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Renal and Islet Transplantation in Diabetes

Renal and Islet Transplantation in Diabetes

Alex Wiseman, M.D.Director, Renal Transplant Clinic

University of Colorado Health Sciences Center

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ObjectivesObjectives 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

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Diabetes50.1%

Hypertension27%

Glomerulonephritis

13%

Other

10%

United States Renal Data System. Annual Data Report. 2000.

No. of patientsProjection95% CI

1984 1988 1992 1996 2000 2004 20080

100

200

300

400

500

600

700

r 2=99.8%

243,524

281,355520,240

No.

of

dial

ysis

pat

ient

s (t

hous

ands

)DM in Renal Failure: A growing epidemicDM in Renal Failure: A growing epidemic

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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.

Adjusted five-year survival, by modality: incident patients Figure 6.34, USRDS 2004

Adjusted five-year survival, by modality: incident patients Figure 6.34, USRDS 2004

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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.

Adjusted survival: 1993-1997 incident patients Figure 6.5 USRDS 2004

Adjusted survival: 1993-1997 incident patients Figure 6.5 USRDS 2004

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Expected remaining lifetimes (years) of dialysis & transplant patients

Expected remaining lifetimes (years) of dialysis & transplant patients

Dialysis Transplant

M F

39.5 40.235.6 36.531.6 32.527.4 28.623.8 25.220.6 22.217.6 19.414.9 16.912.6 14.610.5 12.58.5 10.56.9 8.95.9 7.8

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 F

16.8 15.414.2 13.111.9 10.99.8 9.28.3 8.07.2 6.96.2 6.05.3 5.14.5 4.53.8 3.83.2 3.22.7 2.72.4 2.42.0 2.0

62.557.753.048.243.538.834.329.825.521.517.714.311.2

General Population

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CHow much does a transplant benefit the patient?

How much does a transplant benefit the patient?

Comparison of outcomes of patients receiving a transplant vs. those on the waiting list:

Projected Survival:Age with transplant without

transplant 0-19 y 39y 26y 20-39 31y 14y 40-59 22y 11y 60-74 10y 6y

Wolfe RA et al, NEJM 1999;341:1725

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CIn patients with diabetes, dramatic survival benefit with transplant

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:

Projected Survival:Age with transplant without

transplant 20-39 25y 8y 40-59 22y 8y 60-74 8y 5y

Wolfe RA et al, NEJM 1999;341:1725

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High demand for kidneys!High demand for kidneys!

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Average wait time:Average wait time: By Blood group: Type O 1469 days Type B 1815 days Type A 740 days Type AB 396 days

By Age: 6-17 400 days 18-34 987 days 35-49 1134 days 50-64 1328 days 65+ 1599 days

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C Living donation has increased while deceased donation has remained stable 1990-2002

Living donation has increased while deceased donation has remained stable 1990-2002

0100020003000400050006000700080009000

1990 1992 1994 1996 1998 2000 2002

CadavericLiving

# T

rans

plan

ts b

y do

nor

typ

e

YearOPTN/SRTR 2003 Annual Report

300% increase

12% increase

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C Unrelated/spouse donation has resulted in the increase in living donors

Unrelated/spouse donation has resulted in the increase in living donors

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HUMAN ISLET TRANSPLANTATION HUMAN ISLET TRANSPLANTATION

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General Principle:General Principle:

Normalization of blood glucose (not merely control of blood glucose) will lead to improvements in: Survival Quality of life Protection from heart disease, kidney disease,

retinopathy, and nerve injury

The only method that normalizes blood glucose in patients with diabetes is treatment with insulin-producing cells

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CMethods to treat with insulin-producing cellsMethods 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: Thrombosis of pancreatic

vessels Pancreatic leak 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: Bleeding Thrombosis

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CPancreatic Duct CannulationPancreatic Duct Cannulation

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Final islet prepFinal islet prep

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C “Insulin independence after solitary islet transplantation in type 1 diabetic patients using steroid-free immunosuppression”

“Insulin independence after solitary islet transplantation in type 1 diabetic patients using steroid-free immunosuppression”

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)

Shapiro AMJ et al, NEJM 2000; 343:230

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C600

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2 4 6 8 10 12

2 4 6 8 10

600

500

400

300

200

100

012

a.m. p.m.

Post-transplantPost-transplant

Pre-transplantPre-transplant

Time of dayTime of day

Blo

od

glu

cose

(m

g/d

l)B

loo

d g

luco

se (

mg

/dl)

Blo

od

glu

cose

(m

g/d

l)B

loo

d g

luco

se (

mg

/dl)

Shapiro et al. N Engl J Med 2000; 343:230-238

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CThe Edmonton Protocol: update and follow-upThe Edmonton Protocol: update and follow-up

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

128 procedures: Bleeding in 15, portal vein thrombosis in 5 2+ antihypertensive meds in 42% (6% at entry) Statin use 83% (23% at entry)

Ryan EA, et al, Diabetes 2005; 54:2060

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At 5 years, c-peptide secretion preserved but only 11% maintain insulin independence

At 5 years, c-peptide secretion preserved but only 11% maintain insulin independence

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CHgbA1c remains improved despite return to insulin useHgbA1c remains improved despite return to insulin use

Insulin-free

Lost function

Primary nonftn

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CUniversity of Miami-Insulin independence in 14 of 16 subjects

University of Miami-Insulin independence in 14 of 16 subjects

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Copyright restrictions may apply.

Hering, B. J. et al. JAMA 2005;293:830-835.

IsletUniversity of Minnesota-single donor islet transplantation

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C ITN Multicenter Trial9 centers enrolled 3-5 patients to replicate Edmonton trial

ITN Multicenter Trial9 centers enrolled 3-5 patients to replicate Edmonton trial

0

10

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1 2 3 4 5 6 7 8 9

%Insulin-independent

16/36 patients rendered insulin-independent at one year following final infusion

Data presented by AMJ Shapiro at the ATC 2004

Center

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C Success rates: pancreas vs. islet transplantation

Success rates: pancreas vs. islet transplantation

Transplant: 1998-00 2001-03 Kidney/Pancreas (SPK) 82% 86% Pancreas after kidney (PAK) 74% 79% Pancreas alone (PTA) 76% 76%

Islet Transplant 1990-96 2000-3 Combined data 8% 58%*

*data from 12 participating centers, up to 3 infusions

One-year Graft Survival:

Source: SRTR and CITR

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C5-year graft survival-all organs5-year graft survival-all organs

Kidney 66% Pancreas (PTA) 47% Liver 66% Heart 71% Lung 45%

Source: Scientific Registry of Transplant Recipients Annual Report 2004

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C Islet Cell Resources (ICR)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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C Components of an Islet Transplant ProgramComponents 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 OutcomesClinical Outcomes

fasting pre-tx post-tx Pt Infusion IEQ/kg c-peptide insulin (u/d) insulin (u/d) HgbA1c

1 3 19.5K 2.0 45 7 8.2 -> 6.0

2 2 8.8K 1.9 42 12 6.7 -> 5.2

3 1 5.0K 0.6 43 25 7.6 -> 5.6

4 2 17.5K 1.7 24 6 7.0 -> 4.8

All patients have eliminated life-threatening hypoglycemia unawareness

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The future of islet transplantation

The future of islet transplantation

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IsletsIslets

Possible Reasons for Islet Graft Failure

Allograft rejectionAllograft rejectionDisease recurrenceDisease recurrence

Insufficient islet massInsufficient islet mass Poor quality of isletsPoor quality of islets

Toxicity of anti-Toxicity of anti-rejection drugsrejection drugs

Failure to engraftFailure to engraft

Insulin resistanceInsulin resistance

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C OBSTACLES TO SUCCESSFUL ISLET TRANSPLANTATION: Low engraftment of islets

OBSTACLES TO SUCCESSFUL ISLET TRANSPLANTATION: Low engraftment of islets

The transplanted cell mass is ~50% of the mass present in a normal individual

The engrafted cell mass is ~30% of the transplanted 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? Is islet transplantation safe? Acute complications: Bleeding ~10-

15% Thrombosis ~5% Transaminitis~50%

Long-term complications: Renal function Hypertension Hyperlipidemia Mouth ulcers Risk of sensitization Risk of infection (CMV)

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CIs islet transplantation safe?SAE Report CITR June 2005 Is islet transplantation safe?SAE Report CITR June 2005

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

Most common SAE types: N=26 GI

disorder N=17 Blood/

lymph N=11 Infection

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Adverse events: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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CHepatic Steatosis following islet transplantationHepatic Steatosis following islet transplantation

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C In an era of scarce resources, should one patient population receive special consideration?

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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CSupply and Demand (2003 data): 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: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