
At least 75% of patients with type 1 diabetes will develop
retinopathy by 10 years; 30% will have proliferative
retinopathy and 40% will eventually develop blindness
within 3 years.97 Retinopathy can deteriorate in 10–35%
of patients with unstable eye disease immediately after
pancreas transplantation; however, the benefi ts become
apparent after a few years.98–100 Eye disease, particularly
cataracts, might deteriorate in transplant recipients
because of immune suppression with calcineurin
inhibitors and steroids.101
In a study by Ramsay and colleagues,98 progression or
loss of visual acuity in 22 patients versus 16 controls
with failed pancreas grafts did not diff er but there did
www.thelancet.com Vol 373 May 23, 2009 1813
seem to be a benefi t in terms of reduced deterioration in
eye disease in those with advanced retinopathy at
3 years. Wang and colleagues99 reported regression of
diabetic nephropathy in 43% of patients given SPK
versus 23% given KTA. However, 50% of both groups
showed no benefi t, although follow-up was short (1 year),
and most patients had already been given photo-
Diabetic nephropathy is characterised by accumulation
of extracellular matrix proteins in the mesangium,
glomerular and tubular basement membranes, and
interstitium. Additionally, immunosuppressive agents
can change the deposition of extracellular matrix
proteins through changes characterised by chronic
rejection.102,103 Direct comparisons are often diffi cult to
make because control groups are patients with diabetes
who have KTA and are generally older and medically
unfi t, and have been exposed to long periods of
In general, normoglycaemia can stop the progression
of diabetic glomerulopathy but does not completely
reverse it.104–106 At 10 years, glomerular and basement
tubular membranes show some improvement, and in
some cases the structures of the membranes return to
normal.106 Interstitial expansion and tubular atrophy can
also be improved.107 Nonetheless, up to 35% of recipients
of SPK might not survive for 10 years to have these
benefi ts.6 Functional studies after pancreas transplantation
show improved control of blood pressure and reduced
urinary protein excretion108 but creatinine clearance can
Subtle benefi ts in neuropathy have been noted after
SPK.109–111 However, mild peripheral neuropathy, para-
esthe sia, autonomic neuropathy, and slightly improved
sensory amplitudes have been reported. Patients with
abnormal cardiorespiratory refl exes have reduced rates
of death after undergoing a pancreas transplant but they
are not necessarily improved.112
Microvascular and macrovascular diseases are more
common in patients with diabetes who are on dialysis.
Various immunosuppressive regimens promote weight
gain, dyslipidaemia, hypertension, and insulin resistance.
Macrovascular disease naturally progresses with age in
individuals who do not have diabetes or need a transplant;
therefore, even after a successful pancreas transplant and
in the presence of subsequent normoglycaemia,
macrovascular disease will still progress. Deterioration
therefore depends on the ongoing risks, and cohorts with
similar risks should be compared. However, objective
quantifi cation of risks is particularly diffi cult in patients
Coronary artery disease
Atherosclerosis can regress in nearly 40% of patients
with a functioning pancreas graft.113 Diastolic dys-
function, assessed with radionuclide angiography, can
also return to normal after 4 years.114 Rates of myocardial
infarction and acute pulmonary oedema are lower in
recipients of SPK than in patients with diabetes given
KTA, although these patients tend to be older (41 years
vs 49 years)115–117 and are less likely to have had coronary
angiography before their kidney transplant. Two-
dimensional and M-mode echocardiography before and
up to 2 years after pancreas transplantation suggests an
improvement in left ventricular geometry when
compared with age-matched recipients of a KTA.116
Stabilisation112 and improvement118 of cardiac autonomic
function have also been noted.
Cerebrovascular and peripheral vascular diseases
In a study by Nankivell and colleagues,119 carotid intimal
thickness increased after SPK but cerebrovascular events
seemed to be unrelated to carotid disease (no suitable
controls were used in the study). Although disease
progression has been confi rmed during the fi rst 5 years
after transplantation, the disease course might improve
thereafter.117 Carotid intimal thickness has been seen to
improve within 2 years after pancreas transplantation
with HbA1c concentrations returning to normal and renal
function improving independently of changes in lipid
concentrations, body-mass index, blood pressure,
smoking, or use of hypolipidaemic drugs.120 Peripheral
vascular disease can worsen after pancreas trans-
plantation,121 and might continue worsening for years
after normoglycaemia, suggesting that it is often far too
advanced to reverse.122,123
Whether the benefi ts of pancreas transplantation translate
into increased survival is debatable.124 15-year actuarial
patient survival is 56% (pancreas graft success 36%) for
Waiting time (months)
1 year 4 years
Figure 3: Survival of patients after simultaneous pancreas and kidney transplantation (SPK) versus those
waiting for a pancreas transplant
Month 0 is time of SPK and entry to waiting list for those waiting for a transplant.
www.thelancet.com Vol 373 May 23, 2009
SPK, 42% (18%) for PAK, and 59% (16%) for PTA
(Gruessner AC, Arizona Cancer Center, personal
communication). The most common causes of graft loss
after 10 years are death of the recipient (53%) and chronic
rejection (33%).6 Tyden and colleagues125 noted a
60% increase in survival after SPK versus KTA in
age-matched patients with diabetes at 10 years (80% vs
20%) but this advantage was not clear when patients were
compared with recipients of a kidney transplant from a
living donor. Consequently, Rayhill and colleagues26
analysed more than 600 patients and noted similar
survival rates after SPK and KTA from living-related
donors; these patients did much better than those having
KTA from deceased donors.
The adjusted 10-year survival rate was 67% for recipients
of SPK, 65% for living-donor kidney transplants, and
46% for deceased-donor kidney transplants (p<0·05) in
13 000 patients with type 1 diabetes.126 Recipients of SPK
can be expected to live 10 years longer than patients with
diabetes given KTA from deceased donors (23·4 years vs
12·9 years) but the benefi t is not obvious if patients are
older than 50 years of age at the time of pancreas
transplantation.126 Survival rates were much improved at
5 years and 8 years in recipients of simultaneous
transplants versus those with kidney transplants from
deceased donors.127 Rates of survival were better with
kidneys from living-related donors and the advantage
was not as obvious. The presence of a functioning
pancreas graft increased survival by almost 20% at
8 years.127 Despite increased rates of acute rejection
(15% vs 9%), SPK was associated with improved
renal-graft outcome compared with patients with diabetes
who were given kidney transplants from deceased donors
in an analysis of more than 5000 patients.128
Venstrom and colleagues124 reported that patients with
preserved renal function given solitary pancreas
transplants had worse survival than those with diabetes
who were treated with conventional treatments while
waiting to receive a transplant. SPK is associated with a
1·5-fold reduction in survival rate during the fi rst
90 days after transplantation mainly because of a
surgical procedure. The relative risk is much higher for
PTA (2·27-fold) and PAK (2·89-fold);124 however, after
4 years, the risk is reversed for SPK. Therefore, with the
low mortality rate associated with the medical treatment
of diabetes, is there a need to surgically treat diabetes?
Gruessner and colleagues129 reported that at least 12% of
patients registered in the United Network for Organ
Sharing database were listed in several centres, creating
substantial bias.129 Patients who are listed for one
procedure might eventually go on to have a diff erent
procedure. 10% of patients waiting for an SPK might
eventually have a PAK or just a KTA. In another analysis
of the data in the United Network for Organ Sharing,
the mortality of patients waiting to undergo a pancreas
transplant was underestimated.129 After 1 year, recipients
of SPK, PAK, and PTA do better than do those waiting
for a transplant (fi gure 3), especially in high-volume
centres. At least 50% of candidates on the list for
simultaneous transplants die while waiting for more
than 4 years. Therefore, pancreas transplantation is
justifi ed on the basis of the data for survival, and the
most important factor for long-term survival is
preservation of the pancreas graft.12
SAW was responsible for the literature search and reviewing all the
literature, and wrote the original draft of the Review. JAS was
responsible for reviewing and writing some aspects of the eff ect of
pancreas transplantation on diabetic complications. DERS was
responsible for writing portions and overseeing the production of the
whole Review and for critical revisions.
Confl icts of interest
SAW and JAS have no fi nancial or personal relationship with any people
or organisations that could inappropriately bias this Review. SAW has
received several honoraria from all the major pharmaceutical companies
that supply immunosuppressive drugs for patients given pancreas
transplants. These include Wyeth, Astellas, and Novartis; and has
received research grants from several diabetes-related organisations,
such as Diabetes UK, Novo Nordisk, Insulin Dependent Diabetes
Foundation, and Eli Lilly. JAS has received research funding from the
Medical Research Council, Diabetes UK, Diabetes Foundation, and
Diabetes Research and Wellness Foundation. DERS has no confl icts of
interest, fi nancial interest with any business or commercial entity, or an
intellectual property interest, relating to this Review.
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