UCHSC
Renal and Islet Transplantation in
Diabetes
Alex Wiseman, M.D.
Director, Renal Transplant Clinic
University of Colorado Health Sciences Center
UCHSC
Objectives
 Compare treatment options of dialysis vs. kidney
transplantation in patients with diabetes and renal
failure
 Understand the importance of early kidney
transplantation in patients with diabetes
 Define current success rates of islet transplantation
 List commonly encountered side effects following islet
transplantation
 Describe future directions for islet transplantation
No. of dialysis patients (thousands)
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DM in Renal Failure:
A growing epidemic
Other
10%
700
Glomerulonephritis
13%
Hypertension
27%
Diabetes
50.1%
600
No. of patients
Projection
95% CI
500
400
520,240
300
281,355
200
243,524
100
0
r 2=99.8%
1984
1988
1992
1996
United States Renal Data System. Annual Data Report. 2000.
2000
2004
2008
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Adjusted five-year survival,
by modality: incident patients
Figure 6.34, USRDS 2004
Incident dialysis patients;
adjusted for age, gender,
race, & primary
diagnosis. All ESRD
patients, 1996, used as
reference cohort.
Modality determined on
first ESRD service date;
excludes patients
transplanted or dying
during the first 90 days.
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Adjusted survival:
1993-1997 incident patients
Figure 6.5 USRDS 2004
Incident dialysis patients & patients receiving a first transplant in the calendar year. All probabilities are adjusted for
age, gender, & race; overall probabilities are also adjusted for primary diagnosis. All ESRD patients, 1996, used as
reference cohort. Modality determined on first ESRD service date; excludes patients transplanted or dying during the
first 90 days.
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Expected remaining lifetimes (years)
of dialysis & transplant patients
Dialysis
Age
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
80-84
M
16.8
14.2
11.9
9.8
8.3
7.2
6.2
5.3
4.5
3.8
3.2
2.7
2.4
2.0
F
15.4
13.1
10.9
9.2
8.0
6.9
6.0
5.1
4.5
3.8
3.2
2.7
2.4
2.0
Transplant
M
39.5
35.6
31.6
27.4
23.8
20.6
17.6
14.9
12.6
10.5
8.5
6.9
5.9
General Population
F
40.2
36.5
32.5
28.6
25.2
22.2
19.4
16.9
14.6
12.5
10.5
8.9
7.8
62.5
57.7
53.0
48.2
43.5
38.8
34.3
29.8
25.5
21.5
17.7
14.3
11.2
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How much does a transplant
benefit the patient?
 Comparison of outcomes of patients receiving a
transplant vs. those on the waiting list:





Age
transplant
0-19 y
20-39
40-59
60-74
Projected Survival:
with transplant
without
39y
31y
22y
10y
26y
14y
11y
6y
Wolfe RA et al, NEJM 1999;341:1725
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In patients with diabetes, dramatic
survival benefit with transplant
 Comparison of outcomes of patients with diabetes
receiving a transplant vs. those on the waiting list:

Age
transplant
 20-39
 40-59
 60-74
Projected Survival:
with transplant
without
25y
22y
8y
8y
8y
5y
Wolfe RA et al, NEJM 1999;341:1725
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High demand for kidneys!
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Average wait time:





By Blood group:
Type O
Type B
Type A
Type AB
1469 days
1815 days
740 days
396 days






By Age:
6-17
18-34
35-49
50-64
65+
400 days
987 days
1134 days
1328 days
1599 days
# Transplants by donor type
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Living donation has increased while deceased
donation has remained stable 1990-2002
12% increase
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
1
Cadaveric
Living
300% increase
0
9
9
1
2
9
9
1
4
9
9
1
6
9
9
1
Year
8
9
9
0
20
0
0
20
2
OPTN/SRTR 2003 Annual Report
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Unrelated/spouse donation has resulted
in the increase in living donors
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HUMAN ISLET TRANSPLANTATION
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General Principle:
 Normalization of blood glucose (not merely control
of blood glucose) will lead to improvements in:
n Survival
n Quality of life
n Protection from heart disease, kidney disease,
retinopathy, and nerve injury
 The only method that normalizes blood glucose in
patients with diabetes is treatment with insulinproducing cells
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Methods to treat with insulin-producing cells
 Pancreas transplant
 Pancreas obtained from cadaver
donors, transplanted surgically
within 12 hours
 Surgical procedure involves general
anesthesia, abdominal surgery, and
a 7-10 day hospitalization
 Complications:
n
Thrombosis of pancreatic
vessels
n
Pancreatic leak
n
Infection
 Islet Cell Transplant
 Islet tissue obtained from cadaver
organs by collagenase digestion of
the pancreas and purification of
islets via density gradients
 Islets injected into portal vein for
liver implantation, performed by
interventional radiology, followed by
a 1-2 day hospitalization
 Complications:
n
Bleeding
n
Thrombosis
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Pancreatic Duct Cannulation
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Final islet prep
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“Insulin independence after solitary islet
transplantation in type 1 diabetic patients
using steroid-free immunosuppression”
Shapiro AMJ et al, NEJM 2000; 343:230
 7 consecutive patients achieved euglycemia
during a mean follow-up of 11 months, with
normal HgbA1c and GTT
 6/7 patients required >1 donor (>1 transplant) a
median of 29 days from the first procedure
 Mean islet equivalents =11,400/kg required to
achieve euglycemia
 Cadaveric pancreata from older donors >45 yo (70%
would have been discarded)
Blood glucose (mg/dl)
Blood glucose (mg/dl)
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Shapiro et al.
N Engl J Med 2000;
343:230-238
600
Pre-transplant
500
400
300
200
100
600
500
400
Post-transplant
300
200
100
0
2 4 6 8 1 1
a.m. 0 2
2 4 6 8 10 1
2
p.m.
Time of day
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The Edmonton Protocol: update and
follow-up Ryan EA, et al, Diabetes 2005; 54:2060

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65 patients treated with islet transplantation:
44 completed therapy (defined by insulin independence)
Median duration of insulin independence =15 months
Mean islets transplanted=799,912

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128 procedures:
Bleeding in 15, portal vein thrombosis in 5
2+ antihypertensive meds in 42% (6% at entry)
Statin use 83% (23% at entry)
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At 5 years,
c-peptide
secretion
preserved but
only 11%
maintain
insulin
independence
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HgbA1c remains improved despite
return to insulin use
Insulin-free
Lost function
Primary nonftn
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University of Miami-Insulin
independence in 14 of 16 subjects
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University of Minnesota-single
donor islet transplantation
Hering, B. J. et al. JAMA 2005;293:830-835.
Copyright restrictions may apply.
Islet
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ITN Multicenter Trial
9 centers enrolled 3-5 patients to replicate Edmonton trial
100
16/36 patients
rendered insulinindependent at one
year following final
infusion
90
80
70
60
50
%Insulinindependent
40
30
20
10
0
1
2
3
4
5
6
7
8
9
Center
Data presented by AMJ Shapiro at the ATC 2004
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Success rates:
pancreas vs. islet transplantation
One-year Graft Survival:




Transplant:
1998-00
Kidney/Pancreas (SPK)
82%
Pancreas after kidney (PAK) 74%
Pancreas alone (PTA)
76%
 Islet Transplant
 Combined data
2001-03
86%
79%
76%
1990-96
8%
2000-3
58%*
 *data from 12 participating centers, up to 3 infusions
Source: SRTR and CITR
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5-year graft survival-all organs





Kidney
Pancreas (PTA)
Liver
Heart
Lung
66%
47%
66%
71%
45%
Source: Scientific Registry of Transplant Recipients Annual Report 2004
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Islet Cell Resources (ICR)
•Funded by the NIH to provide islets for use in clinical
protocols and establish and improve isolation procedures
and shipping of islets to outside centers
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Components of an Islet Transplant Program
 Laboratory:
cleanroom specifications, technical support
(4-5 on call at all times), in-process environmental monitoring,
post-isolation quality control testing
 Clinical: recipient eval and post-transplant follow-up, OPO
training/cooperation for organ allocation, transplant procedural
coverage, inpatient care,immune/metabolic monitoring
 Regulatory:
IND for cellular therapy with FDA, annual
reports to FDA and NIH, standard operating procedures for islet
isolation/transplant, training documentation and equipment
validation, UNOS certification and reporting, CITR reporting,
DSMB reporting
 Finance:
NIH, UCH, GCRC, UCHSC, Barbara Davis Center
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Clinical Outcomes





Pt
1
2
3
4
Infusion
3
2
1
2
fasting
IEQ/kg c-peptide
19.5K
2.0
8.8K
1.9
5.0K
0.6
17.5K
1.7
pre-tx
post-tx
insulin (u/d) insulin (u/d)
45
7
42
12
43
25
24
6
HgbA1c
8.2 -> 6.0
6.7 -> 5.2
7.6 -> 5.6
7.0 -> 4.8
 All patients have eliminated life-threatening hypoglycemia unawareness
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The future of
islet
transplantation
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Possible Reasons for Islet Graft Failure
Insufficient islet mass
Poor quality of islets
Failure to engraft
Insulin resistance
Toxicity of antirejection drugs
Islets
Disease recurrence
Allograft rejection
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OBSTACLES TO SUCCESSFUL ISLET
TRANSPLANTATION: Low engraftment of islets
 The transplanted b cell mass is ~50% of the mass
present in a normal individual
 The engrafted b cell mass is ~30% of the
transplanted b cell mass
 Islet engraftment takes weeks before
revascularization is completed, rendering islets
susceptible to:
• Hypoxic injury
• Nonspecific cell-mediated injury: “IBMIR”,
cytokine release, reactive oxygen intermediates
elaborated during postoperative healing/wound
reaction
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



Is islet transplantation safe?
Acute complications:
Bleeding
~10-15%
Thrombosis
~5%
Transaminitis
~50%




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Long-term complications:
Renal function
Hypertension
Hyperlipidemia
Mouth ulcers
Risk of sensitization
Risk of infection (CMV)
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Is islet transplantation safe?
SAE Report CITR June 2005
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150 participants:
N=98
no SAE
N=25
1
N=16
2
N=6
3
N=4
4
N=2
>4




52 pts had 102 SAE’s
N=22
life-threatening
N=61
hospitalization
N=18
prolonged hosp stay

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
Most common SAE types:
N=26
GI disorder
N=17
Blood/lymph
N=11
Infection
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Adverse events:
 Patient 1:
 mouth ulcers, diarrhea, depression
 Patient 2:
 mouth ulcers, abd pain (SAE), hyperlipidemia,
neutropenia, life-threatening clostridia septicum infection
(withdrawl from trial)
 Patient 3:
 mouth ulcers, abd pain (SAE), hyperlipidemia, rash
 Patient 4:
 mouth ulcers, hypertension, liver hemorrhage (SAE), Cr
1.2 to 1.4 (off tacrolimus)
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Hepatic Steatosis following islet
transplantation
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In an era of scarce resources, should one patient
population receive special consideration?
 Type 1 diabetic patients with life-threatening hypoglycemia?
• Pro: Normoglycemia may be life-saving
• Con: Immunosuppression risk/side effects
 Diabetic patients with renal failure?
• Pro: Immunosuppression not a factor
• Con: Benefit of normoglycemia may not significantly impact
survival
 Diabetic patients with early signs of organ damage?
• Pro: Early intervention may prevent costly, life threatening
complications
• Con: Enormous patient population
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Supply and Demand (2003 data):
 5908 deceased donors
 1372 for pancreas tx
 ~4500 pancreata
available for islet
isolation
 ~2000 adequate yield
 ~1000 patients
transplanted
 One million type 1 diabetic
patients in the U.S.
• transplant .1% of patients
 ~5000 Type 1 diabetic
patients with ESRD on tx
list
• transplant 20% of
patients
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CONCLUSIONS:
 Successful islet cell transplantation is now possible
• Less invasive but less durable than pancreas transplants
• Innovations in inhibiting early inflammation, reducing toxicity of
meds needed
 Kidney transplantation is of paramount importance in the
patient with diabetes and renal failure
• Early referral (GFR 20-30 ml/min)
• Evaluation of living donors
 Organ allocation, patient selection, and payment for islet
transplantation will remain controversial topics during the
“growth” phase of development of islet transplant
programs