Pancreas,
Islet, and Kidney Transplantation:
Metabolic
and Endocrine Consequences
Jennifer
Larsen, MD
Professor
and Chief, Diabetes Endocrinology and Metabolism
University
of Nebraska Medical Center
Omaha,
Nebraska
The first pancreas
transplant was done in 1966 at U. of Minnesota. There have now been over
15,000 world-wide (11,000 USA and over 4000 worldwide).
Types (graft
and patient survival in Table 1(1))
Kidney transplant
alone (KTA) Type 2 or Type
1
o
Single kidney, cadaver ~ living related
o
Native kidneys left in place
o
Living related has greatest graft and patient survival
Simultaneous pancreas-kidney transplantation
(SPK) Usually type 1 only
o
Most common pancreas transplant procedure (82%) Best 1 yr graft
survival of any pancreas transplant procedure
o
Kidney can be cadaver or living related, but usually simultaneous
cadaver kidney and pancreas from same donor with advantage of kidney
rejection being marker of pancreas rejection
o
Venous effluent can be connected to portal or systemic circulation-79%
of SPK still systemic because of greater accessibility, larger vessels
with greater flow so less risk of thrombosis
o
Exocrine drainage ‘bladder” (BD)using a small “button” of duodenum
or ‘enteric” into the gut (ED), advantages and disadvantages discussed
below initially 100% 3D, now >50% ED
Pancreas after kidney
transplantation (PAK) Usually
type 1
o
Second most common pancreas graft procedure, 11% of all pancreas
transplants reported to UNOS from 1987-2000, but 18% of those reported
1999-2000
o
A kidney is transplanted from one donor (often living related),
followed by a pancreas transplant from a second donor
o
1 y pancreas graft survival rate has improved significantly,
remains < SPK highest retransplant rate (27% vs 15% for PTA or
1% for SPK) (1)
Pancreas transplant
alone (PTA) Usually type 1
o
Whole pancreas graft in person with “adequate” renal function
(>70 mI/mm) with no intention of following up with a kidney transplant
in the near future
o
PTA is most likely to be used for the treatment of frequent,
severe hypoglycemia events complicating Type 1 diabetes
o
BD may be preferred with this procedure for greater accessible
for surveillance biopsies and ability to use urine amylase to diagnose
early rejection
o
1 year pancreas graft survival rate has improved, similar to
PAK but remains less than SPK
Controversies of Surgery and Candidate
Selection for Pancreas TX
Exocrine Drainage BD vs ED
o
Enteric drainage (ED) is “physiologic”, sodium bicarbonate-rich
exocrine effluent reabsorbed, but if “leak” occurs, consequences are
far greater (abdominal sepsis, shock and death)
o
Bladder drainage (BD) is convenient, allows cystoscopic biopsy
of pancreas graft, can use urine amylase and other studies to evaluate
pancreas function, greater blood pressure improvement: anastomotic
leaks less likely to cause severe consequences, disadvantages include
the severity of sodium bicarbonate loss in some leading to metabolic
acidosis or chronic dehydration requiring intravenous hydration therapy,
hematuria from pancreatic enzymes, leaks, infection, reflux urine
into pancreas =>pancreatitis
o
ED is gradually replacing SD (60%: 40%)
Systemic vs Portal Venous Drainage
o
Systemic venous drainage used originally because of placement
of pancreas graft near the bladder for SD
o
Systemic venous drainage is still used more (>70%) because
easier and more successful in more patients, portal vessels are smaller,
lower flow and less easily reachable so thrombosis is more likely,
surgical outcomes now equal for the two procedures in institutions
where portal done frequently, results in systemic hyperinsulinemia-consequences
unknown
o
With systemic drainage, total lipids same but free cholesterol
greater than with portal suggesting increased cholesteryl ester transferase
activity, animal studies -no increase in aortic intima media thickness
with systemic drainage, systemic hyperinsulinemia does not cause hepatic
insulin resistance
Pancreas transplant for type 2 diabetes’?
o
Many type 2 diabetes patients have decreased insulin secretion
Some type 2 diabetes patients have received SPK with similar outcomes
o
Questions of worsened insulin resistance, blood pressure, and
weight gain with current immunosuppression regimes in type 2 DM patients’?
Effects on atherosclerotic risk’?
“Living related” pancreas transplantation
o
U of Minn has proposed using a segmental pancreas graft from
a living donor Donor’s risk of diabetes (usually a parent) immediate
in some, increases with age.
Benefits of Pancreas and Kidney Transplantation
Usual pancreas transplant
candidate
o
Age 22% 18-34 y, 67% 35-49 y, 10% 50-64 y
o
Gender 50:50
o
Prior duration of diabetes 25y
o
Hemoglobin AIC of transplant candidates improving over time
o
Age of transplant candidates increasing over time
Retinopathy. Nephropathy.
and Neuropathy
o
Glucose concentration immediately normalizes which predicts
improvement in these complications HbA1C=4-5%
o
Retinopathy present in all candidates, borderline improvement
by 3 years, less future laser surgery ri studies greater than 3y
o
Recurrent diabetic nephropathy is observed 2y after KTA in
a diabetic recipient or upon failure of the pancreas graft after SPK,
never reported with a functioning SPK, diabetic nephropathy resolves
between 5-10 y after successful PTA Sensory neuropathy improves after
both KTA and SPK, further improvements> 8y after SPK, more than
that observed after KTA
o
Autonomic neuropathies difficult to quantitate, objective improvement
reported after SPK by 4 years post-transplant, improvement in SPK>
KTA
Vascular Disease the
most common cause of death in diabetes and organ transplant
recipients
o
Immunosuppression can cause weight gain, dyslipidemia, increased
blood pressure, and insulin resistance
o
Lipids SPIK improves lipids more than KTA in diabetic recipients,
but with weight gain or insulin resistance and depending sensitivity
to immune suppressants, lipids can worsen.
o
Blood pressure may improve more with BD than ED, often difficult
after KTA, especially with cyclosporine
o
Improved mortality comparing SPK with KTA or patients on waiting
list for SPI< but may not be “matched”,
o
Carotid intima media thickness (IMT) is increased in SPK candidates
compared to age-matched normals or Type 1 patients with normal renal
function
o
Both cross-sectional and prospective studies of carotid IMT
(19, 20) Increased LV ejection and endothelial-dependent brachial
artery vasodilation
o
Ongoing risk factors => increasing plaque and events
Quality of life
o
All surveys to date show improvements, reflects the benefits
of sustained, normalized glucose with fewer glucose excursions
Potential
Risks of Pancreas and Kidney Transplantation.
Immediate complications
o
Graft rejection
o
Thrombosis
o
Pancreatitis
o
Infection => sepsis
o
Leak or fistula (pseudocysts, fluid collections, abscesses)
o
Death (uncommon)
o
Nonfunction (long cold ischemia time, unrecognized damage)
o
Acute renal failure (for PAK or PTA)
Recurrent diabetes
after pancreas transplantation
o
Acute or chronic rejection
o
Pancreatitis
o
Thrombosis
o
Severe insulin resistance (C-peptide or insulin very high)
Recurrent type 1’?
o
lmmunosuppressant medication injury: cyclosporine and tacrolimus
can cause islet cell apoptosis,
Bone loss after
Kidney or pancreas transplantation
o
Role of both steroids and calcineurin inhibitors
o
Fractures are common in both KTA and SPK recipients (45-49%)
o
Multifactorial hypogonadism, Vitamin 0 def, adynamic bone,
parathyroid disease, thyroid function abnormalities
o
DXA and Vit D screening mandatory how often, when’?
o
How to prevent-oral or iv bisphosphonates, calcitriol, other
agents’?
Immunosuppression
o
Infection, risk of cancer, lymphoproliferative disease
Reproductive Issues after Pancreas
Transplantation
Pregnancy after
transplantation High risk pregnancy
o
Pregnancy should not be considered until 1-2 y after transplant
when graft function stable, doses of immunosuppression may need to
be adjusted so transplant team should be informed
o
Premature birth and low birth weight common after SPK.
o
Risk of graft
loss is greatest with borderline function, increasing serum creatinine
or episodes of rejection during pregnancy
o
Risk of graft loss within 2y of delivery SPK =21%, KTA =2-14%
o
>50% newborn complications
o
Risk of new immunosuppressants to baby unknown (rapamycin or
MMF)
o
Long term impact of neonatal exposure to any immunosuppressants
unknown
Birth control after
transplantation
o
Fertility often improves
o
Birth control strategy should be discussed
o
No studies to guide recommendations for use of birth control
methods
o
Permanent (tubal ligation or vasectomy) preferred in those
not desiring pregnancy
o
IUDs-unknown risk of infection
o
6CR-unknown risk of thrombosis
o
Barrier methods-need education, reliability’?
Hormone replacement
o
Hypogonadism before and after SPK common in women, uncommon
in men
o
Many female SFK recipients may have had early or surgical menopause
in 20’s and 30’s so not just an issue of planning >50y HRT
o
Unknown risk of thrombosis with HrT in transplant patients
o
Benefit for osteoporosis prevention
o
Screening for bypogonadism in men with osteoporosis
Diabetic complication
surveillance
Ongoing surveillance
for diabetic complications is necessary
o
Annual eye appointments are recommended for life
o
Foot checks more important as infections and vascular disease
effects can occur more rapidly and neuropathy does not resolve right
away
o
Amputations still often preventable
o
Risk factor treatment still important (smoking cessation, lipid
treatment) Greater risks of treatment of lipids (myositis or LFTs)
in combination with immunosuppressant medications
o
Pneumococcal vaccine recommended before transplant
o
Annual flu shots
Islet
Transplantation:
o
Experimental procedure using new immunosuppression regime without
long term outcomes
o
Islets only or islet after kidney
Total # performed worldwide 493
through 2000
Collagenase digestion
of pancreas into islets which are infused soon thereafter into portal
vein with simultaneous induction of immunotherapy if not already suppressed
o
May become insulin-free within 1-2 weeks of infusion of 1 pancreas’
islets
o
(required engraftment), most require subsequent transfusions
of 1-2 more
o
pancreas’ islets infused at 1-2 mo intervals until insulin-free
o
No attempt to do HLA matching
o
Outpatient procedure (if no complications)
o
Acute complications partial or complete portal vein thrombosis,
hemorrhage, acute decrease in renal function (50% in Edmonton using
their protocol (29)) neutropenia, mouth ulcers, fatigue, loose stools
and rash
o
Increased cholesterol (50%) common
Number of islets/kg
may be a key factor’?
o
Optimal >6,000
islet equivalents/kg
Inclusion/exclusion criteria at most centers
o
Inclusion criteria Type 1 diabetes defined as no circulating
insulin after stimulation testing
o
Exclusion criteria Age c18y or >65y, Wt >170 pounds, BMI
>28kg/m2, insulin requirements >0 7 u/kg/d, contraindication
to immunosuppression, active proliferative retinopathy, untreated hyperlipidemia,
abnormal LFTs or known liver disease, Ml < 6 months, active infection,
creatinine clearance <60 mI/mm
Outcomes
o
% insulin free at 1 year 40/493=8%, similar in most centers
o
22% 1-year insulin
free from the most recent 237 patients using Edmonton protocol where
>300.000 islets/kg infused but in those that are insulin-tree, only
73% achieving mean HbA1C <7%
o
Glucose intolerance present on OGTT even when insulin-free
o
Longterm effects
on microvascular or macrovascular disease with current immunosuppression
unknown
Conclusions
Table I. Pancreas
and kidney transplant procedures
| Procedure |
DM candidate |
1 year graft survival |
1 year patient
survival |
| Kidney
transplant alone (KTA) |
type
I and type 2 type 1 |
88%
(cadaveric)
93% (living related) |
92%
(cadaveric)
96% (living related) |
|
|
|
82%
pancreas
92% kidney |
95% |
|
Simultaneous pancreas
kidney
(SPK) |
|
|
|
| Pancreas
after kidney (PAK)
Pancreas
--
transplant alone |
type
1 |
74%
pancreas |
94% |
|
|
type
1 |
76% |
100% |
|
Islet allografts
or
Islets after kidney
TX |
type
1 |
8-22%
(defined as insulin-free but HgbA1C may not be normal) |
|
