Kidney, pancreas, and pancreatic islet transplantation outcomes in BC

David N. Landsberg, MD, FRCPC, R. Jean Shapiro, MD, FRCPC

Kidney, pancreas,
and pancreatic islet
transplantation
Many patients with end-stage renal disease are now being helped with
improved transplantation techniques and immunosuppressive
regimens.

ABSTRACT: Kidney transplantation Kidney transplantation ing donor kidneys have steadily im-
is the treatment of choice for many The first kidney transplant in BC was proved. This is mainly due to refine-
patients with kidney failure, and out- performed in 1968. With the dramatic ments in immunosuppressive thera-
comes in BC are excellent. Because improvement in graft and patient sur- pies. Today tacrolimus has largely
donor organ shortage remains a vival, transplantation has become the replaced cyclosporine; mycopheno-
major challenge, BC has developed treatment of choice for many patients late mofetil has replaced azathioprine;
innovative programs to expand the with end-stage kidney disease. How- and the use of steroids is no longer
pool of both living and deceased ever, significant challenges remain. routine. Biological agents such as
donors, and allocation policies for Although immunosuppressive agents basiliximab (an interleukin-2 receptor
deceased donor kidneys have evolv- are effective, they have significant blocker) or antithymocyte globulin
ed to improve utility while maintain- toxicity and individualized therapy is (ATG) are now commonly used at the
ing equity. Other improvements in required to optimize function while time of transplant.1,2 The immunosup-
kidney transplantation have been limiting complications. There are also pressive regimen is determined by a
made by individualizing immunosup- too few deceased donor kidneys to patient’s immunological risk of expe-
pressive therapy to maximize effica- meet patient needs, and waiting times riencing rejection. Low-risk patients
cy while minimizing toxicity. are in excess of 5 years after starting are recipients of first transplants with-
Pancreas and pancreatic islet dialysis. This leads to morbidity in out evidence of antibodies to HLA
transplantation are reserved for patients waiting for transplantation antigens. Patients with detectable
those with type 1 diabetes. Because and affects survival after transplanta- anti-HLA antibodies and those who
of the very limited number of suit- tion. More living kidney donation and have previously rejected a transplant
able organ donors, whole pancreas expansion of the deceased donor pool are high-risk and receive more aggres-
transplantation is restricted to in- are needed to address the deceased sive immunosuppression. Low-risk
dividuals with end-stage renal dis- donor kidney shortage. It is critical
ease who have otherwise limited with deceased donor kidneys to max- Dr Landsberg is the medical director of
comorbidities and who are already imize their utility by appropriate allo- renal transplantation at St. Paul’s Hospital,
on immunosuppressive medication. cation so that potential kidney life Vancouver, BC. He is also a clinical profes-
Successful pancreas transplanta- years are not lost when patients die sor in the Department of Medicine at the
tion can significantly improve both with functioning kidneys. University of British Columbia. Dr Shapiro
quality and quantity of life. Islet is the medical director of Renal Transplan-
transplantation is still in its infancy, Individualizing tation and the medical manager of Solid
but has been shown to improve gly- immunosuppressive therapy Organ Transplantation at Vancouver Gener-
cemic control and stabilize retinopa- Graft survival rates ( Figure 1 ) and pa- al Hospital. She is also a clinical associate
thy and nephropathy. tient survival rates ( Figure 2 ) for BC professor in the Department of Medicine
recipients of deceased donor and liv- at UBC.

www.bcmj.org VOL. 52 NO. 4, MAY 2010 BC MEDICAL JOURNAL 189

Kidney, pancreas, and pancreatic islet transplantation

BC protocols were derived from our
local experience and confirmed by
100%
results of international large-scale tri-
90%
als.3 Results in low-risk patients have
80% been excellent, with 1- and 10-year
70% graft survival at 96.4% and 77.7%.
Survival rate

60% Results in high-risk patients have
50% also improved. This is in part through
40% 2000–2007 first transplant laboratory tests that can detect anti-
1990–1999 first transplant donor antibodies and hence avoid sit-
30% 1968–1989 first transplant
20% 2000–2007 re-transplant uations in which the likelihood of
1990–1999 re-transplant rejection is very high.4,5 In addition to
10% 1968–1989 re-transplant the introduction of potent antirejec-
0%
tion drugs, there has been improve-
0 1 2 3 4 5 6 7 8 9 10
ment in the use of antiviral agents
Years post-transplant and screening for viral infections,
reducing the risk of severe or even
Figure 1. Graft survival for kidney transplants by graft number and year of transplant, fatal complications.6
1968–2007.
Source: BC Transplant
Promoting and expanding
living donation
In BC there has been a decrease in the
100% number of deceased donor kidney
90% transplants performed since 1990, but
80% this has been offset by an increase in
70% the number of living donor transplants
Survival rate

60% ( Figure 3 ). Today the BC program
50%
promotes pre-emptive living donor
2000–2007 first transplant kidney transplant, whereby transplan-
40% 1990–1999 first transplant
1968–1989 first transplant
tation occurs before the initiation of
30%
2000–2007 re-transplant dialysis, as the treatment of choice for
20% 1990–1999 re-transplant most patients with kidney failure. This
10% 1968–1989 re-transplant
approach allows for better outcomes.7
0% Living donation has grown because
0 1 2 3 4 5 6 7 8 9 10 of a number of factors. These include
Years post-transplant the development of programs that help
recipients reach out to identify and
request living donors, the acceptance
Figure 2. Patient survival for kidney transplants by graft number and year of transplant,
1968–2007. of genetically unrelated living donors,
the anonymous living donor program,
the donor exchange program, and pro-
patients receive a protocol consist- exposure. Of these low-risk patients, tocols to desensitize recipients to their
ing of basiliximab, tacrolimus, myco- only those who experience acute living donors. It should be emphasized
phenolate, and rapid steroid elimina- rejection episodes are treated with that living donors undergo rigorous
tion, while high-risk patients receive steroids, and less than 20% of low- medical and psychological testing
ATG, tacrolimus, mycophenolate, and risk patients required steroids over the before being accepted into the pro-
steroids. past 5 years. The steroid-free regimen gram, and are followed lifelong.
In BC approximately 80% of has contributed to reduced morbidity Historically, living donors were
transplant recipients are low-risk and and weight gain, better bone density, close family members, such as parents,
thus receive minimal corticosteroid and improved patient satisfaction. The children, or siblings. With improved

190 BC MEDICAL JOURNAL VOL. 52 NO. 4, MAY 2010 www.bcmj.org


immunosuppressive therapy, HLA
matching is less important and trans-
plants from living unrelated donors 200 DD transplants
LD transplants
are as successful as those from living 180
Total transplants
related donors.8 Today in BC more 160
than 50% of transplants come from 140
ABO compatible living unrelated 120
donors, such as spouses, friends, in- 100
laws, and coworkers. Part of our pre- 80
transplant assessment involves coun- 60
seling patients on ways to reach out 40
for living donors. 20
The BC Transplant kidney trans-
0
plantation program was the first in 90 991 992 993 994 995 996 997 998 999 000 001 002 003 004 005 006 007 008
19 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2
Canada to utilize living anonymous
donors (LAD). After initial research
Figure 3: Living (LD) and deceased (DD) donor transplants in BC by year, 1990–2008.
probing societal views on this issue,9
the first LAD transplant was perform-
ed in 2005. In this program, indivi-
duals who have undergone rigorous
medical and psychological testing
donate their kidney to a recipient who LAD D1 D2 D3 D4
Group 0 Group A Group B Group C Group D
is unknown to them. This is done
anonymously to protect both the re-
cipient and the donor. LAD kidneys ABO ABO Positive ABO
incompatible incompatible crossmatch incompatible
may be given to a patient at the top of
the wait list, or used in the donor x x x x
exchange program.
Up to 30% of donor and recipient R1 R2 R3 R4
Deceased
pairs may be incompatible because of donor
Group 0 Group A Group B Group C
wait list
ABO blood group mismatch or the
presence of donor-specific anti-HLA
antibodies. In paired exchange, ap- D = Donor R = Recipient
proved donor and recipient pairs are
registered into a database where suit- Figure 4. Four-pair transplant chain triggered by a living anonymous donor (LAD) and
resulting in one kidney going to a recipient on the deceased donor wait list.
able combinations are identified. In
the simplest example, pair 1 has a
donor who is blood group A and a paired donor exchange registry, which Expanding the deceased
recipient who is blood group B. Pair 2 will facilitate matches. The use of donor pool
has a blood group B donor and a blood LADs in the exchange program great- Historically, organ donation has
group A recipient. The exchange oc- ly enhances the number of possible occurred when donors have been
curs by the A donor from pair 1 donat- matches, as the LAD is not tied to a declared brain dead but have main-
ing to the A recipient from pair 2, and recipient who must receive a trans- tained circulation and hence organ
vice versa. In more complicated situ- plant and thus can act as a key to perfusion. Until recently, donors who
ations, chains are established to allow unlock a chain of transplants. In the suffered cardiac death have not been
multiple transplants. The success of example shown in Figure 4 , the use of used because of concerns that irre-
the paired donor exchange program is the LAD kidney allows a four-way versible organ damage will have fol-
based on the number of donor and exchange to take place and still gener- lowed circulatory collapse. However,
recipient pairs who are entered into ates a kidney for the deceased donor in controlled situations, organ dam-
the exchange. There is now a national wait list. age, especially kidney damage, can be



over the age of 60 has recently been
implemented and will be carefully
monitored to ensure that it is achiev-
Pancreas-kidney transplants
12
Pancreas-after-kidney transplants
ing the desired results and maintain-
ing fairness for all patient groups.
10
Pancreas transplantation
8 As is the case for kidney transplanta-
tion, demand is far greater than supply
6
for pancreas transplantation and this
disparity appears to be increasing.13
4
The goals of pancreas transplantation
2
are to provide sustained normogly-
cemia without insulin and, over time,
0 to reverse or minimize microvascular
86 88 90 92 94 96 98 00 02 04 06 08 and macrovascular complications.
19 19 19 19 19 19 19 20 20 20 20 20
With whole pancreas transplantation,
Figure 5. Simultaneous pancreas-kidney (SPK) and pancreas-after-kidney (PAK) transplants unlike pancreatic islet transplantation,
in BC, 1986–2008. the counter-regulatory axes are also
Source: BC Transplant restored. Most centres have found that
successful pancreas transplantation
significantly improves both quality
reduced to the point where the organs kidney damage, such as hypertension, and quantity of life.14,15
can be effectively utilized for trans- have traditionally not been used for Pancreas transplantation is reserv-
plantation. This process is referred to transplantation. However, there has ed for those with insulinopenic type 1
as donation after cardiac death (DCD). been increased utilization of such diabetes. There are only six to eight
In this case family may consent or donors, termed expanded criteria don- suitable pancreas donors annually in
request that organ retrieval occur after ors (ECD), as long as renal function is BC, and hence eligibility criteria are
the heart has stopped and death has adequate. Older recipients who receive fairly strict to maximize the likelihood
been declared. Withdrawal of life sup- ECD kidneys benefit because of of successful outcomes. Individuals
port occurs in the operating room or reduced time on the wait list.10,11,12 In being considered for simultaneous
an adjacent area, with the retrieval BC the ECD program allows recipi- pancreas-kidney transplantation (SPK)
team on standby. The patient is moni- ents who have received the appropri- must have end-stage renal disease,
tored but there are no interventions. If ate information and consented to this good cardiac function, minimal peri-
cardiac standstill ensues quickly with- procedure to receive these kidneys. pheral vascular disease, be nonsmok-
out a prolonged period of hypoten- ing, and have few other significant
sion, the organs are still viable and Kidney allocation comorbidities. SPK in BC did not
organ retrieval commences 5 minutes Transplant recipients may die with really begin to flourish until the
after the heart stops. If cardiac arrest their transplant still functioning well, mid-1990s ( Figure 5 ).15 SPK with both
does not occur within 2 hours of an event termed “death with a func- grafts from a common deceased donor
removal of life support, organ dona- tioning graft.” It would be optimal to was the usual form of transplantation.
tion does not occur and the patient direct kidneys with shorter expected However, because the waiting time for
receives the same palliative care that duration of function into older recipi- SPK is now so prolonged, prospective
would have occurred after life support ents who have shorter life expectan- recipients are encouraged to identify
withdrawal. The first DCD in BC cies, and kidneys from younger donors potential live kidney donors, and wait
occurred in November 2008. We into younger recipients.12 In BC a sys- for pancreas-after-kidney transplanta-
believe that this donor source will tem preferentially allocating kidneys tion (PAK). The usual waiting time
increase the donor pool by 20%. from donors under the age of 35 to between kidney transplantation and
Donors over the age of 60 or recipients under 55, and kidneys from PAK is in the order of several years,
younger donors with risk factors for donors over the age of 60 to recipients with blood groups O and B waiting



the longest. Candidates for PAK, in Pancreas transplantation requires more reliable indicator of acute rejec-
addition to the requirements for SPK, more intensive immunosuppression tion and should prompt pancreas bi-
must have achieved good renal graft than kidney transplantation alone. For opsy. By the time impaired glucose
function and be free of severe im- SPK, patients receive induction ther- levels are established, pancreatic
munological or infectious disease risk. apy with an interleukin-2 receptor rejection has probably been present
Recipients opting for PAK have sig- antibody and methylprednisolone; for some time, and the pancreatic allo-
nificantly enhanced long-term patient maintenance therapy consists of myco- graft may be difficult to salvage. Loss
survival compared with those who phenolate, tacrolimus, and steroids. of pancreas function can also occur
wait for deceased donor kidneys.14 The standard protocol differs from from recurrence of type 1 diabetes
This has been attributed to lessening that in renal transplant recipients in (autoimmune loss versus alloimmune
the morbidity and mortality from that steroids are continued. For those loss). These two entities can be reliably
excessive amounts of urea, which ac- undergoing PAK, the induction regi- distinguished by pancreas biopsy.17
cumulates while the recipient waits.
Recipients with good kidney function
at the time of PAK experience fewer
perioperative complications and shor-
ter hospital stays compared with those
with renal failure. Pancreas transplant
alone (PTA) is an option that has been
offered to individuals with brittle dia- Active pancreas rejection rates are
betes but no end-stage renal disease.
However, patient selection is prob- difficult to quantify, as pancreatic
lematic, and there are higher than biopsies are not performed as
expected rates of graft failure and
development of renal failure.15 routinely as kidney biopsies.
Initial surgical approaches in the
1970s and 1980s utilizing a form
of enteric drainage were abandoned
because of surgical complications.
Exocrine pancreas drainage was redi-
rected to the bladder, which allowed
monitoring of pancreas rejection by
urinary amylase. However, bladder men consists of a T-cell depleting For patients with type 1 diabetes
drainage posed its own problems, agent (antithymocyte globulin) and and end-stage renal disease, timely
mainly from the exocrine secretions methylprednisolone, with maintenance transplantation is particularly impor-
(metabolic acidosis from loss of uri- treatment the same as for SPK. It is tant. Death on the wait list for SPK
nary bicarbonate, chronic bladder controversial whether the two grafts candidates is very common, with a
inflammation, bladder stones) and in are independent in terms of develop- reported 4-year mortality of 41.3%
the mid-1990s most pancreas pro- ing rejection or if rejection in one graft compared with 18.3% for those wait-
grams switched back to a simplified is always concordant with simultane- ing for PAK.14,18 This underscores the
version of enteric drainage. In this ous rejection in the other graft.16 Acute significant mortality attached to ure-
operation, the donor duodenum with pancreas rejection rates are difficult to mia and highlights the reason we
the attached pancreas is anastomosed quantify, as pancreatic biopsies are not advise patients to seek live donor kid-
end-to-side to the recipient small performed as routinely as kidney ney transplant while they wait for a
bowel and placed in the pelvis in a biopsies. Deteriorating renal function, pancreas.
way similar to kidney transplantation. reflected by a rise in serum creatinine, Patient and graft survival for pan-
The arterial anastomosis is to the is sometimes used as an indicator of creas transplantation in BC are good.
recipient’s iliac artery and either sys- pancreas rejection, although it is rec- In patients with SPK, cumulative 5-
temic or portal venous drainage can ognized that this is an insensitive year kidney graft survival in BC over
be used. marker. Rising serum amylase is a several different transplant eras is



Islet transplantation
Despite the initial success of islet trans-
100%
plantation reported from Edmonton in
95% 2000,19 this therapy is still considered
90%
experimental and offered only to those
who have refractory hypoglycemia
Survival rate

85% or who are being treated in experienc-
80% ed centres undertaking research.20,21
The goals of islet transplantation are
75% Kidney graft to decrease or eliminate the need for
70% Pancreas graft insulin, to improve HbA1c readings,
and to minimize or prevent diabetes
65% complications in patients with type 1
60% diabetes.
0 1 2 3 4 5
There are significant technical and
Years post-transplant medical challenges with islet trans-
plantation. Islet isolation requires ex-
Figure 6. Graft survival for the first simultaneous pancreas-kidney (SPK) transplants in BC pertise, and the quality and quantity
by organ, 1986–2008. of islets must be assessed before being
Source: BC Transplant deemed suitable for donation. Most
individuals require multiple islet
transplants in order to achieve suffi-
cient functioning islet mass. Place-
100% ment of islets is also problematic, and
95% although current practice relies on
90%
portal venous embolization, this site
is probably not optimal.22 At the time
Survival rate

85% of transplantation, the immediate
80% problems include an acute intrahepat-
ic coagulation reaction, and promo-
75%
tion of cell viability and engraftment.
70% Over time, the potential for alloim-
65% mune and autoimmune destruction
becomes apparent.
60%
0 1 2 3 4 5 In BC the islet program began in
Years post-transplant the context of research, comparing islet
transplantation with intensive insulin
Figure 7. Patient survival for the first simultaneous pancreas-kidney (SPK) transplants in
therapy. Candidates had to have nor-
BC, 1986–2008. mal renal function, minimal albumin-
uria, and minimal retinopathy. The
first islet transplantation occurred in
2003, and since then 70 islet trans-
87.5%, while the rate for pancreas mortality in the first 90 days follow- plantations have been performed in 31
graft survival is 80.5% ( Figure 6 ). ing SPK,14,18 successful SPK confers a patients.23 Our results have demon-
Patient survival for this same time significant survival advantage, with strated stable and improved metabol-
span is 94.5% ( Figure 7 ), comparable more than 20 life years gained over ic control, with significantly lower
to US registry data with 5-year patient those on a wait list.14 Failure of the HbA1c values in islet transplant recip-
survival reported at 83% to 87% for pancreatic graft leads to increased ients compared with those on inten-
SPK13,14 and pancreas graft survival at mortality,18 the most important contrib- sive medical therapy. As well, renal
73%.13 While there is an initial excess utor being cardiovascular disease.14,15,18 function has not declined, and ret-



inopathy has stabilized in transplant
recipients compared with medical
controls.23 Renal transplant recipients in BC enjoy
Immunosuppressive regimens excellent success rates, but there remains
continue to be refined. The original
Edmonton protocol relied on a combi- the ongoing challenge of the shortage of
nation of sirolimus and tacrolimus, but donor organs for transplantation.
this combination proved more nephro-
toxic than anticipated. In BC we use
induction with antithymocyte globu-
lin for the first transplant and mainte-
nance with tacrolimus and mycophe- risk of immune sensitization, particu- after-kidney transplantation with
nolate in a steroid-free regimen. For larly as multiple donors are required, preceding live donor kidney trans-
subsequent transplants, induction is which may significantly limit access plantation offers superior long-term
with basiliximab. Other centres use a to future renal transplantation should graft and patient survival compared
variety of induction agents and main- that be required.21,27 Unlike whole pan- with either kidney transplant alone
tenance regimens.24 There is also a creas transplantation, islet transplan- from a deceased donor or remaining
nonimmunological component in the tation does not have a durable response, on the wait list.14
therapy of islet transplantation, with with less than 50% of patients remain- Pancreatic islet transplantation
drugs directed at the coagulation cas- ing insulin-independent at 3 years.28 holds promise for individuals with
cade, and antiapoptotic strategies uti- type 1 diabetes. However, there are
lizing incretin-based therapies.25,26 Conclusions still significant technical and medical
The advantages and disadvantages Kidney transplantation has been one hurdles to overcome. Newer treatment
of islet transplantation are summa- of the true medical miracles of the past strategies include refining immuno-
rized in the accompanying Table . A 50 years. Renal transplant recipients suppressive protocols and developing
sufficient functioning islet mass must in BC enjoy excellent success rates, agents that will improve islet viability
be obtained to achieve the principal but there remains the ongoing chal- and function.
advantages—freedom from or reduc- lenge of the shortage of donor organs
tion in insulin requirements, improved for transplantation. The BC renal Competing interests
metabolic profile, and stabilization of transplant program has developed and None declared.
diabetic complications. However, these implemented innovative strategies to
benefits come with the cost of lifelong deal with these issues. References
immunosuppression and its attendant For those with type 1 diabetes, 1. Halloran PF. Immunosuppressive drugs
risks, including infection and malig- successful simultaneous pancreas- for kidney transplantation. N Engl J Med
nancy. In addition, there is also the kidney transplantation or pancreas- 2004;351:2715-2729.
2. Ekberg H, Tedesco-Silva H, Demirbas A,
et al. Reduced exposure to calcineurin
Table. Advantages and disadvantages of pancreatic islet transplantation.
inhibitors in renal transplantation. N Engl
J Med 2007;357:2562-2575.
Advantages Disadvantages
3. Vincenti F, Schena FP, Paraskevas S, et al.
Freedom from insulin injections Not a durable transplant, with more than 50% returning to A randomized, multicenter study of
over the short term some insulin use after 3 years
steroid avoidance, early steroid with-
Improved glycemic control, Requires lifelong immunosuppression with attendant risks drawal or standard steroid therapy in kid-
with less hypoglycemia, better (infection and malignancy)
ney transplant recipients. Am J Trans-
HbA1c, measurable C-peptide
plant 2008;8:307-316.
Stability or improvement in May need multiple classes of drugs: oral hypoglycemic agents; 4. Gebel H, Bray R, Nickerson P. Pre-trans-
nephropathy, retinopathy glucagon-like peptide-1 agonists (exenatide) or dipeptidyl-4
inhibitors (januvia) for successful long-term results plant assessment of donor-reactive,
HLA-specific antibodies in renal trans-
Risk of sensitization, jeopardizing future renal transplant
opportunities plantation: Contraindication vs. risk. Am
J Transplant 2003;3:1488-1500.



5. Bray R, Nolen J, Larsen C, et al. Trans- creas transplantation. Lancet 2009;373 al. Effect of glucagon-like peptide-1 (7-
planting the highly sensitized patient: The (9677):1808-1817. 37) on beta-cell function after islet trans-
emory algorithm. Am J Transplant 16. Kaplan B, West-Thielke PM, Herren H, et plantation in type 1 diabetes. Diabetes
2006;6:2307-2315. al. Reported isolated pancreas rejection Res Clin Pract 2006;74:189-193.
6. Asberg A, Humar A, Rollag H, et al. Oral is associated with poor kidney outcomes 27. Campbell PM, Senior PA, Salam A, et al.
valganciclovir is noninferior to intra- in recipients of a simultaneous pancreas High risk of sensitization after failed islet
venous ganciclovir for the treatment of kidney transplant. Transplantation 2008; transplantation. Am J Transplant 2007;
cytomegalovirus disease in solid organ 86:1229-1233. 7:2311-2317.
transplant recipients. Am J Transplant 17. Drachenberg CB, Odorico J, Demetris 28. Alejandro R, Barton FB, Hering BJ, et al.
2007;7:2106-2113. AJ, et al. Banff schema for grading pan- 2008 Update from the Collaborative Islet
7. Weir M. Preemptive kidney transplanta- creas allograft rejection: Working pro- Transplant Registry. Transplantation
tion: Why not? Am J Transplant 2003;3: posal by a multi-disciplinary international 2008;86:1783-1788.
1336-1340. consensus panel. Am J Transplant 2008;
8. Chkhotua AB, Klein T, Shabtai E, et al. 8:1237-1249.
Kidney transplantation from living-unre- 18. Gruessner RW, Sutherland DE, Gruess-
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with living-related and cadaveric trans- creas transplants. Am J Transplant 2004;
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9. Henderson AJZ, Landolt MA, McDonald with type 1 diabetes mellitus using a glu-
MF, et al. The living anonymous kidney cocorticoid-free immunosuppressive
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2003;3:203-213. 238.
10. Schold JD, Meier-Kriesche HU. Which 20. Robertson RP, Davis C, Larsen J, et al.
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Am Soc Nephrol 2006;1:532-538. The islet transplant experiment: Time for
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